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AIIMS PROTOCOL

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CONTENT
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Symposium on AIIMS Protocols in Neonatology IV

Acute Renal Failure in Neonates

Sreeram Subramanian, Ramesh Agarwal, Ashok K. Deorari, Vinod K. Paul and Arvind Bagga1

Department of Pediatrics, Divisions of Neonatology, 1Nephrology, All India Institute of Medical Sciences, Ansari
Nagar, New Delhi, India

ABSTRACT
Acute renal failure (ARF) is a common condition seen in neonatal intensive care units. It is broadly classified into prerenal,
intrinsic renal and post renal failure. There is no consensus on the definition of neonatal ARF. Of utmost importance is to
differentiate prerenal from intrinsic renal failure. The most common causes of neonatal ARF are hypovolemia, hypotension
and, hypoxia. Among several indices that are available for differentiating prerenal failure from intrinsic renal failure, fractional
excretion of sodium is the preferred index. Diagnostic fluid challenge with or without frusemide is a bed side method for
differentiating prerenal failure from intrinsic renal failure. Babies with ARF have to be monitored for several metabolic
derangements like hyponatremia, hyperkalemia, hypocalcemia, and acidosis and have to be managed accordingly. Fluid
balance should be precise in order to avoid fluid overload. It is difficult to provide adequate calories due to fluid restriction.
Dialysis has to be instituted to preempt complications. Peritoneal dialysis is the easiest and safest modality. These babies need
long term follow up as they are prone for long term complications. [Indian J Pediatr 2008; 75 (4) : 385-391] E-mail :
arvindbagga@hotmail.com

Key words : Acute renal failure; Neonate, Hyperkalemia; Dialysis

Acute renal failure (ARF) is a frequent clinical condition in DIAGNOSIS OF ARF

neonatal intensive care unit. There is wide variation in the
incidence of ARF across studies. It affects approximately
1-24% of newborns in the NICU. 1,2 ARF is an acute
reduction in glomerular filtration rate (GFR) with both
failure to remove solutes and water leading to concurrent
net solute and water retention oligoanuric renal
failure. 2
Classification of ARF
Based on the urine output, it can be of two types:
(i) Oligoanuric (ii) Non oliguric
Based on the site of origin of insult it can be of 3 types:
(i) Prerenal (75- 80%) (ii) Intrinsic renal (10-15%) (iii)
Post renal (5%).
Persistence of insult can convert pre renal or post renal
failure to intrinsic renal failure.
Correspondence and Reprint requests : Prof Arvind Bagga,
Division of Nephrology, Department of Pediatrics, All India
Institute of Medical Sciences, Ansari Nagar, New Delhi -110029,
India.
[Received March 28, 2008; Accepted March 28, 2008]
Plasma creatinine
ARF is suspected if
Plasma creatinine is more than 1.5 mg/dL for at least 24
to 48 hrs, if mothers renal function is normal.2
Serum creatinine is increasing by 0.3 mg/dL/day
Serum creatinine fails to fall below maternal plasma
creatinine within 5-7 days
The above definitions can be used with a reasonable
3 degree of accuracy in term neonates. In preterm neonates,
the physiological decline in plasma creatinine can extend
over 2-3 weeks. In fact the plasma creatinine can rise
transiently and then decline. The plasma creatinine
remains elevated due to reabsorption of creatinine across
permeable tubules.
Urine output
Oliguria: It has been defined as urine output less than 1
mL/kg/h after first day of life for both term and preterm
neonates. One should also be aware of the fact that some
term neonates may void for the first time at around 24 h
of life.
ARF can also present with normal renal output in one
third of the cases. This can happen especially in

Indian Journal of Pediatrics, Volume 75April, 2008 385

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S. Subramanian et al
asphyxiated neonates. Hence it is essential to monitor
plasma creatinine apart from urine output. The common
clinical scenario that leads to suspicion of renal failure is
oliguria. In face of such an event it becomes extremely
important to differentiate prerenal and intrinsic renal
failure as in the former the damage to the kidneys is yet to
begin where as in the later it already has.
Concept of acute kidney injury (AKI)4
Several definitions have been proposed for defining ARF
and there is no consensus. An attempt has been made to
define parameters and to bring uniformity across age
groups and various clinical situations. The product of
such an attempt is the concept of acute kidney injury.
An abrupt (within 48 h) reduction in kidney function
currently defined as an absolute increase in serum
creatinine of more than or equal to 0.3 mg/dL, a
percentage increase in serum creatinine of more than or
equal to 50% (1.5-fold from baseline), or a reduction in
urine output (documented oliguria of less than 0.5 mL/
Kg/h for more than six hours).
Pre renal vs intrinsic renal failure
Several methods have been developed to differentiate
them; the sheer number reflects the importance. When a
baby has not passed urine in the past 12 hrs, the first and
the foremost thing is to look for distended bladder.
Palpation of the abdomen, ultrasound of the abdomen (if
available at bed side) can be employed to look for
distended bladder. It is better to avoid catheterization of
the bladder in order to prevent infection but it may be
necessary in sick babies. In such situations it has to be
done under strict asepsis. Compression of the bladder
(suprapubic pressure) should be avoided especially in
preterm infants for the fear of VUR and rarely bladder
and renal rupture. 1
After confirming the absence of urine in the bladder,
fluid challenge should be given (Fig. 1). The common
causes of prerenal azotemia are hypovolemia, systemic
hypotension and hypoxia (in more than 80% of cases). 2 It
is essential to look for signs of fluid excess and fluid
deficit. In the absence of obvious sign of fluid overload or
congestive cardiac failure, a normal saline bolus of 10
mL/kg should be given over 20 min (some experts advise
20 mL/kg over 2 h). If baby fails to pass urine with in one
hour the fluid bolus should be repeated. In spite of two
fluid bolus if urine output fails to ensue, frusemide
should be given in a single dose of l mg/kg (in a non
dehydrated patient). Urine output ensues in 2-3 hrs in
prerenal failure. If this fails it is intrinsic renal failure.
Role of indices
Differentiation of pre renal and intrinsic renal can be done
basing on urinary indices. Several indices have been
386
proposed to differentiate them. Most important among
them would be urine sodium, renal failure index (RFI)
and fractional excretion of sodium (FENa) (Table 1). The
important prerequisite is that the urine sample for
measuring indices must be obtained prior to fluid and
diuretic challenge. This is difficult to obtain in many
babies as the babies are oliguric and results are not
available immediately and hence practically they are of
limited utility. Among the various indices available FENa
is the preferred index. FENa more than 2.5 to 3.0% is
found to be associated with intrinsic ARF. Preterm babies
lose sodium in the urine due to the tubular immaturity,
hence higher cutoffs must be used. An FENa of more than
6% can be used to define intrinsic ARF in babies born
between 29- 32 weeks of gestation.5 Urine sodium more
than 50 mEq/L is suggestive of intrinsic ARF whereas
urine sodium less than 20 mEq/L is seen in pre renal
failure.
TABLE 1. Parameters to Differentiate Prerenal from Intrinsic
Renal Failure1
Parameters Prerenal Intrinsic renal
UNa 20 mEq/L >50
Renal failure index* Low < 1 High > 4
Fractional excretion of Na$ 1 >3
urine Na plasma creatinine
*Renal failure index = 100
urine creatinine
urine Na plasma creatinine
$Fractional excretion = 100
of sodium plasma sodium urine creatinine
The renal failure index (RFI) can also be used. RFI
more than 4 in term and more than 8 in preterm babies
less than 32 weeks is suggestive of intrinsic ARF.
Urianalysis: The presence of granular casts, hyaline
casts, RBC, proteins and tubular cells suggests an
intrinsic cause.
Ultrasonography and Doppler: Useful in ruling out
congenital anomalies like polycystic kidneys, dysplasia of
kidneys and obstructive causes of renal failure like
posterior urethral valves. Renal doppler studies are
helpful in diagnosing vascular thrombosis.
Voiding cystourethrography : Can identify lesions of
the lower urinary tract that cause obstruction, such as
posterior urethral valves.
Etiology of renal failure
Having differentiated prerenal from intrinsic renal failure,
evaluate for the exact etiology of renal failure. There are
several causes of ARF (Table 2)
Indian Journal of Pediatrics, Volume 75April, 2008
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Acute Renal Failure in Neonates

TABLE 2. Etiology of Neonatal Renal Failure
I. Congenital malformations
 Renal agenesis
 Renal hypoplasia/dysplasia
 Cystic diseases of kidney e.g., autosomal recessive poly-
cystic kidney
II. Acquired renal disorders
Acute tubular necrosis
 Perinatal asphyxia
 Perinatal hypoxia due to respiratory distress syndrome,
traumatic delivery
 Sepsis
 Hypovolemia due to dehydration, severe patent ductus
arteriousus
Vascular
 Arterial thrombosis or embolism or stenosis
 Venous thrombosis
Drugs: maternal use of ACE inhibitors, indomethacin
Baby: indomethacin, tolazoline, aminoglycosides
III. Urinary tract obstruction
Posterior urethral valves
Pelviureteric obstruction, ureterovesical obstruction
ACE: angiotensin converting enzyme.
Babies with ARF must be investigated not only for
evaluating the cause and but also for complications. Blood
levels of creatinine urea, electrolytes, pH bicarbonate and
urinary levels of sodium and creatinine must be done.
Microscopic examination of urine must be done for RBC,
granular or hyaline casts. Urine culture must be done
especially in cases of obstructive lesions where babies are
prone for urinary tract infection. Ultrasound imaging of
the kidneys is useful in evaluating congenital lesions and
obstructions. Doppler can define the vascular supply of
the kidney.
MANAGEMENT OF RENAL FAILURE
Fluid management
Fluids must be restricted to insensible water loss (IWL)
along with urinary loss. The urinary loss must be replaced
volume for volume. The insensible water loss in a term
neonate is 25 mL/kg/day. In preterm neonates this can
vary widely depending on gestation, postnatal age, use of
radiant warmers, phototherapy. It can vary from 40-100
mL/kg/day. IWL can be assumed to be 40 mL/kg/day in
preterm infants for calculating fluids in neonates
(adequate care must be taken to reduce IWL by using
caps, socks, cling wrap, oil especially for preterm babies
under radiant warmer). 6 It is advisable to revise fluid
requirement every eight hourly basing on urine output.
The fluid should be electrolyte free, 10% dextrose water.
Hyponatremia
Babies can have hyponatremia in oliguric renal failure.
Hyponatremia is due to dilution secondary to water
retention, hence has to be corrected with fluid
restriction. In most of the cases, there is no sodium
deficit.
If serum sodium is between 120-135 mEq/L,

TABLE 3. Management of Hyperkalemia

Medication Level of K+ at which it Dose Mechanism Onset of action

is instituted

Calcium ECG changes suggestive of 0.5 to 1 mL/kg over 5-10 min Modifies myocardial 5-10 min
gluconate hyperkalemia excitability
Sodium K+ - 6.0-6.5 mEq/L 1 mEq/kg over 10-30 min Intracellular uptake 30 min
bicarbonate of K+
Glucose and K+ - 6.5-7.5 mEq/L 0.5 g/kg/h of glucose and 0.2 U of Intracellular uptake 30 min.
insulin regular insulin per g of glucose of K+
over 2 h
Salbutamol IV K+ - 6.5-7.5 mEq/L 4 g/kg over 20 min Intracellular uptake of Min
infusion* K+
Cation exchange K+ more than 6.0 mEq/L 1 g/kg intrarectally q 6 h Exchange of K for Na 1-2 h
resin (Na/Ca or Ca2+ .
polystyrene
sulfonate)**
Exchange K+ more than 7.5 mEq/L Washed RBC reconstituted with 5% Uptake of K + by RBC. Minutes
transfusion albumin
Peritoneal K+ more than 7.5 mEq/L Use a dialysate with low K + Dialysis Minutes
dialysis concentration

*Administration of salbutamol can cause a transient increase in serum K concentration, so it should not be used as the first line
medication. Salbutamol aerosol is not very effective in neonates.
**Oral administration of polystyrene resin should be avoided in VLBW infants and those with poor peristalsis (gastric bezoars after
oral administration and cecal perforation after enema, other complications like hypernatremia, fluid retention can occur)

Indian Journal of Pediatrics, Volume 75April, 2008 387

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S. Subramanian et al
restriction of fluids will suffice. serum sodium must
be monitored at least 12 hourly.
If hyponatremia is associated with symptoms like
seizures, or if hyponatremia is less than 120 mEq/L
it requires prompt correction with 3% hypertonic
saline at a dose of 5 mL/kg over 4-5 h.
Hyponatremia unresponsive to above therapy is an
indication for dialysis.
Babies with non-oliguric ARF may have very large
urinary sodium losses of up to 10 mEq/kg/day, and
these must be replaced.
Hyperkalemia
Hyperkalemia (K+ more than 6.0 mEq/L) is one of the
most dangerous complications that develops in babies
with ARF. Extremely low birth weight (ELBW) babies are
at higher risk of hyperkalemia. The reasons are
multifactorial. Reduction in glomerular filtration rate,
urinary potassium secretion, acidosis, immature tubular
response to aldosterone all contribute to the development
of hyperkalemia.
The first step in the management of hyperkalemia is to
stop administration of potassium in the fluids; various
medications are available to reverse dangerous
hyperkalemia. ECG will help in diagnosing cardiac effects
of hyperkalemia (Table 3). If ECG changes are evident
calcium gluconate 10% is given. This will decrease the
myocardial excitability but will not lower the potassium
levels. This should immediately be followed by methods
to decrease the potassium levels. Hyperkalemia which is
unresponsive to medications is one of the most common
indications for instituting dialysis.
Hypocalcemia
Hypocalcemia can develop in babies with ARF. It may
result from hyperphosphatemia and skeletal resistance to
parathyroid hormone. Symptomatic hypocalcemia should
be corrected by infusing 10% calcium gluconate at a dose
of 0.5-1 mL/kg over 5-10 min under cardiac monitoring.
Role of dopamine
Renal blood flow increases with low dose of dopamine;
action is via DA1 and DA2 receptors. There is a definite role
of dopamine in babies who are hypotensive, who are in
congestive cardiac failure, as these babies will need
inotropic and vasoactive support. Preterm infants are
hypersensitive to alpha receptors and hence even low
doses of dopamine can cause vasoconstriction and raise
renal vascular resistance.7 This may explain the difficulty
in dosing of dopamine for improving renal function.
Dopamine when combined with frusemide has been
shown to cause natiruresis and diuresis in preterm infants
RDS and oliguria.8 Cochrane review concluded that
dopamine has no role in the management of ARF due to
388
indomethacin.9 At present low dose dopamine does not
seem to have any role in the prevention or treatment of
ARF except as on intrope in patients with hypotension or
congestive cardiac failure.
Role of theophylline
Adenosine antagonists are able to reverse the intra-renal
vasoconstrictor state of ARF. Low dose theophylline (0.5-
1mg/kg) has been shown to prevent hypoxia induced
renal insufficiency in newborn rabbits.10 The mechanism
is adenosine antagonism and not by cyclic AMP
phosphodiesterase antagonism. In vasomotor
nephropathy of very preterm infants with respiratory
distress syndrome, early theophylline administration
improves renal function during the first two days of life.11
Prophylactic theophylline, given early after birth, has
beneficial effects on reducing the renal dysfunction in
asphyxiated full-term infants. 12 Thus theophylline may
have role in the management of renal dysfunction but
data are limited, further studies are needed. Presently it
has no role in the management of ARF.
Nutrition
The goal is to provide 100 kcal/kg/day. Proteins or
amino acids are provided in a dose of 1-2 g/kg/day.13
Total parenteral nutrition can be provided if enteral
nutrition cannot be established. If enteral feeding is
possible, breast milk should be used. Caloric density can
be increased by adding corn oil, medium chain
triglycerides or maltodextrins. If breast milk cannot be
given low phosphate formula milk with low renal solute
load can be given.
Acidosis
Mild metabolic acidosis is common in babies with ARF. If
pH is less than 7.2 sodium bicarbonate can be used for
correction of acidosis. It is given in a dose of 1-2 mEq/kg
over 3-4 hrs. But this should be done carefully as it can
cause fluid overload, hypernatremia, intracranial
hemorrhage and intracellular acidosis. Babies with
persistent acidosis require dialysis.
Hypertension
Fluid overload in neonatal ARF can result in mild
hypertension, which can be controlled with fluid
restriction and antihypertensive agents. The development
of severe hypertension in the setting of neonatal ARF
should raise the suspicion for renal artery or venous
thrombosis.
Drug dosage modification
Dosage of the drugs has to be modified in babies with
ARF as the major pathway of excretion of several drugs is
kidneys. In ARF such drugs can accumulate and can
cause toxicity. For modifying drug dosage, the creatinine
clearance has to be calculated.
Indian Journal of Pediatrics, Volume 75April, 2008
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Acute Renal Failure in Neonates

Oliguria : urine output < 1 ml/kg/h for the past 12 hrs in a baby more than 24 hrs of age

Assess urinary bladder size by clinical or

bedside USG if available
Assess and correct hydration
Check for any underlying condition
predisposing to ARF like hypotension,
hypoxia, and hypovolemia.
Estimate creatinine and sodium in blood and
urine
No evidence of CCF

Normal saline bolus 20 ml/kg over 2 h

Urine output present < 1 mL/kg/h

Urine output present >1 mL/kg/h

IV Frusemide
1 mg/kg stat

UOP UOP
< /mL/kg/h > 1 mL/kg/h

INTRINSIC RENAL FAILURE PRE RENAL FAILURE

Fig. 1. Evaluation of Baby with Oliguria. UOP : Urine output CCF : congestive cardiac failure

k length in cm for renal replacement therapy are fluid overload,

Creatinine clearance = hyperkalemia, hyponatremia and severe metabolic
Serum creatinine
acidosis which are unresponsive to medical management.
where k in Dialysis has to be instituted to preempt complications in
Term babies is 0.44 renal failure. A newborn who is anuric and is having
Preterm babies is 0.33 metabolic complications will ultimately require dialysis
(e.g., hyperkalemia in anuric baby is unlikely to respond
Basing on creatinine clearance the dosage of the drugs
to medical management alone and require dialysis).
have to be modified.
Dialysis and filtration techniques are the available
Renal replacement therapy
modalities. Dialysis is a process of removal of plasma
Before instituting dialysis, it is always better to consider solutes by diffusion down their concentration gradients
the prognosis of the condition. The common indications across a semi permeable membrane. The membrane may

Indian Journal of Pediatrics, Volume 75April, 2008 389

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S. Subramanian et al
be a synthetic one (hemodialysis) or peritoneum
separating the splanchnic blood from fluid instilled into
the peritoneal space (peritoneal dialysis).14 Filtration
involves removal of protein free plasma water across a
membrane by convection. The filtered water contains
other plasma solutes at a concentration similar to plasma
and can be thought of as glomerular filtrate equivalent.
Hemodiafiltration involves both dialysis and filtration.
PD has major advantages as the access is relatively
easy and is technically simple. Peritoneal dialysis has to
be done only under strict aseptic conditions.
Peritoneal dialysis catheters: 15 PD catheters are made up of
soft silastic, which is smooth silicone polymer of methyl-
silicate, either in curled or straight configurations. Most of
the catheters have side holes that allow for easy ingress
and egress of fluid regardless of the catheter position in
the peritoneum. Permanent catheters have cuffs. Pig-tail
catheters and straight catheters without cuffs have been
used in neonates who are anticipated to need PD access
for a brief period of time. Straight Tenckhoff and coiled
Tenckhoff catheters are available. Coiled Tenckhoff
catheters are useful for chronic dialysis.
Procedure
The catheter is inserted into the peritoneal cavity and
connected to a three way cannula. The common sites of
insertion are in the midline below the umbilicus, right or
left lower quadrant of the abdomen. Urinary bladder
must be emptied before insertion of the catheter. The
dialysate fluid is connected to a pediatric burette set and
its terminal end is connected to one of the ports of three
way cannula. The remaining port of the three way is
connected to a intravenous (IV) set, the end of which is let
into a sterile container (empty IV fluid bottle). The
abdomen is distended with 20 mL/kg of peritoneal
dialysis fluid. 20-30 mL/kg of dialysis fluid is infused
over 10 min. A dwell time of 20-30 min is used before
draining the fluid over 10 min. The dwell time can be
reduced in case of respiratory compromise. A total of 20-
40 cycles can be used or it can be continued till the desired
effect is obtained. Blood sugar, serum electrolytes have to
be monitored every 6 hourly and serum creatinine every
24 hourly.
The common dialysate fluid contains 1.7% dextrose
with lactate. If higher gradient is required as in case of
fluid overload 3% solution can be used. This can be
prepared by adding 25 mL of 50% dextrose to one liter of
1.7% PD fluid. In case of liver failure lactate free
bicarbonate containing fluid has to be used. If baby
becomes hypokalemic during the procedure, add 1.5 mL
of KCl to one liter of dialysate fluid. At the end of the
procedure the catheter can be removed and the tip and
the fluid are sent for culture.
PD is invasive procedure and complications can occur.
390
Hyperglycemia can occur due to absorption of dextrose
from PD fluid especially in cases where higher
concentrations of dextrose are used. Bleeding, perforation
of abdominal viscera, peritonitis, adhesion of catheter tip
to omentum (Be careful while removing catheter or else
will be delighted to see omentum!) PD cannot be done in
babies with necrotizing enterocolitis, babies who
underwent abdominal surgery and in those with severe
respiratory compromise as it may worsen with abdominal
distension.
Hemofiltration and hemodiafiltration are effective in
neonates with ARF in whom PD is contraindicated. The
complication rates are less. Hemofiltration is particularly
useful in the presence of fluid overload.
Hemodiafiltration is more useful in the presence of fluid
overload and azotemia with electrolyte disturbances. 2
Outcome
Non oliguric renal failure has a better prognosis when
compared to oliguric renal failure. Mortality ranges from
25 to 78% in oligoanuric renal failure. 16 Long term
abnormalities in GFR and tubular function are common in
babies who survive ARF and is secondary to hyper-
filtration in the surviving nephrons. The long term
consequence of such an acute insult is not known.
Follow up
All babies who develop ARF need follow up. Adequacy
of growth and nutrition, blood pressure, and renal
function status has to be monitored. Newborns who have
ARF are predisposed to the development of chronic renal
failure in the future. Long-term follow-up of extremely
low birth weight infants who had neonatal ARF has
shown that prominent risk factors for progression of renal
disease at 1 year of age included a spot urinary protein/
creatinine ratio of greater than 0.6 and serum creatinine
greater than 0.6 mg/dL.17
REFERENCES
1. Suhas M Nafday et al. In MG MacDonald, eds. Renal Disease
Averys Neonatology pathophysiology and management of
newborn, 6th ed. Lippincott Williams and Wilkins. 2005; 981-
1065.
2. Gouyon J B, Guignard J P, Management of acute renal failure
in newborns. Pediatr Nephrol 2000; 14 : 1037-1044.
3. Hentschel R, Lodige B, Bulla M. Renal insufficiency in the
neonatal period. Clin Nephrol 1996; 46 : 54-58.
4. Ravindra LM, John AK, Sudhir VS, Bruce AM, Claudio R,
David GW et al. Acute Kidney Injury Network: report of an
initiative to improve outcomes in acute kidney injury. Critical
Care 2007; 11 : R31.
5. Ishizaki Y et al. Evaluation of diagnostic criteria of acute renal
failure in premature infants. Acta Paediatr Jpn 1983; 35: 311-
315.
6. Chawla D, Agarwal R, Deorari AK, Paul VK. Fluid and
electrolyte management in term and preterm neonates.
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Acute Renal Failure in Neonates
AIIMS-NICU protocols 2008, www.newbornwhocc.org.
7. Seri I et al. Effects of low dose dopamine infusion on
cardiovascular and renal functions cerebral blood flow and
plasma cathecolamines levels in sick preterm neonates.
Pediatric Res 1993; 34 : 742-749.
8. Tulassy T, Seri I. Acute oliguria in preterm infants with
hyaline membrane disease; interaction of dopamine and
frusemide. Acta Pediatr Scand 1986; 75 : 420-424.
9. Barrington K, Brion LP. Dopamine versus no treatment to
prevent renal dysfunction in indomethacin-treated preterm
newborn infants. Cochrane Database of Systematic Reviews
2002, Issue 3. Art. No.:CD003213.
10. Toth-Heyn P, Drukker A, Guignard J P, The stressed neonatal
kidney; from pathophysiology to clinical management of
neonatal vasomotor nephropathy. Pediatr Nephrol 2000, 14 :
227-239.
11. Huet F, Semama D, Guignard JP et al. Effect pf theophylline on
renal insufficiency in neonates with respiratory distress
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syndrome. Intensive Care Med 1995; 21 : 511-514.
12. Jenik AG, Ceriani Cernadas JM, Gorenstein A, Ramirez JA,
Vain N, Armadans M et al. A randomized, double-blind,
placebo-controlled trial of the effects of prophylactic
theophylline on renal function in term neonates with perinatal
asphyxia. Pediatrics 2000; 105 : E45.
13. Philippe SF Jacquelyyn RE, Tivadar T, Seri I. In William T,
Roberta B, Christine AG, eds. Acute and chronic renal failure,
Averys diseases of newborn, 8th ed. Saunders, 2005; 1298-1306.
14. Coulthard M G, Brayan V, Managing acute renal failure in
very low birthweight infants. Arch Dis Child 1995; 73: F187-
F192.
15. Marsha ML, Annabelle NC, Peter DY. Neonatal peritoneal
dialysis. Neo Reviews 2005; 6 : e384-e391.
16. Chevalier R. Prognostic factors in neonatal acute real failure.
Pediatrics 1984; 74: 165-272.
17. Annabelle NC, Minnie MS. Acute renal failure management in
the neonate. Neo Reviews 2005, 6: e369-e376.
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Symposium on AIIMS Protocols in Neonatology 1

Apnea in the Newborn

Satish Mishra, Ramesh Agarwal, M. Jeevasankar, Rajiv Aggarwal1, Ashok K. Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New
Delhi, 1Narayana Hridalaya, Bangalore, Karnataka, India

ABSTRACT
Apnea, defined as cessation of breathing resulting in pathological changes in heart rate and oxygen saturation, is a common
occurrence especially in preterm neonates. It is due to immaturity of the central nervous system (apnea of prematurity) or
secondary to other causes such as metabolic disturbances etc. Secondary causes of apnea should be excluded before a
diagnosis of apnea of prematurity is made. Methylxanthines and continuous positive airway pressure form the mainstay of
treatment. Mechanical ventilation is reserved for apnea resistant to the above therapy. An approach to the management of apnea
in neonates is described. [Indian J Pediatr 2008; 75 (1) : 57-61] E-mail: vinodkpaul@hotmail.com

Key words : Apnea; Methylxanthines

About 30-45% of preterm babies exhibit a periodic
breathing pattern characterized by 3 or more respiratory
pauses of greater than 3 seconds duration. Periodic
breathing is a normal event, reflective of immaturity of
respiratory control system in these infants and does not
merit any treatment. In contrast, apnea is a pathological
cessation of breathing that results in hemodynamic
disturbances and hence merits treatment.
Definition
Apnea is defined as cessation of respiration for longer
than 20 sec, or shorter duration in presence of cyanosis or
bradycardia.1
Incidence
Apnea in preterm infants is usually related to immaturity
of the central nervous system and is called apnea of
prematurity (AOP). It can also occur secondary to other
causes and is a common manifestation of most neonatal
diseases. Incidence of AOP is inversely proportional to
gestational age. It varies from 10% in infants born at
gestation of 34 weeks or more to more than 60% in infants
born at less than 28 weeks of gestation.1
ETIOLOGY OF APNEA2,3
Apnea of prematurity(AOP). It is probably related to
immaturity of the central nervous system. This condition
usually presents after 1-2 days of life (the detection may
be delayed by the presence of ventilatory support in the
initial days of life) and within the first 7 days.
Secondary causes: Secondary causes of apnea
include: (a) Temperature instability: hypothermia and
hyperthermia, (b) Neurological: birth trauma, drugs,
intracranial infections, intracranial hemorrhage, seizures,
perinatal asphyxia, congenital myopathies or
neuropathies, placental transfer of narcotics, magnesium
sulphate, or general anesthetics, central nervous system
malformations, (c) Pulmonary: respiratory distress
syndrome (RDS), pneumonia, pulmonary hemorrhage,
obstructive airway lesion, pneumothorax, hypoxemia,
hypercarbia, tracheal occlusion by neck flexion, (d)
Cardiac: congenital cyanotic heart disease, hypo/
hypertension, congestive heart failure, patent ductus
arteriosus, increased vagal tone (e) Gastro-intestinal:
gastro esophageal reflux, abdominal distension, (f)
Hematological: anemia, (g) Infections: sepsis, pneumonia,
meningitis, necrotizing enterocolitis, (h) Metabolic:
acidosis, hypoglycemia, hypocalcemia, hyponatremia,
hypernatremia and, (i) Inborn errors of metabolism.
AOP is a diagnosis of exclusion and should be
considered only after secondary causes of apnea have
been excluded. Common causes of secondary apnea
include sepsis, pneumonia, asphyxia, temperature
instability and anemia.

Correspondence and Reprint requests : Dr. Vinod K Paul, Professor,
Department of Pediatrics, All India Institute of Medical Sciences,
Ansari Nagar, New Delhi-110029, India
[Received November 3, 2007; Accepted December 3, 2007]
TYPES OF APNEA4
Central apnea: (40%) Central apnea is characterized by
total cessation of inspiratory efforts with no evidence of
obstruction.

Indian Journal of Pediatrics, Volume 75January, 2008 57

 15
S. Mishra et al
Obstructive apnea. (10%) In obstructed apnea, the
infant tries to breathe against an obstructed upper airway,
resulting in chest wall motion without airflow throughout
the entire apneic episode
Mixed apnea. (50%) Mixed apnea consists of
obstructed respiratory efforts usually following central
pauses. Purely obstructive apnea in the absence of a
positional problem is probably uncommon.
MONITORING
All babies less than 34 weeks gestation should be
monitored for at least in the first week of life or till
absence of apneic episodes for at least 7 days. Babies 34
weeks gestation should be monitored if they are sick.3
Apnea Monitors5
Pulse oximeters: These are commonly used for
monitoring of apnea. These monitors detect changes in
heart rate and/or saturation due to apneic episodes.
Facility for detecting chest wall movement is absent in
these monitors.
Other apnea monitors
Movement sensors
(i) Ripple type mattress
(ii) Mattress with sensory pad
(iii) Pressure sensitive capsule
These monitors interpret chest/abdominal movements
as respiration. In general, these monitors will fail to
diagnose obstructive apnea and may not distinguish
body movements from breathing.
Thoracic impedence based monitors: These monitors
translate changes in thoracic impedence that occur with
breathing as respiratory activity. Like the movement
sensors, these monitors also fail to diagnose obstructive
apnea.
Respiratory inductive plethysmography: It uses
abdominal and thoracic movements during respiration.
Abdominal thoracic bands or the Graseby capsule are
used, the inductance of which changes with breathing.
Magnetometer: Electrical signal produced by chest or
abdominal movement then can be detected by the sensor.
Apnea monitors based on chest wall movement are
likely to miss obstructive apnea. Monitors with facilities
for measuring heart rate and oxygen saturation would be
more useful in the monitoring of significant apnea in
preterm infants.
Differential Diagnosis
Periodic breathing: It consists of breathing for 10-15
seconds, followed by apnea for 5-10 sec without change
58
9
of heart rate or color.
Subtle seizures: Apnea is an uncommon presentation of
a neonatal seizure in preterm infants. Sudden alteration
in muscle tone, twitching movements, vacant stare and
up rolling of eyes suggests a seizure. Also tachycardia
preceding/ accompanying an apneic attack usually
suggests seizure activity.
EVALUATION OF A CHILD WITH APNEA
Emergency treatment
The neonate should be checked for bradycardia, cyanosis
and airway obstruction. The neck should be positioned in
slight extension; oro-pharynx gently suctioned, if
required and tactile stimulation should be given. Most
apneic spells respond to tactile stimulation. Oxygen by
head box or nasal cannula is provided if the infant is
hypoxic (maintain saturation between 90-93%). If the
neonate continues to remain apneic and does not respond
to tactile stimulation, ventilation with bag and mask
(BMV) using 100% oxygen should be initiated. If BMV
fails to initiate spontaneous respiration in the newborn,
then the infant should be managed with positive pressure
ventilation.
Clinical examination
After stabilization, the infant should be evaluated for a
possible underlying cause. History should be reviewed
for possible causes of secondary apnea including
perinatal asphyxia, maternal drugs, neonatal sepsis and
feed intolerance. The infant should be examined for
temperature instability, hypotension, jaundice, pallor,
cardiac murmur for PDA and poor perfusion. Onset of
apnea within the first 7 days in a premature infant
(gestation < 34 weeks) would be suggestive of apnea of
prematurity (AOP).
Investigations
Neonates with apnea should be investigated to exclude
common causes of secondary apnea. Investigations that
should be considered include blood glucose, hematocrit,
electrolytes, sepsis8 screen, blood culture, arterial blood
gas, chest X-ray, abdominal X-ray, ultrasound head and
other investigations depending on the history and
physical examination.
TREATMENT
General measures
Maintain airway, breathing and circulation.
Avoid vigorous suctioning of oro-pharynx
Avoid oral feeds repeated episodes of apnea
requiring BMV.
Indian Journal of Pediatrics, Volume 75January, 2008
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Apnea in the Newborn

Decrease environmental temperature to lower end
of thermo-neutral range. Avoid swings in
environmental temperature.
Treatment of the underlying cause: sepsis, anemia,
polycythemia, hypoglycemia, hypocalcemia,
respiratory distress syndrome (RDS).
Transfuse packed cells if hematocrit <30%.
Specific measures for AOP
These include
Drugs including aminophylline, caffeine, doxapram
Continuous positive airway pressure (CPAP)
Mechanical ventilation
Kinesthetic stimulation
Pharmacotherapy for AOP
Aminophylline, caffeine and doxapram have been used
in the treatment of AOP. The indications for starting
drugs are:
Mechanical ventilation
For treatment for apnea of prematurity.6
Post extubation to reduce the incidence of apnea.7

Algorithm for management of neonatal apnea

Neonate with apnea

Emergency treatment
Maintain temperature, ABC

Investigations
BS,PCV,ABG
Evaluation to exclude secondary Sepsis screen
causes of apnea CXR, AXR
Na, K, Ca
US Head

Apnea of prematurity

Start specific
Treatment
Start aminophylline

Apnea responds No response

Continue till CPAP

34 weeks
Trial of doxapram Responds
No response

Stop drugs if Fails

no apnea for
last 7 days IMV/sNIPPV Continue x 48 hours

(ABC: airway; breathing; circulation; BS: blood sugar; PCV: packed cell volume; ABG: arterial blood gas; Na: sodium;
K: potassium; Ca: calcium; US: ultrasound; CPAP: continuous positive airway pressure; IMV: intermittent mandatory
ventilation); SNIPPV: Synchronised nasal intermittet positive preserve ventilation)

Indian Journal of Pediatrics, Volume 75January, 2008 59

 17
S. Mishra et al
Methylxanthines
Methylxanthines have been the mainstay of
pharmacologic treatment of AOP. Xanthine therapy
increases minute ventilation, improves CO2 sensitivity,
decreases hypoxic depression of breathing, enhances
diaphragmatic contractility, and decreases periodic
breathing. The major mechanism of action is likely
through competitive antagonism of adenosine receptors.
Adenosine acts as an inhibitory neuro-regulator in the
central nervous system and is released during hypoxia.
Neonates exhibit hypoxic respiratory depression, and the
ability of methylxanthines to block this response may
contribute to their effect on apnea. A recent Cochrane
review of the use of methylxanthines concluded that
methylxanthines are effective in reducing the number of
apneic attacks and the use of mechanical ventilation.
The loading dose of intravenous aminophylline is 5 to
6 mg/Kg, followed by 1.5 to 3 mg/Kg every 8 to 12 hours.
Oral theosphylline can be administered once the infant
becomes stable in the same dose. Caffeine, both oral and
intravenous use, has some advantages over theophylline.
Because it has a higher therapeutic index, toxicity is less
of a concern. Also, once-daily dosing is possible due to its
longer half-life. A typical loading dose of 20 mg/Kg
caffeine citrate is followed in 24 hours by 5 to 8 mg/Kg
per dose, administered once every 24 hours.
Recommended therapeutic levels are 5 to 10 g/ml for
aminophylline and 8 to 20 g/ml for caffeine. 8
Aminophylline should be continued till 34 weeks
corrected gestational age and stopped thereafter if no
episodes of apnea have occurred in the last 7 days.
Aminophylline initiated in order to facilitate extubation
may be stopped after 7 days.9
Elimination of methylxanthines is prolonged in infants
especially in preterm neonates. Xanthine therapy should
be discontinued at least 1 to 2 weeks prior to discharge, a
guideline that is especially relevant for caffeine because
of its longer half-life. Do not discharge the patient until
methylxanthines have been stopped. There is no role for
prophylactic use of methylxanthines for prevention of
apnea, bradycardia, or desaturation in premature
infants.10 Adverse effects include tachycardia, jitteriness,
irritability, feed intolerance, vomiting and
hyperglycemia. The drug is available as:
Injection: Aminophylline ampoule 250 mg per 10-ml
ampoule.
Oral: Theophylline 50 mg/5 ml in Theoped syrup
Caffeine: The drug is not available in India at present.
Doxapram11, 12
Intravenous Doxapram might reduce AOP in the short
term. The possible effects of treatment are usually not
sustained after 48 hours of commencement of doxapram
treatment. More over, doxapram is associated with
serious side effects and hence should be used with
60
11
caution or preferably avoided.
At present, indications for doxapram include failure
to respond to both methylxanthine and CPAP therapy.
The loading dose is preferably avoided. Doxapram
infusion is started at 0.5 mg/Kg/hour and increased
gradually to a maximum of 2-2.5 mg/Kg/hr. Doxapram
may be tried for a period of 48 hours before weaning the
drug. Methylxanthine therapy should be continued
during doxapram infusion. Adverse effects include
seizures, hypertension, hyperactivity, hyperglycemia and
abdominal distension. It should be avoided in the first
week of the life or if the serum bilirubin is high, because
an association with intraventricular hemorrhage and
kernicterus has been reported.13 Injection doxapram has
0.9% benzyl alcohol as a preservative. The recommended
dose of 2-2.5 mg/Kg/hr would deliver 21.6-32.4 mg/Kg/
day of benzyl alcohol. Although this dose is below the
toxic dose of alcohol (45 mg/Kg/day), there have been
case reports of gasping syndrome with this lower dose
in literature.
Which drug to use?
Present evidence shows that aminophylline, caffeine and
doxapram are equally effective in the treatment of AOP.
However, their clinical use is dependent upon adverse
effects. The drug of choice would be caffeine, which is not
available in India. Hence, we prefer to use aminophylline
as the drug of choice in the management of AOP.
Continuous positive airway pressure
Continuous positive airway pressure (CPAP), usually
administered using nasal prongs (NCPAP), is also an
effective treatment of AOP and is typically used when
clinically significant episodes persist despite optimal
methylxanthine therapy.15 At CPAP level of 5 cm water,
infants with AOP will have fewer episodes. This
reduction is primarily related to significant reduction in
episodes of obstructive and mixed apneas and has been
attributed to splinting open of the upper airways by the
positive airway pressure. If NCPAP in conjunction with
a methylxanthine, is not sufficient to prevent recurring
episodes associated with bradycardia and intermittent
hypoxemia, some investigators have suggested use of
nasal intermittent positive pressure ventilation (NIPPV).
NIPPV may most likely be needed when episodes are
related predominantly to central apneas and are not
effectively eliminated by the NCPAP.3 CPAP may also be
used to reduce post-extubation apnea in preterm
infants.16
A CPAP of 5 cm H2O is usually used. CPAP may be
delivered by nasal prongs or nasopharyngeal tube.
Endotracheal CPAP is not used in the treatment of apneic
spells. CPAP has no role in prophylaxis against apnea of
prematurity. Adverse effects of CPAP include
barotrauma, abdominal distension, feeding intolerance
and local nasal irritation
Indian Journal of Pediatrics, Volume 75January, 2008
 18
Apnea in the Newborn
Mechanical Ventilation
The infant should be ventilated if both pharmacotherapy
and CPAP have been tried and significant apneas
continue to occur. If the lungs are normal, the infant
should be ventilated at minimum pressures (peak
inspiratory pressure of 10-12 cm of water and positive
end expiratory pressure of 3-5 cm of water), low rate (20-
25 per minute), short Ti (0.35-0.40 seconds) and low FiO2
(0.3-0.5). This method is effective in all forms of apnea.
Kinesthetic stimulation
Water bed, oscillating bed mattress. Present evidence
does not support any role for this mode of therapy either
in the prevention or treatment of apnea.17
PERSISTENT APNEA
Apneic episodes may persist beyond 37-40 weeks in some
infants, especially those born before 28 weeks of
gestation. Methylxanthine therapy should be continued if
apneic episodes continue to occur beyond 34 weeks of
corrected gestational age. The neonate should be re-
evaluated for secondary causes of apnea especially
neurological problems and gastro-esophageal reflux.
Home monitoring is not possible in our country and these
infants would require NICU care until drugs can be
weaned and stopped.
SUDDEN INFANT DEATH SYNDROME
(SIDS) AND APNEA
AOP is not found to be an independent risk factor for
SIDS. Only 2-4% of patients with SIDS have a history of
AOP.
NEURODEVELOPMENT OUTCOME
Most reports have found little evidence of any
neurodevelopment risk directly attributed to a history of
AOP. Precisely measured predischarge apnea related to
AOP, however, has been reported to be predictive of
Indian Journal of Pediatrics, Volume 75January, 2008
12
lower developmental indices at two years.3
REFERENCES
1. Hunt CE. Apnea and sudden infant death syndrome. In
Kligman RM, Neider ML, Super DM, eds. Practical strategiesin
pediatric diagnosis and therapy. Philadelphia; WB Saunders,
1996: 135-147.
2. Bhatia J. Current options in the management of apnea of
prematurity. Clin Pediatr 2000; 39 : 327-336.
3. Thompson MW, Hunt CE. In MacDonald MG, Mullett MD,
Seshia MMK, eds. Averys Neonatology Pathophysiology &
Management of the Newborn 6 th ed. Philadelphia; Lippincott
Williams and Wilkins, 1998; 539-45.
4. Martin RJ, Abu-Shaweesh, Baird TM. Pathophysiologic
Mechanisms Underlying Apnea of Prematurity. Neo Reviews
2002; 3 : e59.
5. Deorari AK. In Deorari AK, Paul VK, eds. Neonatal Equipment
Everything that you like to know 3rd ed. New Delhi; Sagar
Publication, 2006; 60-61.
6. Henderson-Smart DJ, Steer P. Methylxanthine treatment for
apnea in preterm infants. Cochrane Database Syst Rev 2000.
7. Henderson-Smart DJ, Steer P. Prophylactic methylxanthine for
extubation in preterm infants. Cochrane Database Syst Rev 2004.
8. Martin RJ, Abu-Shaweesh , Baird TM. Clinical Associations,
Treatment, and Outcome of Apnea of Prematurity. Neo
Reviews 2002; 3: e66.
9. Miller MJ, Martin RJ. Apnea of prematurity. Clin Perinatol
1992; 19 : 789-808.
10. Henderson-Smart DJ, Steer PA. Prophylactic methylxanthine
for prevention of apnea in preterm infants. Cochrane Database
Syst Rev 2006.
11. Henderson-Smart DJ, Steer PA. Doxapram treatment for
apnea in preterm infants. Cochrane Database Syst Rev 2004.
12. Hansen T, Corbet A. Control of breathing. In Taeusch HW,
Ballard RA, eds. Averys diseases of the newborn, 7 th ed.
Philadelphia, WB Saunders, 1998; 552-561.
13. Jardine DS, Rogers K. Relationship of benzyl alcohol to
kernicterus, intraventricular hemorrhage, and mortality in
premature infants. Pediatrics; 83 : 721.
14. Kumar M, Kabra NS, Paes B. Carnitine supplementation for
preterm infants with recurrent apnea. Cochrane Database Syst
Rev 2004.
15. Henderson-Smart DJ, Subramanian P, Davis PG. Continuous
positive airway pressure versus theophylline for apnea in
preterm infants. Cochrane Database Syst Rev 2005.
16. Davis PG, Henderson-Smart DJ. Nasal continuous positive
airway pressure immediately after extubation for preventing
morbidity in preterm infants. Cochrane Database Syst Rev 2003.
17. Osborn DA, Henderson-Smart DJ. Kinesthetic stimulation for
treating apnea in preterm infants. Cochrane Database Syst Rev
2003.
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 23 13

Symposium on AIIMS Protocols in Neonatology III

Approach to Inborn Errors of Metabolism Presenting in

the Neonate
Suvasini Sharma, Pradeep Kumar, Ramesh Agarwal, Madhulika Kabra, Ashok K. Deorari and
Vinod K. Paul

Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

ABSTRACT
Inborn errors of metabolism (IEM) are an important cause of acute illness in newborns. Presentation may mimic common
neonatal conditions such as sepsis. Prompt detection requires a high index of suspicion and the early measurement of
biochemical markers such as blood ammonia. Diagnosis is important not only for treatment but also for genetic counselling.
Guidelines for diagnosis and early management of IEM presenting in the neonatal period are described. [Indian J Pediatr
2008; 75 (3) : 271-276] E-mail: ashokdeorari_56@hotmail.com

Key words : Inborn errors of metabolism; Encephalopathy; Hyperammonemia

Inborn errors of metabolism (IEM) are disorders in which Family history of neonatal deaths
there is a block at some point in the normal metabolic Rapidly progressive encephalopathy and seizures of
pathway caused by a genetic defect of a specific enzyme. unexplained cause
The number of diseases in humans known to be Severe metabolic acidosis
attributable to inherited point defects in metabolism now Persistent vomiting
exceeds 500.1 While the diseases individually are rare, Peculiar odor
they collectively account for a significant proportion of Acute fatty liver or HELLP (hemolysis, elevated liver
neonatal and childhood morbidity and mortality. enzymes and low platelet counts) during pregnancy:
Diagnosis is important not only for treatment and seen in women carrying fetuses with long-chain-3-
prognostication but also for genetic counselling and hydroxyacyl-coenzyme dehydrogenase deficiency
antenatal diagnosis in subsequent pregnancies. (LCHADD).
Table 1 describes examination findings that may
provide a clue to the underlying IEM.
CLINICAL PRESENTATION
TABLE 1. Clinical Pointers Towards Specific IEMs
Severe illness in the newborn, regardless of the Clinical finding Disorder
underlying cause, tends to manifest with non-specific
findings, such as poor feeding, drowsiness, lethargy, Coarse facies Lysosomal disorders
Cataract Galactosemia, Zellweger syndrome
hypotonia and failure to thrive. IEM should be considered Retinitis pigmentosa Mitochondrial disorders
in the differential diagnosis of any sick neonate along with Cherry red spot Lipidosis
common acquired causes such as sepsis, hypoxic-ischemic Hepatomegaly Storage disorders, urea cycle defects
encephalopathy, duct-dependant cardiac lesions, Renal enlargement Zellweger syndrome
congenital adrenal hyperplasia and congenital infections. Eczema/alopecia Biotinidase deficiency
Abnormal kinky hair Menke disease
Clinical pointers towards an underlying IEM include.2
Decreased pigmentation Phenylketonuria
Deterioration after a period of apparent normalcy
Parental consanguinity Patterns of presentation include.2,3
(i) Encephalopathy with or without metabolic acidosis:
Encephalopathy, seizures, and tone abnormalities are
Correspondence and Reprint requests : Dr Ashok K Deorari, predominant presenting features of organic acidemias,
Professor, Department of Pediatrics, All India Institute of Medical urea cycle defects and congenital lactic acidosis.
Sciences, Ansari Nagar, New Delhi 110029, India Intractable seizures are prominent in pyridoxine
[Received February 7, 2008; Accepted February 7, 2008] dependency, non-ketotic hyperglycinemia, molybdenum

Indian Journal of Pediatrics, Volume 75March, 2008 271

 24 14

S. Sharma et al

co-factor defect and folinic-acid responsive seizures. Fig 1 gives the algorithmic approach to a newborn
with suspected IEM. Disease category can be diagnosed
(ii) Acute liver disease: This could manifest as-
based on blood ammonia, blood gas analysis and urine
Jaundice alone- Gilbert syndrome, Criggler-Najjar ketone testing. Hyperammonemia without acidosis is
syndrome caused by urea cycle defects. Metabolic acidosis with or
Hepatic failure (jaundice, ascites, hypoglycemia, without hyperammonemia is a feature of organic
coagulopathy)- Tyrosinemia, galactosemia, neonatal acidemias and fatty acid oxidation defects. Fig. 2 explains
hemochromatosis, glycogen storage disease type IV. the algorithmic approach to neonate with persistent
hypoglycemia and suspected underlying IEM. Table 2
Neonatal cholestasis: alpha-1 antitrypsin deficiency,
explains the categorization of IEM based on simple
Niemann-Pick disease type C.
metabolic screening tests.
Hypoglycemia: persistent and severe hypoglycemia
TABLE 2. Categorization of Neonatal IEM Using Metabolic
may be an indicator of an underlying IEM.
Screening Tests
Hypoglycemia is a feature of galactosemia, fatty acid
oxidation defects, organic acidemias, glycogen storage Acidosis Ketosis -Lactate -Ammonia Diagnosis
disorders and disorders of gluconeogenesis.
- + - - Maple syrup urine
(iii) Dysmorphic features: Seen in peroxisomal disorders, disease
pyruvate dehydrogenase deficiency, congenital disorders + +/- - +/- Organic aciduria
+ +/- + - Lactic acidosis
of glycosylation (CDG), and lysosomal storage diseases. - - - + Urea cycle
Some IEMs may present with non-immune hydrops - - - - Non-ketotic
fetalis; these include lysosomal storage disorders and hyperglycinemia
CDG. sulfite oxidase
deficiency,
(iv) Cardiac disease: Cardiomyopathy is a prominent peroxisomal,
feature in some IEM including fatty acid oxidation Phenylketonuria,
defects, glycogen storage disease type II and galactosemia
mitochondrial electron transport chain defects.
Second line investigations (ancillary and confirmatory
INVESTIGATIONS tests)
These tests need to be performed in a targeted manner,
Metabolic investigations should be initiated as soon as the based on presumptive diagnosis reached after first line
possibility is considered. The outcome of treatment of investigations:
many IEM especially those associated with Gas chromatography mass spectrometry (GCMS) of
hyperammonemia is directly related to the rapidity with urine- for diagnosis of organic acidemias.
which problems are detected and appropriate
management instituted. Plasma amino acids and acyl carnitine profile: by
tandem mass spectrometry (TMS)- for diagnosis of
First line investigations (metabolic screen) organic acidemias, urea cycle defects,
The following tests should be obtained in all babies with aminoacidopathies and fatty acid oxidation defects.
suspected IEM. High performance liquid chromatography (HPLC):
Complete blood count: (neutropenia and for quantitative analysis of amino acids in blood and
thrombocytopenia seen in propionic and urine; required for diagnosis of organic acidemias
methylmalonic academia) and aminoacidopathies.

Arterial blood gases and electrolytes Lactate/pyruvate ratio- in cases with elevated
Blood glucose lactate.
Plasma ammonia (Normal values in newborn: 90- Urinary orotic acid- in cases with hyperammonemia
150 g/dl or 64-107 mol/L) for classification of urea cycle defect.
Arterial blood lactate (Normal values: 0.5-1.6 mol/ Enzyme assay: This is required for definitive
L) diagnosis, but not available for most IEMs.
Liver function tests Available enzyme assays include: biotinidase assay-
Urine ketones in cases with suspected biotinidase deficiency
Urine reducing substances. (intractable seizures, seborrheic rash, alopecia); and
Serum uric acid (low in molybdenum cofactor . GALT (galactose 1-phosphate uridyl transferase )
deficiency). assay- in cases with suspected galactosemia

272 Indian Journal of Pediatrics, Volume 75March, 2008

 25
Approach to Inborn Error of Metabolism Presenting in the Neonate
Fig 1. Approach to newborn with suspected metabolic disorder Suspected Metabolic Disorder
(hypoglycemia, cataracts, reducing sugars in urine).
Neuroimaging: MRI may provide helpful pointers
towards etiology while results of definitive
investigations are pending. Some IEM may be
associated with structural malformations e.g.,
Zellweger syndrome has diffuse cortical migration
and sulcation abnormalities. Agenesis of corpus
callosum has been reported in Menkes disease,
pyruvate decarboxylase deficiency and nonketotic
hyperglycinemia.4 Examples of other neuroimaging
findings in IEM include:
Maple syrup urine disease (MSUD): brainstem and
cerebellar edema
Propionic and methylmalonic acidemia: basal
ganglia signal change
Glutaric aciduria: frontotemporal atrophy, subdural
hematomas
Indian Journal of Pediatrics, Volume 75March, 2008
15
Magnetic resonance spectroscopy (MRS): may be
helpful in selected disorders e.g. lactate peak
elevated in mitochondrial disorders, leucine peak
elevated in MSUD.
Electroencephalography (EEG): some EEG
abnormalities may be suggestive of particular IEM;
e.g., comb-like rhythm in MSUD, burst suppression
in NKH and holocarboxylase synthetase deficiency.5
Plasma very long chain fatty acid (VLCFA) levels:
elevated in peroxisomal disorders.
Mutation analysis when available.
CSF aminoacid analysis: CSF Glycine levels elevated in
NKH.
Precautions to be observed while collecting samples
Should be collected before specific treatment is started or
feeds are stopped, as may be falsely normal if the child is
off feeds.
273
 26
S. Sharma et al
Fig. 2. Approach to newborn with persistent hypoglycemia and suspected IEM
Samples for blood ammonia and lactate should be
transported in ice and immediately tested. Lactate
sample should be arterial and should be collected after 2
hrs fasting in a preheparinized syringe. Ammonia sample
is to be collected approximately after 2 hours of fasting in
EDTA vacutainer. Avoid air mixing. Sample should be
free flowing.
Detailed history including drug details should be
provided to the lab. (sodium valproate therapy may
increase ammonia levels).
Samples to be obtained in infant with suspected IEM
when diagnosis is uncertain and death seems inevitable
(Metabolic autopsy)6
Blood: 5-10 ml; frozen at -200C; both heparinized (for
chromosomal studies) and EDTA (for DNA studies)
samples to be taken
Urine: frozen at 20oC
CSF: store at 20oC
Skin biopsy: including dermis in culture medium or
saline with glucose. Store at 4-80C. Do not freeze.
Liver, muscle, kidney and heart biopsy: as indicated.
Clinical photograph (in cases with dysmorphism)
Infantogram (in cases with skeletal abnormalities)
TREATMENT
In most cases, treatment needs to be instituted empirically
without a specific diagnosis. The metabolic screen helps to
274
16
broadly categorize the patients IEM (e.g., urea cycle
defect, organic academia, congenital lactic acidosis etc), on
the basis of which, empirical treatment can be instituted.
Aims of treatment
1. To reduce the formation of toxic metabolites by
decreasing substrate availability (by stopping feeds
and preventing endogenous catabolism)
2. To provide adequate calories
3. To enhance the excretion of toxic metabolites.
4. To institute co-factor therapy for specific disease and
also empirically if diagnosis not established.
5. Supportive care- treatment of seizures (avoid
sodium valproate may increase ammonia levels),
maintain euglycemia and normothermia, fluid,
electrolyte and acid-base balance, treatment of
infection, mechanical ventilation if required.
Management of hyperammonemia7,8
Discontinue all feeds. Provide adequate calories by
intravenous glucose and lipids. Maintain glucose infusion
rate 8-10mg/kg/min. Start intravenous lipid 0.5g/kg/
day (up to 3g/kg/day). After stabilization gradually add
protein 0.25 g/kg till 1.5 g/kg/day.
Dialysis is the only means for rapid removal of
ammonia, and hemodialysis is more effective and faster
than peritoneal dialysis, however peritoneal dialysis may
be more widely available and feasible. Exchange
transfusion is not useful.
Indian Journal of Pediatrics, Volume 75March, 2008
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Approach to Inborn Error of Metabolism Presenting in the Neonate
Alternative pathways for nitrogen excretion:
Sodium benzoate (IV or oral)- loading dose 250 mg/kg
then 250-400 mg/kg/day in 4 divided doses. (Intravenous
preparation not available in India).
Sodium phenylbutyrate (not available in India)-
loading dose 250 mg/kg followed by 250-500 mg/kg/
day.
L-arginine (oral or IV)- 300 mg/kg/day (Intravenous
preparation not available in India)
L-carnitine (oral or IV)- 200 mg/kg/day
Supportive care: treatment of sepsis, seizures,
ventilation. Avoid sodium valproate.
Acute management of newborn with suspected organic
acidemia9
The patient is kept nil per orally and intravenous
glucose is provided.
Supportive care: hydration, treatment of sepsis,
seizures, ventilation.
Carnitine: 100 mg/kg/day IV or oral.
Treat acidosis: Sodium bicarbonate 0.35-0.5mEq/
kg/hr (max 1-2mEq/kg/hr)
Start Biotin 10 mg/day orally.
Start Vitamin B12 1-2 mg/day I/M (useful in B12
responsive forms of methylmalonic acidemias)
Start Thiamine 300 mg/day (useful in Thiamine-
responsive variants of MSUD).
If hyperammonemia is present, treat as explained
above.
Management of congenital lactic acidosis
Supportive care: hydration, treatment of sepsis,
seizures, ventilation. Avoid sodium valproate.
Treat acidosis: sodium bicarbonate 0.35-0.5mEq/
kg/hr (max 1-2mEq/kg/hr)
Thiamine: up to 300 mg/day in 4 divided doses.
Riboflavin: 100 mg/day in 4 divided doses.
Add co-enzyme Q: 5-15 mg/kg/day
L-carnitine: 50-100 mg/kg orally.
Treatment of newborn with refractory seizures with no
obvious etiology (suspected metabolic etiology)10
If patient persists to have seizures despite 2 or 3
antiepileptic drugs in adequate doses, consider trial
of pyridoxine 100 mg intravenously. If intravenous
preparation not available, oral pyridoxine can be
given (15 mg/Kg/day).
If seizures persist despite pyridoxine, give trial of
biotin 10 mg/day and folinic acid 15 mg/day
(folinic acid responsive seizures).
Rule out glucose transporter defect: measure CSF
Indian Journal of Pediatrics, Volume 75March, 2008
17
and blood glucose. In glucose transporter defect,
CSF glucose level is equal to or less than 1/3rd of the
blood glucose level. This disorder responds to the
ketogenic diet.
Management of asymptomatic newborn with a history
of sibling death with suspected IEM:
After baseline metabolic screen, start oral dextrose
feeds (10% dextrose).
After 24 hours, repeat screen. If normal, start breast
feeds. Monitor sugar, blood gases and urine
ketones, blood ammonia 6 hourly.
Some authorities recommend starting medium
chain triglycerides (MCT oil) before starting breast
feeds,3 however, this is not being followed in our
center (because of unpalatibility of MCT oil).
After 48 hours, repeat metabolic screen. Obtain
samples for TMS and urine organic acid tests.
The infant will need careful observation and follow-
up for the first few months, as IEM may present in
different age groups in members of the same family.
Long term treatment of IEM
The following modalities are available
Dietary treatment: This is the mainstay of treatment in
phenylketonuria, maple syrup urine disease,
homocystinuria, galactosemia, and glycogen storage
disease Type I and III. Special diets for PKU and MSUD
are commercially available in the west. These are not
available in India, but can be imported. These special diets
are however very expensive, and cannot be afforded by
most Indian patients. Based on the amino acid content of
some common food products available in India, dietary
exchanges are calculated and a low phenylalanine diet for
PKU and diet low in branched chain amino acids for
MSUD are being used in our center. However, there are
no studies to document the efficacy of these indigenous
diets. Some disorders like urea cycle disorders and
organic acidurias require dietary modification (protein
restriction) in addition to other modalities.11
Enzyme replacement therapy (ERT): ERT is now
commercially available for some lysosomal storage
disorders.12 However, these disorders do not manifest in
the newborn period, an exception being Pompes disease
(Glycogen storage disorder Type II)which may present in
the newborn period and for which ERT is now available.
Cofactor replacement therapy: The catalytic properties of
many enzymes depend on the participation of non
protein prosthetic groups, such as vitamins and minerals,
as obligatory cofactors. The following co-factors may be
beneficial in certain IEM:13
Thiamine: mitochondrial disorders, thiamine
responsive variants of MSUD, PDH deficiency &
complex I deficiency)
275
 28 18

S. Sharma et al

Appendix: Commercially Available Formulations Used in IEM

Co-factor Trade name, formulation

Pyridoxine Tab Benadon (40mg) (Nicholas Piramal), Inj Vitneurin (1 ampoule contains
50 mg pyridoxine)
Hydroxycobalamin (Vitamin B12) Inj Trineurosol (1000mcg/ml) (Tridoss Laboratories)
Thiamine Tab Benalgis (75 mg) (Franco India)
Riboflavin Tab Riboflavin (5 mg) (Shreya)
Biotin Tab Essvit (5mg, 10mg) (Ecopharma)
Carnitine Syrup L-Carnitor (5ml=500 mg), Tab L-Carnitor (500 mg), Inj carnitor (1g/
5ml) (Elder)
Folinic acid Tab Leukorin (15 mg) (Samarth)
Sodium Benzoate Satchet 20g (Hesh Co.)
Arginine ARG-9 Satchet (3g) (Noveau Medicament)
Coenzyme Q Tab CoQ 30 mg, 50 mg. (Universal Medicare)

Riboflavin: Glutaric aciduria Type I, Type II, mild
variants of ETF, ETF-DH, complex I deficiency
Pyridoxine: 50% of cases of homocystinuria due to
cystathionine -synthetase deficiency, pyridoxine
dependency with seizures, xanthurenic aciduria,
primary hyperoxaluria type I, Hyperornithemia
with gyrate atrophy
Cobalamin: Methylmalonic academia (cblA, cblB),
Homocystinuria and methylmalonic academia
(cblC, cblD, cblF)
Folinic acid: Hereditary orotic aciduria, Methionine
synthase deficiency, Cerebral folate transporter
deficiency, hereditary folate malabsorption, Kearns-
Sayre syndrome
Biotin: Biotinidase deficiency, holocarboxylase
synthetase deficiency
PREVENTION
Neonatal screening: Tandem mass spectrometry is used in
some countries for neonatal screening for IEM. Disorders
which can be detected by TMS include aminoacidopathies
(phenylketonuria, MSUD, Homocystinuria, Citrullinemia,
Argininosuccinic aciduria, hepatorenal tyrosinemia), fatty
acid oxidation defects, organic acidemias (glutaric
aciduria, propionic acidemia, methylmalonic acidemia,
isovaleric acidemia). The cost of this procedure is high, a
potent dis-inventive for resource poor countries like India.
Also, the though the test is highly sensitive, the specificity
is relatively low; and there are difficulties in interpretation
of abnormal test results in apparently healthy infants.
Genetic counselling and prenatal diagnosis: Most of the IEM
are single gene defects, inherited in an autosomal
recessive manner, with a 25% recurrence risk. Therefore,
when the diagnosis is known and confirmed in the index
case, prenatal diagnosis can be offered, wherever
available for the subsequent pregnancies. The samples
required are chorionic villus tissue or amniotic fluid.
Modalities available are:14
Substrate or metabolite detection: useful in
phenylketonuria, peroxisomal defects.
Enzyme assay: useful in lysosomal storage
disorders like Niemann-Pick disease, Gaucher
disease.
DNA based (molecular) diagnosis: Detection of
mutation in proband/ carrier parents is a
prerequisite.
REFERENCES
1. Childs B, Valle D, Jimenez-Sanchez. The Inborn error and
biochemical variability. In Scriver CR, Beaudet AL, Sly WS,
Valle D, eds. The metabolic and molecular basis of inherited
disease, 8th ed, New York; McGraw-Hill, 2001: 155-166.
2. Clarke, JTR. A Clinical guide to inherited metabolic diseases. 3rd
Ed. Cambridge University Press, Cambridge; 2006.
3. Cataltepe SU, Levy HL. Inborn errors of metabolism. In
Cloherty JP, Eichenwald EC, Stark AR, eds. Manual of neonatal
care. 6th ed. Philadelphia; Lippincott Williams and Wilkins,
2008; 558-573.
4. Blaser S, Feigenbaum A. A neuroimaging approach to inborn
errors of metabolism. Neuroimag Clin N Am 2004; 14: 307-329.
5. Nordli DR, De Vivo DC. Classification of infantile seizures:
Implications for identification and treatment of inborn errors
of metabolism. J Child Neurol 2002; 17 (Suppl 3): 3S3-3S8.
6. Leonard JV, Morris AAM. Diagnosis and early management
of inborn errors of metabolism presenting around the time of
birth. Acta Pediatrica 2006; 95: 6-14.
7. Summar M. Current strategies for the management of
neonatal urea cycle disorders. J Pediatr 2001; 38: S30-S39.
8. Leonard JV, Morris AAM. Urea cycle disorders. Semin
Neonatol 2002; 7: 27-35.
9. de Baulny HO, Saudubray JM. Branched-chain organic
acidurias. Semin Neonatol 2002; 7: 65-74.
10. Wolf NI, Bast T, Surtees S. Epilepsy in inborn errors of
metabolism. Epileptic Disord 2005; 7 : 67-81.
11. Kabra M. Dietary management of Inborn errors of
metabolism. Indian J Pediatr 2002; 69: 421-426.
12. Brady RO, Schiffmann R. Enzyme-replacement therapy for
metabolic storage disorders. Lancet Neurol 2004; 3: 752-756.
13. Saudubray JM, Sedel F, Walter JH. Clinical approach to
treatable inborn metabolic diseases: an introduction. J Inherit
Metab Dis 2006; 29: 261-274.
14. Elias S, Simpson JL, Shulman LP. Techniques for prenatal
diagnosis. In Rimoin DL, Connor JH, Pyeritz RE, Korf BR, eds.
Emery and Rimoins Principles and practice of medical genetics.
London; Churchill-Livingstone, 2002: 802-825.

276 Indian Journal of Pediatrics, Volume 75March, 2008

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Symposium on AIIMS Protocols in Neonatology - V

Blood and Blood Component Therapy in Neonates

Richa Jain, Bipin Jose, Poonam Coshic1, Ramesh Agarwal and Ashok K. Deorari

Division of Neonatology, Department of Pediatrics, 1Department of Transfusion Medicine, All India Institute of
Medical Sciences, New Delhi, India

ABSTRACT
Blood component therapy is a very common intervention practiced in newborns; nearly 85% of extremely low birth weight
(ELBW) babies get transfusions during their hospital stay. However, there are no set guidelines for transfusion of blood
component therapy in newborns. This protocol includes available types of blood components , their methods of preparation,
indications and side effects of transfusion, in relation to newborns. [Indian J Pediatr 2008; 75 (5) : 489-495] Email:
aranag@rediffmail.com

Key words: Transfusion; Packed red cells; Platelets; Newborn

Blood components used in modern day practice
include, apart from whole blood, a variety of other
products, like red blood cell components, platelet
concentrates, and plasma. Blood component
transfusion has been considered to be a safe and low
risk procedure. In the last few decades there has been
recognition of hazards of transfusion of blood and its
products. It is no longer considered to be a low or no
risk procedure, and consequently an increasing need for
stricter guidelines for transfusing blood products has
been recognized, not just to check infections, but also to
minimize other side effects of transfusion. Preterm
neonates comprise the most heavily transfused group of
patients, and about 85% of extremely low birth weight
newborns receive a transfusion by the end of their
hospital stay.1,2
RED BLOOD CELL PRODUCTS
Red cells and their products include packed red blood
cells (PRBCs) and modified blood products used for
specific situations including:
Leukocyte reduced RBCs
Irradiated RBCs
Washed RBCs
RBCs with low CMV risk
Correspondence and Reprint requests : Dr Ramesh Agarwal,
Assistant Professor, Division of Neonatology, Department of
Pediatrics, All India Institute of Medical Sciences, New Delhi,
India.
[Received April 24, 2008; Accepted April 24, 2008]
Indications for PRBC transfusion in neonatal practice
PRBCs are the most commonly used blood product in
neonatal transfusions. 3 Indications for transfusion of
PRBCs are mainly for resolution of symptomatic
anemia and improvement of tissue oxygenation. Tissue
oxygenation depends on cardiac output, oxygen
saturation and hemoglobin concentration. Once cardiac
output and oxygen saturation are optimal, tissue
oxygenation can only be improved by increasing the
hemoglobin level. The guidelines for transfusion of
PRBC vary according to age, level of sickness and
hematocrit (Table 1).3
Packed Red Blood Cells (PRBCs)
Most RBC components available today are derived from
the collection of 350-450 mL of whole blood into sterile
plastic bags containing citrate-phosphate-dextrose
(CPD) anticoagulant. The whole blood is spun to
sediment out the RBCs, and most of the plasma is
removed by pushing it into a pre-attached satellite bag.
Generally, 100 to 110 mL of a nutrient additive solution
is added back to the packed RBCs, creating an
additive RBC product that has a final hematocrit of
55% to 60%. A variety of additive solutions are in use
today, each of which contains a particular mix of
glucose, adenine, and mannitol. These solutions
prolong the shelf life of the RBC product from 21 days
(packed RBCs in CPD) to 42 days (additive RBCs). A
transfusion of 10 mL/kg of additive RBCs would be
expected to raise the newborns hematocrit by 7% to 8%.
Red cells collected in CPDA-1 are kept as packed RBCs,
that is, additive solution is not added. CPDA-1 packed
RBCs have a hematocrit of approximately 75% and a
shelf life of 35 days. An infusion of 10 mL/kg of CPDA-

Indian Journal of Pediatrics, Volume 75May, 2008 489


Richa Jain et al
TABLE 1. Guidelines for Packed Red Blood Cells (PRBCs)
Transfusion Thresholds for Preterm Neonates 3
Less than 28 days of age and
Assisted ventilation with FiO 2 more than 0.3: Hb 12.0 gm/
dL or PCV less than 40%
Assisted ventilation with FiO2 less than 0.3: Hb 11.0 g/dL
or PCV less than 35%
CPAP: Hb less than 10 gm/dL or PCV less than 30%
More than 28 days of age and
Assisted ventilation: Hb less than 10 gm/dL or PCV less
than 30%
CPAP: Hb less than 8 gm/dL or PCV less than 25%
Any age, breathing spontaneously and
On FiO2 more than 0.21: Hb less than 8 gm/dL or PCV less
than 25%
On Room Air: Hb less than 7 gm/dL or PCV less than 20%
1 packed RBCs would be expected to raise the patients
hematocrit by 9% to 10%.
Modified RBC products
Leukocyte reduced RBCs
Leukocyte depletion or reduction has been defined as
achieving a concentration of less than 5 x 10 6
leukocytes per unit of RBCs. Leukocyte reduction is
important in neonatal transfusion. It helps in
preventing non-hemolytic febrile transfusion reactions
(NHFTR), HLA alloimmunization, transmission of
leukotropic viruses (CMV, EBV and HTLV-1),
transfusion related GVHD, and transfusion related
acute lung injury (TRALI).4
Methods of leuko-reduction include the following: 4
a. Centrifugation and removal of buffy coat (pre-
storage leukoreduction)
b. Use of leukocyte filters (pre or post storage)
c. Washing of RBCs with saline
d. Freezing and thawing of red cells
Gamma irradiation
Gamma irradiation of blood components including
RBCs, platelets and white blood cell products is done to
inactivate donor T cells, and the associated risk of
transfusion associated graft versus host disease (TA-
GVHD), which may occur in immunosupressed
patients, very small babies, in large volume transfusions
and during intrauterine transfusions.5
Irradiation causes an increase in the rate of leakage
of potassium out of RBCs during storage, and irradiated
RBCs have a shortened shelf life of only 28 days.
Irradiation does not adversely affect the function or
viability of platelets.6 While most blood banks use a
dose of 1,500 cGy, the selection of an appropriate dose
of gamma irradiation remains an issue.7
Washed RBCs
Saline washing is mainly done to remove plasma from
490
34 20
the RBCs. It may also be done to reduce potassium in
stored RBCs in large volume transfusions. Isotonic
saline is added to blood components, and
centrifugation is done followed by removal of
supernatant, and resuspension of the cells in saline.
Washed products must be used within 4 hours of
processing, if stored at room temperature or within 24
hours, if stored in the refrigerator.
CMV reduced RBCs
CMV reduced RBCs are used to reduce the risk of
transmitting CMV, which may be a cause of
considerable concern in newborns. CMV reduction can
be achieved by either leukoreduciton of blood
components, or by pre-selecting donors who are CMV
negative. Providing CMV reduced blood is important in
preterm infants, who have a more severe form of CMV
infection than term newborns.
Whole blood versus PRBC
Overriding indication for whole blood transfusion is
when there is need for concurrent replacement of
volume and coagulation factors (only fresh blood will
supply coagulation factors).
Reconstituted whole blood
It is obtained by resuspension of PRBCs, which is
frozen and deglycerolized. Red cells are frozen with
glycerol and stored at -80 oC in vapor phase of liquid
nitrogen. RBCs can be suspended in compatible but not
necessarily group-specific plasma. Reconstituted blood
can be used in case of rare blood groups or when
neonate has multiple antibodies from previous
transfusions so that compatible blood is difficult to
procure.
Practical Issues
Amount of transfusion to be given: It has been seen that
transfusion with PRBC at a dose of 20 mL/kg is well
tolerated and results in an overall decrease in
number of transfusions compared to transfusions
done at 10 mL/kg. There is also a higher rise in
hemoglobin with a higher dose of PRBCs.8
Properties of RBC products used in neonatal transfusion:
a. RBCs should be freshly prepared and should not
be more than 7 days old. This translates into a
high 2, 3-DPG concentration and higher tissue
extraction of oxygen. Other concerns with old
RBCs are hyperkalemia, and a reduced RBC life
span.
b. In small and sick neonates, where it is anticipated
that blood component therapy may be needed
more than once, it may help to have aliquots from
a single donor given as sequential transfusions.9
This is done practically by reserving a bag of fresh
Indian Journal of Pediatrics, Volume 75May, 2008

Blood and Blood Component Therapy in Neonates
PRBC for up to 7 days for a newborn and
withdrawing small aliquots required repeatedly
from that bag under laminar flow using a sterile
connecting device, into a fresh blood bag. The
PRBC bag is immediately resealed under the
laminar flow, and can be reused for withdrawing
similar small quantities of blood for up to 7 days.
Choosing the blood group for neonatal transfusions:4
a. It is preferable to take samples from both, mother
and the newborn, for initial testing prior to
transfusion. Mothers sample should be tested for
blood group and for any atypical red cell
antibodies.
b. ABO compatibility is essential while transfusing
PRBCs. Though ABO antigens may be expressed
only weakly on neonatal erythrocytes, neonates
serum may contain transplacentally acquired
maternal IgG anti-A and/or anti-B.
c. Blood should be of newborns ABO and Rh group.
It should be compatible with any ABO or atypical
red cell antibody present in the maternal serum.
d. In exchange transfusions for hemolytic disease of
newborn, blood transfused should be compatible
with mothers serum. If the mothers and the
babys blood groups are the same, use Rh negative
blood of babys ABO group. In case mothers and
babys blood group is not compatible, use group O
and Rh negative blood for exchange transfusion.
Volume and rate of transfusion
a. Volume of packed RBC = Blood volume (mL/kg)
x (desired minus actual hematocrit)/ hematocrit
of transfused RBC
b. Rate of infusion should be less than 10 mL/kg/
hour in the absence of cardiac failure.
c. Rate should not be more than 2 mL/kg/hour in
the presence of cardiac failure.
d. If more volume is to be transfused, it should be
done in smaller aliquots.
Expected response
Each transfusion of 9 mL/kg of body weight should
increase hemoglobin level by 3 g/dL. Meticulous
monitoring of input, output and vital signs are
mandatory during blood transfusion.
PLATELET TRANSFUSION
Thrombocytopenia is defined as platelet count less than
1.5 lakh/cubic mm. 10 Presence of thrombocytopenia
leads to an increase in risk of bleeding. Dysfunctional
Indian Journal of Pediatrics, Volume 75May, 2008
35 21
platelets in the presence of normal platelet counts may
also cause bleeding tendency. Thrombocytopenia has
been observed in 15% of newborns at birth.11-13 Severe
thrombocytopenia defined as platelet count of less than
50,000/cubic mm may occur in 0.10.5% of newborns.13-
14
In NICU, there is a higher incidence; with thrombo-
cytopenia being observed in up to 2235% of all babies
admitted to NICUs and in up to 50% of those admitted
to NICUs who require intensive care. Significant
proportions (20%) of these episodes of
thrombocytopenia are severe.15-16 Thus a large number of
neonates are at risk for bleeding disorders in NICU.
Immune thrombocytopenia
a. Neonatal alloimmune thrombocytopenia (NAIT)
The best choice of platelet transfusion is human platelet
antigen (HPA) compatible platelets, which are generally
maternal platelets, meticulously washed and
irradiated. The aim is to maintain the platelet count
above 30,000/ cubic mm.17 However; HPA compatible
platelets are not easily available. In the absence of
immunologically compatible platelets, random donor
platelet transfusions may be an acceptable alternative,
and has been shown to increase platelet counts above
40,000/cubic mm in most of the transfused patients.18
An alternative approach is the use of intravenous
immunoglobulin (IVIG) (1 g/kg/day on two
consecutive days or 0.5 g/kg/day for four days), alone
or in combination with random donor platelet
transfusion. 19
b. Neonatal autoimmune thrombocytopenia
The goal is to keep the count above 30,000/cubic mm.
IVIG is given if counts are less than the acceptable
minimum at a dose of 1 g/kg/day on two consecutive
days. 20
Nonimmunologically mediated thrombocytopenia
Low platelet count occurring at less than 72 hours of
age is caused most commonly by placental
insufficiency, maternal PIH, early onset sepsis (EOS),
and perinatal asphyxia. EOS and asphyxia may, in
particular, lead to severe thrombocytopenia.
Thrombocytopenia occurring beyond the initial 72
hours is most commonly caused by sepsis and
necrotising enterocolitis. Other infrequent causes
include intrauterine infections, metabolic errors and
congenital defects in platelet production.10, 16 Indications
for platelet transfusion in nonimmune thrombo-
cytopenia depend on the level of sickness of newborn
(Table 2).3
Types of platelets available
Random donor platelet (RDP)
Each unit of a random donor pool is obtained from a
491

Richa Jain et al
TABLE 2. Indications for Platelet Transfusion in Nonimmune
Thrombocytopenia in Newborn
Platelet count less than 30,000/cubic mm: transfuse all
neonates, even if asymptomatic
Platelet count 30,000 to 50,000/cubic mm: consider
transfusion in
a. Sick or bleeding newborns
b. Newborns less than 1000 gm or less than 1 week of age
c. Previous major bleeding tendency (IVH grade 3-4)
d. Newborns with concurrent coagulopathy
e. Requiring surgery or exchange transfusion
Platelet count more than 50,000 to 99,000/cubic mm:
transfuse only if actively bleeding
single whole blood unit. Multiple such units from many
donors can be pooled together or each such unit can be
given separately. PRBC is separated from the platelet
rich plasma, which is then respun at a higher speed to
make a concentrated platelet button
Single donor platelet (SDP)
SDP units are obtained by a process called
plateletpheresis. Here, from a single donor itself
multiple platelet units are separated. This is achieved
by returning RBCs and platelet poor plasma to donors
circulation after plateletpheresis. The procedure is
repeated 4 to 6 times, yielding 4 to 6 units of platelets
from one individual. It is especially useful to prevent
alloimmunization in multiply transfused patients. Both
SDPs and RDPs are irradiated. It is more cost effective to
screen the larger SDP units for bacterial contamination,
than to screen individual random donor units.21 The
concentration of platelets is more in SDP than in RDP,
with SDP having a platelet concentration of 3x1011/unit
and RDP having a concentration of 0.5x1010/unit. In
neonatal transfusion practice, RDP is generally
adequate to treat thrombocytopenia. SDP is required
only if prolonged and severe thrombocytopenia is
anticipated, requiring multiple platelet transfusions.
Platelet storage: Platelets are stored at 20C to 24C
using continuous gentle horizontal agitation in storage
bags specifically designed to permit O 2 and CO 2
exchange to optimize platelet quality. The storage time
from collection to transfusion of platelets (RDPs) is 5
days. SDPs can be stored for up to 7 days.
Practical Issues
Platelets should never be filtered through a
micropore blood filter before transfusion, as it will
considerably decrease the number of platelets.
Female Rh-negative infants should receive platelets
from Rh-negative donors to prevent Rh sensitization
from the contaminating red blood cells.
The usual recommended dose of platelets for
neonates is 1 unit of platelets per 10 kg body weight,
which amounts to 5 mL/kg. The predicted rise in
492
36 22
platelet count from a 5-mL/kg dose would be 20 to
60,000/cubic mm.15 Doses of up to 10-20 ml/kg may
be used in case of severe thrombocytopenia.9
PLASMA DERIVATIVES
Plasma contains about 1 unit/mL of each of the
coagulation factors as well as normal concentrations of
other plasma proteins. Labile coagulation factors, like
factors V and VIII, are not stable in plasma stored for
prolonged periods at 16 C; therefore plasma is
usually stored frozen at 18 C or lower. Fresh frozen
plasma (FFP) is stored within 8 hours of collection. It
contains about 87% of factor VIII present at the time of
collection and must contain at least 0.70 IU/mL of factor
VIII.22
Fresh frozen plasma
FFP has traditionally been used for a variety of reasons,
including volume replacement, treatment of
disseminated intravascular coagulopathy (DIC), during
the treatment of a bleeding neonate, for prevention of
intraventricular hemorrhage, and in sepsis.3 It has not
been shown to have any survival benefits in most of
these conditions and currently the only valid
indications for transfusing FFP in a newborn include
Disseminated intravascular coagulopathy
Vitamin K deficiency bleeding
Inherited deficiencies of coagulation factors
Other rare indications include patients with
afibrinogenemia, von Willebrand factor deficiency,
congenital antithrombin III deficiency, protein C
deficiency and protein S deficiency when specific factor
replacement is not available. It is also used for
reconstitution of blood for exchange transfusion.
Cryoprecipitate
It is prepared from FFP by thawing at 2 4 o C.
Undissolved cryoprecipitate is collected by
centrifugation and supernatant plasma is aseptically
expressed into a satellite bag.
Cryoprecipitate contains about 80 to 100 U of factor
VIII in 10-25 mL of plasma, 300 mg of fibrinogen and
varying amounts of factor XIII. It is stored at a
temperature of -20o C or below.
Indications for use of cryoprecipitate
Congenital factor VIII deficiency
Congenital factor XIII deficiency
Afibrinogenemia and dysfibrinogenemia
von Willebrand disease
Practical Issues:9
FFP should be group AB, or compatible with
Indian Journal of Pediatrics, Volume 75May, 2008
 37
Blood and Blood Component Therapy in Neonates
recipients ABO red cell antigens
Volume of FFP to be transfused is usually 1020 mL/
kg
Volume of cryoprecipitate to be transfused is usually
5 mL/kg.
TRANSFUSION ASSOCIATED RISKS
Blood transfusion reactions may be broadly classified
as
Infectious
Non-infectious
a. Acute
i. Immunologic
ii. Non-immunologic
b. Delayed
Infectious complications
In India, it is mandatory to test every unit of blood
collected for hepatitis B, hepatitis C, HIV/AIDS,
syphilis and malaria. 23 However, transfusion
transmitted infections are still a considerable risk,
because of the relative insensitivity of screening tests,
and several other organisms besides those tested for,
which may be transmitted through blood.
Viral infections: Transmissible diseases can be caused
by viruses like human immunodeficiency virus (HIV),
hepatitis B and C viruses (HBV & HCV), and
cytomegalovirus (CMV). Other uncommon viruses
like hepatitis G virus, human herpes virus-8 and
transfusion-transmitted virus have also been
detected. Viral infections contaminate platelet
products more commonly than RBC products due to
a higher temperature used for storage of platelet
products.24 Though screening for HIV, HBV and HCV
is mandatory in blood banks, other viruses still
present an unaddressed problem. Insensitivity of
pathogen testing is also an issue, and risk of viral
infections with blood transfusions remains real. Risk
of post transfusion hepatitis B/C in India is about
10% in adults despite routine testing because of low
viraemia and mutant strain undetectable by routine
ELISA. 25 HIV prevalence among blood donors is
different in various parts of the country.
CMV: Transfusion related CMV infections in
newborns were initially identified in the year 1969,
and since then transfusion associated CMV
transmission is a well known entity. It has been
reported that there is a seroconversion rate of 10-30%
in preterm newborns transfused with CMV positive
blood. Leukodepletion and selection of CMV
negative donors decreases the risk of transfusion
transmitted CMV.26
Bacterial infections: Bacteria in donor blood are
Indian Journal of Pediatrics, Volume 75May, 2008
23
derived from either asymptomatic bacteraemia in the
donor, or from inadequate skin sterilization leading
to bacterial contamination of the blood. Platelets are
at a higher risk of causing bacterial infection than
other blood components, as they are stored at room
temperature, leading to rapid multiplication of
infectious organisms. The highest fatality is seen
when the contaminating organism is a gram-
negative bacteria. In case of a febrile non-hemolytic
reaction post transfusion, bacterial contamination
always remains a possibility. It generally causes a
higher rise in temperature than other febrile
transfusion reactions.
Parasites: Plasmodium, trypanosome, and several
other parasites may be transmitted through blood,
depending on the endemicity of the area.
Transfusion transmitted malaria is not uncommon
in India, and may occur in spite of blood bag testing,
as the screening tests for malaria are insensitive.25
Prions : Variant Cruetzfold Jacob Disease ( v CJD) is
an established complication of blood transfusion
and has been reported since 2004. It is thought to
have an incubation period of approximately 6.5
years. There is no easy test as yet to detect the
presence of prions. It is not very clear whether leuko-
reduction prevents transmission of CJD.24 Restricted
transfusions and avoidance of transfusions unless
essential, are the only ways currently to prevent
transmission.
Noninfectious complications
These can be further sub classified as immune mediated
and nonimmune mediated reactions, and as acute and
delayed complications.
Acute immune mediated reactions
Immune mediated hemolysis : Acute hemolytic
transfusion reactions are a common cause of
transfusion related fatality in adult patients, but these
are rare in neonates. Newborns do not form red blood
cell (RBC) antibodies; all antibodies present are
maternal in origin.
(i) Newborns must be screened for maternal RBC
antibodies, including ABO antibodies if non-O
RBCs are to be given as the first transfusion.
(ii) If the initial results are negative, no further testing is
needed for the initial 4 postnatal months.
Infants are at a higher risk of passive immune
hemolysis from infusion of ABO-incompatible plasma
present in PRBC or platelet concentrates. Smaller
quantities of ABO-incompatible plasma (less than 5
mL/kg) are generally well tolerated. Newborns do not
manifest the usual symptoms of hemolysis that are
observed in older patients, such as fever, hypotension,
493
 38
Richa Jain et al
and flank pain. An acute hemolytic event may be
present as increased pallor, presence of plasma free
hemoglobin, hemoglobinuria, increased serum
potassium levels, and acidosis. Results of the direct
antiglobulin (Coombs) test may confirm the presence of
an antibody on the RBC surface. Treatment is mainly
supportive and involves maintenance of blood pressure
and kidney perfusion with intravenous saline bolus of
10 to 20 mL/kg along with forced diuresis with
furosemide. Enforcing strict guidelines for patient
identification and issue of blood; and minimizing
human error is essential in preventing immune
mediated hemolysis.
TRALI (Transfusion related acute lung injury): It refers to
noncardiogenic pulmonary edema complicating
transfusion therapy. It is a common and under-reported
complication occurring after therapy with blood
components. It has been associated with all plasma-
containing blood products, most commonly whole
blood, packed RBCs, fresh-frozen plasma, and platelets.
It has also been reported after the transfusion of
cryoprecipitate and IVIG. The most common symptoms
associated with TRALI are dyspnea, cough, and fever,
associated with hypo- or hypertension. It occurs most
commonly with in the initial 6 hours after transfusion.
The presence of anti-HLA and/or anti-granulocyte
antibodies in the plasma of donors is implicated in the
pathogenesis of TRALI. Diagnosis requires a high
index of suspicion, and confirmation of donor serum
cross-reacting antibodies against the recipient.
Treatment is mainly supportive in this self-limiting
condition. 27, 28
Febrile nonhemolytic transfusion reactions (FNHTR) are
suspected in the absence of hemolysis with an increase
in body temperature of less than 2C. For reactions
associated with a temperature rise of greater than 2C or
with hypotension, bacterial contamination also should
be suspected and a Gram stain and microbial culture
performed on the remaining blood product.
Allergic reactions : Allergic reactions are caused by
presence of preformed immunoglobulin E antibody
against an allergen in the transfused plasma, and are a
rare occurrence in newborns. In some cases, release of
residual cytokines or chemokines (e.g., RANTES) from
stored platelets also may cause allergic reactions. These
reactions are generally mild, and respond to
antihistaminics. Severe anaphylactic reactions are rare.
Acute non immune reactions
Fluid overload: Neonates are at increased risk of fluid
overload from transfusion because the volume of the
blood component issued may exceed the volume that
may be transfused safely into neonates. Care should
be taken to ensure that, in the absence of blood loss,
volumes infused do not exceed 10 to 20 mL/kg.
494
24
There is no role for routine use of furosemide while
transfusing newborns.
Metabolic complications:29 These complications occur
with large volume of transfusions like exchange
transfusions.
a) Hyperkalemia: In stored blood, potassium levels
tend to be high. It has been seen that after storage
for around 42 days, potassium levels may reach
50 meq/L in a RBC unit.30 Though small volume
transfusions o not have much risk of metabolic
disturbances, large volume transfusions may lead
to hyperkalemia. Washing PRBCs before
reconstituting with FFP before exchange
transfusion helps in preventing this complication.
b) Hypoglycemia: Blood stored in CPD blood has a
high content of glucose leading to a rebound rise
in insulin release 1-2 hours after transfusion. This
may lead to hypoglycemia and routine
monitoring is necessary, particularly after
exchange transfusion, after 2 and 6 hours, to
ensure that this complication does not occur.
c) Acid- base derangements: Metabolism of citrate in
CPD leads to late metabolic alkalosis. Metabolic
acidosis is an immediate complication occurring
in sick babies who cannot metabolize citrate.
d) Hypocalcemia and hypomagnesemia are caused by
binding of these ions by citrate present in CPD
blood.
Delayed complications
Alloimmunization: Alloimmunization is an
uncommon occurrence before the age of 4 months,
and is caused by transfusion of blood products with
are mismatched for highly immunogenic antigens
like Rh. 31
Transfusion associated graft versus host disease (TA-
GVHD): Newborns are at risk for TA-GVHD if they
have received intrauterine transfusions, exchange
transfusions, or are very small, or immuno-
compromised. Unchecked donor T cell proliferation
is the cause of TA-GVHD, and it can be effectively
prevented by leukoreduction of the transfused blood
products in at risk patients.
REFERENCES
1. Bell EF, Strauss RG, Widness JA, Mahoney LT, Mock DM et
al. Randomized Trial of Liberal Versus Restrictive
Guidelines for Red Blood Cell Transfusion in Preterm
Infants. Pediatrics 2005; 115 : 1685-1691.
2. Ohls R J. Transfusions in the Preterm Neonates. NeoReviews
2007;8 :377-386.
3. Murray NA, Roberts IAG. Neonatal transfusion practice.
Arch Dis Child FN 2004; 89 : 101-107.
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Blood and Blood Component Therapy in Neonates
4. Chatterjee K, Sen A. Step by Step Blood Transfusion Services. 1st
ed. New Delhi. Jaypee Publishers; 2006; 238-300.
5. Schroeder ML. Transfusion-associated graft-versus-host
disease. Br J Haematol 2002; 117 : 275-287.
6. Moroff G, Holme S, AuBuchon JP, Heaton WA, Sweeney
JD, et al. Viability and in vitro properties of AS-1 red cells
after gamma irradiation. Transfusion 1999; 39: 128-134.
7. Pelszynsky MM, Moroff G, Luban NLC, Taylor BJ, Quinones
RR. Effect of y Irradiation of Red Blood Cell Units on T-cell
Inactivation as Assessed by Limiting Dilution Analysis:
Implications for Preventing Transfusion-Associated Graft-
Versus-Host Disease. Blood 1994; 83 : 1683-1689.
8. Paul DA, Leef KH, Locke RG, Stefano JL. Transfusion
volume in infants with very low birth weight: a randomized
trial of 10 versus 20 ml/kg. J Pediatr Hematol Oncol 2002;
24 : 43-46.
9. British Committee for Standards in Haematology. Available
at: www.bcshguidelines.com. Accessed on April 20, 2008.
10. Roberts I,Murray NA. Neonatal thrombocytopenia: causes
and management. Arch Dis Child FN 2003; 88 : F359-F364.
11. Hohlfeld P, Forestier F, Kaplan C, Tissot JD, Daffos F. Fetal
thrombocytopenia: a retrospective survey of 5,194 fetal
blood samplings. Blood 1994; 84 : 1851-1856.
12. Burrows RF, Kelton JG. Incidentally detected
thrombocytopenia in healthy mothers and their infants. N
Engl J Med 1988; 319 : 142-145.
13. Sainio S, Jarvenpaa A-S, Renlund M, Riikonen S, Teramo K
et al. Thrombocytopenia in term infants: a population-
based study. Obstet Gynecol 2000; 95 : 441-446.
14. Uhrynowska M, Niznikowska-M M, Zupanska B. Neonatal
and maternal thrombocytopenia: incidence and immune
background. Eur J Haematol 2000; 64 : 42-46.
15. Castle V, Andrew M, Kelton J, Girm D, Johston M et al.
Frequency and mechanism of neonatal thrombocytopenia. J
Pediatr 1986; 108 : 749-755.
16. Murray NA, Howarth LJ, McCloy MP, Letsky EA, Roberts
IAG. Platelet transfusion in the management of severe
thrombocytopenia in neonatal intensive care unit (NICU)
patients. Transfus Med 2002; 12 : 35-41.
17. Rothenberger S. Neonatal alloimmune thrombocytopenia.
Ther Apher 2002; 6 : 32-35.
18. Kiefel V, Bassler D, Kroll H, Paes B, Giers G et al. Antigen-
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positive platelet transfusion in neonatal alloimmune
thrombocytopenia (NAIT). Blood 2006; 107 : 3761-3763.
19. Blanchette VS, Johnson J, Rand M. The management of
alloimmune neonatal thrombocytopenia. Baillieres Clin
Haematol 2000; 13 : 365-390.
20. Kelton JG. Idiopathic thrombocytopenic purpura
complicating pregnancy. Blood Rev 2002; 16 : 43-46.
21. Galel SA Therapeutic techniques: Selection of Blood
Components for Neonatal Transfusion. NeoReviews 2005; 6:
e351-e355.
22. Tucci M. Goal-directed blood transfusion therapies Current
Concepts in Pediatric Critical Care Refresher Course.
available at : http://sccmcms.sccm.org.accessed on april
15, 2008.
23. Choudhury LP, Tetali S. Ethical challenges in voluntary
blood donation in Kerala, India. J Med Ethics 2007; 33 : 140-
142.
24. Madjdpour C, Heindl V, Spahn DR. Risks, benefits,
alternatives and indications of allogenic blood transfusion.
Minerva Anestesiol 2006; 72 : 283-298.
25. Choudhury N, Phadke S. Transfusion transmitted diseases.
Indian J Pediatr 2001; 68 : 951-958.
26. Bowden RA, Slichter SJ, Sayers M, Weisdorf D, Cays M et al.
A Comparison of Filtered Leukocyte-Reduced and
Cytomegalovirus (CMV) Seronegative Blood Products for
the Prevention of Transfusion-Associated CMV Infection
After Marrow Transplant. Blood 1995; 86 : 3598-3603.
27. Yang X, Ahmed S, Chandrasekaran V. Transfusion-related
acute lung injury resulting from designated blood
transfusion between mother and child: a report of two cases.
Am J Clin Pathol 2004; 121 : 590-592.
28. Looney MR, Gropper MA, Manhay MA. Transfusion-
Related Acute Lung Injury. A Review. Chest 2004; 126: 249-
258.
29. Martin CR, Cloherty JP. Neonatal hyperbilirubinemia. In
Cloherty JP, Eichenwald ER, Stark AR, eds. Manual of
Neonatal Care. 5th ed. Philadelphia, Lippincott Willams and
Wilkins, 2004; 185-221.
30. Strauss RG. Transfusion approach to neonatal anemia.
NeoReviews 2000;1:e74-e80.
31. Galel S A, Fontaine MJ. Hazards of Neonatal Blood
Transfusion. NeoReviews 2006;7:e 69-e75.
495
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 44 26

Symposium on AIIMS Protocols in Neonatology IV

Chronic Lung Disease in Newborns

M. Jeeva Sankar, Ramesh Agarwal, Ashok K. Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar,
New Delhi, India

ABSTRACT
Chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) occurs in preterm infants who require respiratory support
in the first few days of birth. Apart from prematurity, oxygen therapy and assisted ventilation, factors like intrauterine/postnatal
infections, patent ductus arteriosus, and genetic polymorphisms also contribute to its pathogenesis. The severe form of BPD
with extensive inflammatory changes is rarely seen nowadays; instead, a milder form characterized by decreased alveolar
septation due to arrest in lung development is more common. A multitude of strategies, mainly pharmacological and
ventilatory, have been employed for prevention and treatment of BPD. Unfortunately, most of them have not been proved to
be beneficial. A comprehensive protocol for management of BPD based on the current evidence is discussed here. [Indian
J Pediatr 2008; 75 (4) : 369-376] Email: ashokdeorari_56@hotmail.com

Key words : Bronchopulmonary dysplasia; Prematurity; Prevention; Treatment

Chronic lung disease (CLD) or bronchopulmonary
dysplasia (BPD) occurs in preterm infants who require
mechanical ventilation and/or oxygen therapy for a
primary lung disorder in the initial few days after birth.
Though the incidence of CLD has largely remained
unchanged over the years, the improved survival of more
immature infants has led to increased numbers of infants
with this disorder.1 These infants are more likely to have
persistent respiratory symptoms requiring frequent
hospital admissions especially in the first two years after
birth.
DEFINITION AND INCIDENCE
The lack of uniformity in the diagnostic criteria for CLD
partly explains the wide variation in the reported
incidence among different centers.2 The initial diagnostic
criteria mandated continuing oxygen dependency during
the first 28 days of life with compatible clinical and
radiographic findings to label an infant as having BPD.3
The fact that many infants would have intervals in the
first few weeks during which they do not require any
supplemental oxygen signified the major drawback of this
definition. Later, it was proposed to use the need for
supplemental oxygen at 36 weeks postmenstrual age
(PMA) as the diagnostic criterion especially in preterm
very low birth weight (VLBW) infants. 4 The later
definition, used widely in clinical trials even now, has the
limitation of spuriously labeling more mature infants (e.g.,
those born at 34-35 weeks) as having CLD.
To address the inconsistencies in the diagnostic criteria,
the US National Institute of Health (NIH) organized a
consensus conference in the year 2000 which suggested a
new definition by incorporating many elements of the
previous definitions of BPD. The suggestion was to use
oxygen need for > 28 days and at 36 weeks PMA to
identify different severity of BPD (Table 1).5
Recently, Ehrenkranz et al validated the consensus
definition in a cohort of preterm (<32 weeks) extremely
low birth weight (ELBW) infants and reported an
incidence of 77% by the new criteria.6 Few reports are
available from the centers in India; one study from
Chandigarh found the incidence of CLD (defined as need
for oxygen at or beyond 28 days of life) to be 50% and 9%
in ELBW and VLBW infants respectively.7
PATHOGENESIS

CLD has a multifactorial etiology; the major risk factors

Correspondence and Reprint requests : Prof. Ashok K. Deorari,
Professor, Department of Pediatrics, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi 110029, India.
[Received March 24, 2008; Accepted March 24, 2008]
include prematurity, oxygen therapy, mechanical
ventilation, infection, patent ductus arteriosus (PDA), and
genetic predisposition.8 By far the most important factor
in the pathogenesis of CLD is prematurity. Exposure of

Indian Journal of Pediatrics, Volume 75April, 2008 369

 45
M.J. Sankar et al
TABLE 1. Definition of BPD5
Gestational age
< 32 weeks
Time point of assessment 36 weeks PMA or discharge*
Treatment with oxygen > 21% for at least 28 days
BPD
Mild Breathing room air at 36 weeks PMA or
discharge*
Moderate Need* for <30% oxygen at 36 weeks PMA
or discharge*
Severe Need for > 30% oxygen and/or positive
pressure (IMV/CPAP) at 36 weeks PMA
or discharge*
*- whichever comes first
(PMA, Postmenstrual age; BPD, bronchopulmonary dysplasia; IMV, Intermittent mandatory ventilation; CPAP, continuous positive
airway pressure)
immature lungs to high O2 concentrations and positive
pressure ventilation results in oxidative stress and
ventilator induced lung injury (barotrauma/volutruma).
The resulting injury and inflammation lead to abnormal
reparative processes in the lung. This is compounded by
inflammation resulting from infections (intra-uterine/
postnatal) that occur commonly in these infants. PDA
contributes further to this process by inducing pulmonary
edema and vascular endothelial injury. Recently, genetic
polymorphisms are also thought to play a role in the
causation of BPD.9
PATHOLOGY: OLD VS NEW BPD
The severe form of BPD (old BPD) seen in infants who
received aggressive ventilation and were exposed to high
inspired oxygen concentration from birth is rare
nowadays. This form was characterized by severe
morphological changes including emphysema, atelectasis,
and fibrosis and marked epithelial metaplasia and smooth
muscle hypertrophy in the airways and in the pulmonary
vasculature.10
In contrast, the milder forms of BPD (new BPD) seen
today occurs in infants who had only mild respiratory
failure requiring shorter duration of ventilation and/or
oxygen therapy immediately after birth. Pathologically,
this form is characterized by a striking decrease in
alveolar septation and impaired vascular development,
changes more compatible with an arrest in lung
development than with mechanical injury.11
CLINICAL AND RADIOLOGICAL FEATURES
Respiratory signs in infants with CLD include fast but
shallow breathing, retractions, and paradoxical breathing.
Rales and coarse rhonchi are usually heard on
auscultation.
370
27
> 32 weeks
> 28 days but < 56 days postnatal age or discharge*
> 21% for at least 28 days
Breathing room air at 56 days postnatal age or discharge*
Need* for <30% oxygen at 56 days postnatal age or
discharge*
Need for > 30% oxygen and/or positive pressure
(IMV/CPAP) at 56 days postnatal age or discharge*
Radiographic features of old and new BPD are quite
different, not surprising given the vastly different
pathologic findings. Old BPD, as originally described by
Northway, had four distinct stages: stage 1, consistent
with hyaline membrane disease; stage 2, opaque lung
fields with air bronchograms due to areas of atelectasis
alternating with emphysema; stage 3, small radiolucent
cysts; and stage 4, hyperinflated lungs with generalized
cystic areas and dense fibrotic strands. 10 In contrast,
infants with new BPD show only haziness reflecting
diffuse loss of lung volume or increased lung fluid.
Occasionally they have dense areas of segmental or lobar
atelectasis or pneumonic infiltrates, but they do not show
severe over inflation.
MANAGEMENT
Given the multitude of factors that contribute to the
pathogenesis of bronchopulmonary dysplasia, it is not
surprising that there is no magic bullet for its prevention
and/or treatment. Indeed, the best bet for prevention of
BPD would be to prevent preterm births itself, an
implausible option as of now.
PREVENTION
Prevention requires a multidisciplinary approach starting
right from the antenatal period.
ANTENATAL PERIOD
Use of antenatal steroids in mothers at risk for delivering
a premature infant reduces the incidence of neonatal
deaths and RDS but does not reduce the incidence of CLD.
This could arguably be due to increased survival of very
immature infants who are at high risk of BPD or because
of the to inability to detect a real protective effect.12
Antenatal thyrotropin-releasing hormone (TRH) has not
Indian Journal of Pediatrics, Volume 75April, 2008
 46
Chronic Lung Disease in Newborns
been effective in prevention of BPD.13
AFTER BIRTH
A. Ventilatory strategies
Given that no ideal pharmacological agents are available
for prevention of BPD, attention has now shifted to
optimal ventilatory strategies that would prevent/
reduce lung injury and permit adequate lung
development.
Continuous positive airway pressure (CPAP): Early
initiation of nasal CPAP has been shown to reduce the
need for intubation and mechanical ventilation. Since,
need for mechanical ventilation is one of the major risk
factors for BPD, use of early CPAP should logically reduce
its incidence. Numerous studies, mostly non-randomized,
have reported the benefits of early CPAP in minimizing
the need for mechanical ventilation and thes the incidence
of chronic lung disease.14 Surprisingly few randomized
controlled trials are available till date in this regard.
Recently, a multi-centric study on CPAP vs intubation and
ventilation in infants born at 25-28 weeks gestation found
significant reduction in the need for oxygen at 28 days of
life but not at 36 weeks PMA.15 Similarly, extubation to
CPAP following early surfactant administration
(INtubateSURfactantExtubate) has been shown to reduce
the need for mechanical ventilation but it is still uncertain
if BPD is reduced by this approach. Clearly, more
evidence is needed in this regard before coming to any
meaningful conclusion.
Nasal intermittent positive pressure ventilation (NIPPV):
NIPPV is a method of augmenting NCPAP by delivering
ventilator breaths via the nasal prongs. It is thought to
improve the tidal and minute volumes and decrease the
inspiratory effort required by neonates as compared to
nCPAP. This should reduce the need for reintubation thus
avoiding ventilator induced lung injury (VILI). The
Cochrane review that included three RCTs found a trend
towards reduction in the rates of chronic lung disease
with NIPPV (typical RR 0.73; 95% CI: 0.49, 1.07). 16
However, more trials are required to document the safety
and effectiveness of this relatively new modality.
Patient-triggered ventilation (PTV): Patient triggered
modes (SIMV, assist-control, and pressure support
ventilation) improve the infant-ventilator asynchrony; this
should theoretically reduce the risk of VILI. The Cochrane
review concluded that though PTV is associated with
shorter duration of ventilation, it does not reduce the
incidence of BPD.17
High-frequency ventilation (HFV): Animal studies
indicate that HFV could lead to less lung injury when
compared to conventional ventilation. However,
randomized controlled trials comparing elective use of
Indian Journal of Pediatrics, Volume 75April, 2008
28
HFV with conventional ventilation in preterm infants
have yielded conflicting results. A recent meta-analysis
that included 17 RCTs of conventional vs high frequency
ventilation found no significant difference in the incidence
of BPD. Therefore, elective use of HFV cannot be
recommended for preterm infants with RDS at present.18
Volume targeted ventilation: The observation that
volutrauma and not barotrauma is the primary
determinant of VILI has enthused neonatologists to use
volume controlled/targeted modes of ventilation in place
of conventional pressure controlled modes. Only a few
randomized trials are available in this regard till date. The
Cochrane review that included four RCTs found
significant reduction in the duration of ventilation and
pneumothorax rates but only a borderline reduction in the
incidence of BPD (typical RR 0.34; 95% CI: 0.11, 1.05).19
The trials did not report the combined outcome of BPD
and death as well as long term respiratory/
neurodevelopmental outcomes.
Permissive hypercapnia: Retrospective studies have
suggested that hypocapnia that occurs during assisted
ventilation is an independent risk factor for BPD.
Subsequently, minimal ventilation using smaller tidal
volumes / less peak inflation pressures while accepting
mild hypercapnia (PaCO2 45-55 mm Hg) was studied in
preterm infants. One such study in preterm ELBW infants
(target PaCO2 >52 mm Hg in the study group) reported
less need for mechanical ventilation but no reduction in
the need for supplemental oxygen at 36 weeks PMA.20
Clearly, more studies are needed to prove the intended
benefits of this promising strategy.
Permissive hypoxemia: Exposure to high oxygen
concentration has long been recognized as an important
factor in the pathogenesis of BPD. Preterm infants are
more vulnerable to the harmful effects of free oxygen
radicals. Surprisingly, there are few data to suggest either
the optimal oxygen level required or the optimum target
range for oxygen saturations (SpO 2) in these infants.
Observational studies suggest that in comparison with the
more liberal oxygen therapy, the restrictive approach of
accepting lower oxygen saturation values is associated
with decreased incidences of CLD and ROP. Two RCTs
have been conducted to evaluate whether it is better to
aim for high oxygen saturation in infants who are more
than a few weeks old: BOOST-trial and STOP-ROP trial.21,
22
Both these studies indicate that maintaining higher
oxygen saturation (>95%) is associated with increased
need for oxygen at 36 weeks PMA and greater use of
postnatal steroids and diuretics in premature infants
when compared to maintaining lower oxygen saturation
of 89-94%. Still, the uncertainty about optimal
oxygenation has led to wide variation of policies on
oxygen-monitoring and therapy in neonatal nurseries. In
response to the growing demand to resolve this
uncertainty, an international collaborative effort has been
371
 47
M.J. Sankar et al
mounted to conduct large multicentre RCTs, the results of
which may help determine the optimal oxygen saturation
targets in very premature infants.
B. Fluids and Nutrition
Fluid restriction: Anecdotal data indicate that relative fluid
restriction reduces the incidence of BPD in preterm
infants. However, systematic review of the studies on
fluid restriction has not found any significant reduction.23
Moreover, what represents fluid restriction in VLBW
infants is not definitely known. Hence, no definite
recommendation can be made regarding fluid restriction
as a strategy for reducing the incidence of BPD.
Nutrition: Nutrition plays an important role in lung
development and maturation. Aggressive parenteral
nutrition and early enteral feeding may help decrease the
incidence of BPD in VLBW infants.24 Ideally, nutritional
management should begin from day one of life to
minimize the respiratory morbidities. The initial
management should meet the estimated fluid, protein,
and energy needs. Since enteral feeding is often delayed
in these infants due to gastrointestinal immaturity,
parenteral nutrition with proteins and lipids should be
initiated as soon as possible after birth. It should be
continued until daily oral intake reaches at least 130 mL/
kg. Only expressed breast milk is to be used for enteral
feeding. Fortifying breast milk with human milk fortifier
(HMF) will make up for deficiencies of protein and
minerals like calcium and phosphorus. If fluids need to be
restricted, addition of fat such as medium chain
triglyceride (MCT) oil or glucose polymers will help in
achieving the adequate growth.
The role of specific nutrients (e.g., inositol, vitamin E,
selenium, glutamine etc. except for vitamin A) however,
remains speculative till now.
C. Pharmacological strategies
(i) Exogenous surfactant: Prophylactic surfactant therapy in
infants born before 30 weeks of gestation has not been
shown to reduce the incidence of BPD. However,
surfactant treatment for established RDS (rescue therapy)
in infants born at or after 30 weeks gestation is associated
with significant reduction in the incidence of BPD.25 The
apparent lack of effect in the first group could probably be
due to the increased survival of more immature infants
(similar to antenatal steroids).
(ii) Vitamin A: Vitamin A is essential for maintaining
the integrity of respiratory tract epithelial cells. Very
preterm infants are relatively deficient in vitamin A which
has been shown to be associated with CLD. A large RCT
of 807 infants with a birth weight of less than 1000 g has
shown that intramuscular vitamin A (5000 units three
times a week for 4 weeks from birth) decreases the risk of
CLD (OR 0.89; 95%CI 0.8-0.99).26 A meta-analysis of seven
RCTs has confirmed this finding.27 We use intramuscular
372
29
vitamin A (in the above said dose) for ELBW infants with
respiratory distress requiring supplemental oxygen or
mechanical ventilation at 24 hours of age.
(iii) Methylxanthines: Xanthines such as caffeine and
aminophylline have been routinely used for prevention/
treatment of apnea and for facilitation of extubation in
premature infants. Recently, a large RCT that used
caffeine for these indications in infants with birth weight
of 500-1250g has shown a significant reduction in the
incidence of BPD. The authors attributed this rather
unexpected finding to reduced duration of mechanical
ventilation in the caffeine treated group. 28 However,
caffeine is not available in India and one should be careful
before extrapolating the beneficial effects to
aminophylline. We use aminophylline after extubation
and for treatment of apnea of prematurity in preterm
VLBW infants.
(iv) Indomethacin / Ibuprofen therapy for PDA: Patent
ductus arteriosus is one of the major risk factors for BPD.
Hence, prevention or treatment of PDA should ideally
reduce its risk. However, prophylactic use of
indomethacin in very low birth weight infants has failed
to show any reduction in the incidence of BPD despite a
significant reduction in the incidence of PDA.29 Similar
results are obtained with ibuprofen, another drug used
for closure of PDA. 30 In contrast, treatment of
symptomatic PDA could possibly reduce the incidence of
BPD.31
(v) Postnatal steroids: Given that inflammation plays a
central role in the pathogenesis of BPD, steroids were
thought to be a natural choice for its management.
However, this therapy has turned out to be the most
controversial area of care following reports of adverse
neurodevelopmental outcomes. Conventionally, steroid
therapy for BPD is categorized into 3 broad groups based
on the timing of initiation: early (during the first 96 hrs
after birth), moderately early (between postnatal days 7
and 14), and delayed (after 3 weeks of age). Meta-analyses
of RCTs of the first two regimes have shown a significant
reduction in the incidence of BPD at 36 weeks PMA.32, 33
However, there are important concerns regarding both
short-term (hypertension, gastrointestinal perforation,
poor somatic growth) as well as long-term adverse effects
(neurodevelopmental outcomes including cerebral palsy).
One systematic review in this regard concluded that
infants who received steroids were twice as likely to
develop cerebral palsy as the control infants.34 In view of
these findings, routine early use of high-dose steroids is
not recommended at present. Considering the fact that no
other treatment options have proved to be consistently
beneficial in preventing BPD, some centers still
recommend moderately early use of steroids at lower
doses and for shorter duration in ventilator-dependent
infants. We use steroids occasionally in ELBW infants
who continue to be on mechanical ventilation even after
Indian Journal of Pediatrics, Volume 75April, 2008
 48
Chronic Lung Disease in Newborns
10-14 days of life (3-day course using low dose
dexamethasone). 35
Inhaled steroids thought to reduce the adverse effects
associated with systemic administration have not been
shown to be beneficial either for prevention or for
treatment.36
(vi) iNO: Animal studies have shown that iNO therapy,
in addition to causing pulmonary vasodilatation also
reduces lung inflammation and promotes lung growth.
Unfortunately, most clinical studies in preterm infants
with severe respiratory failure have not demonstrated any
reduction in the risk of death or CLD with iNO. 37
Recently, two large RCTs conducted in this regard
indicate that iNO therapy might be beneficial in a select
group of preterm infants. 38, 39 However, one should
remember that the appropriate dose, timing, duration,
and more importantly, the subgroup of infants who are
likely to benefit with this mode of therapy have not yet
been clearly defined. Moreover, the prohibitive cost of
iNO therapy precludes its use on a routine basis.
(vii) Diuretic therapy: Diuretics help by increasing the
reabsorption of fluid from the lungs. Though studies
have shown beneficial effects in lung physiology, no such
effects were observed in mortality or the incidence of
BPD. Coupled with the potential risks involved with long
term therapy, chronic use of furosemide or any other
diuretics cannot be recommended now. However,
diuretics can be used sparingly if there are clinical/
radiographic features of pulmonary edema in an infant
with evolving or established BPD.40 We use furosemide
0.5-1 mg/kg/day in infants with features suggestive of
excess lung fluid; we stop it after 24-48 hours if no
improvement is noted in the clinical condition.
(viii) Mast cell stabilizers: Cromolyn sodium has been
shown to decrease neutrophil migration and activation
thus minimizing inflammation in the lungs. Two trials
that have studied the possible role of cromolyn for
TABLE 2. BPD - Preventive Strategies and Their Current Status
Strategies Proven benefit Promising
(needs more studies)
Ventilatory - NIPPV
Volume targeted ventilation
Permissive hypercapnia
Permissive hypoxemia
Fluids and nutrition - Aggressive early enteral and
parenteral nutrition
Pharmacological Vitamin A Superoxide dismutase
Postnatal steroids
(but harmful as well)
(NIPPV, Nasal intermittent positive pressure ventilation; CPAP, continuous positive airway pressure; iNO, Inhaled nitric oxide; TRH,
Thyrotropin releasing hormone)
Indian Journal of Pediatrics, Volume 75April, 2008
30
prevention and treatment of BPD have not shown any
benefit.41
(ix) Bronchodilators: They have not been found to be
useful for prevention of BPD. 42
(x) Emerging therapies: Preterm infants are susceptible to
oxidant injury because they are deficient in antioxidant
enzymes. Hence, antioxidants such as superoxide
dismuatase (SOD) promise to be an exciting strategy for
prevention of BPD. A randomized trial that enrolled
around 300 infants proved the safe nature of the drug
CuZnSOD, but did not find any difference in the primary
outcome of BPD at 36 weeks PMA. Interestingly, SOD
treated infants had fewer episodes of respiratory illness at
I year of age suggesting that the drug could prevent long-
term lung injury caused by reactive oxygen species.43
Further studies are needed to define its exact role in the
management of BPD. Other antioxidants/free radical
scavengers like vitamins C and E, allopurinol, N-acetyl-
Cysteine have not been proved to be useful till now.
The options available for prevention and their current
status are summarized in table 2.
TREATMENT OF EVOLVING/ESTABLISHED BPD
There are extremely limited data from clinical trials on
which to base optimal ventilatory management in
established BPD. The major goal is to maintain adequate
gas exchange with as minimal support as possible. CPAP
and NIPPV should be attempted as much as possible. For
infants on ventilator, the settings should be titrated
keeping in mind the rapidly changing pulmonary
mechanics (increasing airway resistance as well as
improving compliance). Often, slow rates with long Ti are
needed as the disease progresses. Some neonates with
marked variability in compliance and resistance may
benefit from volume targeted ventilation. Similarly, PTV
Probably beneficial No benefit
(effects + )
Early CPAP High frequency
Patient triggered modes ventilation
Fluid restriction
Antenatal steroids Antenatal TRH
Exogenous surfactant Prophylactic
Methylxanthines indomethacin/ibuprofen
iNO therapy Inhaled steroids
Diuretics Bronchodilators
Mast cell stabilizers
373
 49 31

M.J. Sankar et al

may be useful in infants who fight the ventilator.44 agitation.

Accepting relatively high PaCO2 (45-55 mm Hg provided
pH >7.25) and slightly low saturations (88-93%) would
help in minimizing the ventilator settings and thus help in
early extubation (Table 3).
The role of drugs in evolving/established BPD is
minimal except in select group of infants (Table 3). Most
of the drugs used in this regard have already been
discussed under prevention of BPD. Diuretics and
bronchodilators can be used if the clinical condition
warrants but should be stopped if no response occurs
within 24-48 hours of initiation of therapy. This is
especially important in case of diuretic therapy. Steroids
initiated after 3 weeks of life (late regime) does not reduce
the need for oxygen at 36 weeks PMA but definitely
reduces the need for home oxygen therapy. However, it is
associated with increased incidence of growth failure and
hypertension.45 One should weigh the risk-benefit ratio
before initiating steroids for an infant with established
BPD. Infants with BPD spells (sudden episodes of
deterioration due to marked expiratory airflow limitation)
may require sedation and muscle relaxation to reduce
Infants developing BPD require 20 to 40% more
calories than their age-matched healthy controls. Their
caloric requirement varies from 120 to 150 Kcal/kg/day.
This can be achieved by fortifying breast milk with
human milk fortifier (HMF) or infant formula. For infants
who require more calories, fat supplementation (e.g. MCT
oil) is preferable to adding carbohydrates because of the
less pronounced effects on CO2 levels (Table 3).24
Fig. 1 summarizes the steps of prevention and
treatment of BPD (starting from the antenatal period until
the time of discharge) in a preterm VLBW infant.
REFERENCES
1. Smith VC, Zupancic JA, McCormick MC, Croen LA, Greene J,
Escobar GJ, Richardson DK. Trends in severe BPD rates
between 1994 and 2002. J Pediatr 2005; 146 : 469-473.
2. Bancalari E, Claure N. Definitions and diagnostic criteria for
bronchopulmonary dysplasia. Semin Perinatol 2006; 30 : 164-
170.
3. Bancalari E, Abdenour GE, Feller R, Gannon J.

TABLE 3. Management of Evolving or Established BPD#

Evolving BPD Established BPD

(2-4 weeks age) (>4 weeks age)

Ventilatory strategies Minimizing ventilatory support Minimizing ventilatory support

(e.g. using nCPAP whenever possible) Tolerating higher PaCO2 (55-60 mm Hg provided
Tolerating slightly higher PaCO2 (45-55 mm Hg pH >7.25)
provided pH >7.25) Target SpO2 : 89-94%
Target SpO2 : 88-93% If on IMV:
If on IMV: o Use PTV if possible
o Use PTV if possible o Slow rates (20-40/min)
o Slow rates (25-40/min) o Moderate PEEP (4-8 cm H2O)
o Moderate PEEP (4-5 cm H2O) o Longer Ti (0.4-0.7 sec)
o Moderate Ti (0.35-0.45 sec) o Larger tidal volume (5-8 mL/kg)
o Low tidal volume (3-6 mL/kg)
o Early extubation to CPAP

Pharmacological strategies
Methylxanthines to facilitate extubation Steroids:* Individualize based on the clinical
Steroids:* Consider in ELBW infants on ventilator condition
support even after 10-14 days of age
Specific management: Specific management:
o Diuretics for features of pulmonary edema o Bronchodilators for bronchospasm
o Bronchodilators for bronchospasm o Sedation and muscle relaxation for BPD
spells

Others Nutrition:
o Increase daily calorie intake to 120 to 150 Kcal/ Same as for evolving BPD
kg/d
o Give expressed breast milk fortified with HMF
o Use fat supplementation (e.g. MCT oil) for
providing additional calories
o Give multivitamin supplements to meet RDA
#
Modified from Reference 44
* Could result in potentially harmful effects including adverse neurodevelopmental outcomes; counsel parents before initiation of therapy
(nCPAP, nasal continuous positive airway pressure ;IMV, intermittent mandatory ventilation; PTV, patient triggered ventilation; PEEP,
positive end expiratory pressure; Ti, Inspiratory time; HMF, human milk fortifier; MCT, medium chain triglycerides; RDA, recommended
dietary allowance)

374 Indian Journal of Pediatrics, Volume 75April, 2008

 50 32

Chronic Lung Disease in Newborns

Antenatal period Antenatal steroids (2 doses of betamethasone 24 hrs apart)

At birth Avoid excessive pressure during resuscitation (use appropriate size bag for BMV)

Birth to 24 hrs
Fluids: 60-80 mL/kg/d
Nutrition: oral feeds - breast milk (MEN/full feeds) to be initiated in stable infants
Early CPAP
If on ventilator:
o Early rescue surfactant as indicated
o Settings: fast rates (50-60/min), moderate PEEP (4-5 cm H2O), short Ti (0.25-0.4 s)
o Target values- SpO2: 87-92%; PaCO 2 45-55 mm Hg; pH: 7.25-7.35
o Early extubation to CPAP
o Methylxanthines to facilitate extubation

Fluids: daily increment of 15-20 mL/kg/d to reach a maximum of 150 mL/kg/d by

24 hrs to 1 week
day7
Nutrition:
o Parenteral: TPN for ELBW infants till full enteral feeds are achieved
o Enteral: Gradually increase feed volume by 20-30 mL/kg/d if accepting well; give
only breast milk; fortify with HMF after reaching 100 mL/kg/d
If on ventilator:
o Settings and target values as above
o Extubate to CPAP if possible
o Methylxanthines to facilitate extubation
For ELBW infants on oxygen or ventilator support at 24 hrs: Inj. vitamin A 5000 units
IM thrice weekly for 4 weeks

1 to 4 weeks Fluids: 150 to 160 mL/kg/d

Nutrition: Fortify breast milk with HMF; add more calories if needed
If on ventilator:
o Settings and target values as in Table 3
o Extubate to CPAP as early as possible
Diuretics/steroids/bronchodilators as indicated (see Table 3)

> 4 weeks Fluids: 150 to 160 mL/kg/d

Nutrition: Fortify breast milk with HMF; add more calories if needed
If on ventilator:
o Settings and target values as in Table 3
o Extubate to CPAP as early as possible
Sedatives/steroids/bronchodilators as indicated (see Table 3)

Fig. 1. Flow-chart for management of BPD

(BMV, bag and mask ventilation; CPAP, continuous positive airway pressure; PEEP, positive end expiratory pressure; MEN, Minimal
enteral nutrition; ELBW, extremely low birth weight infants; TPN, total parenteral nutrition; HMF, human milk fortifier; PTV, patient
triggered ventilation; Ti, Inspiratory time)

Bronchopulmonary dysplasia: clinical presentation. J Pediatr Pediatrics 2005; 116 : 1353-1360.

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4. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM.
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5. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J
Respir Crit Care Med 2001; 163 : 1723-1729.
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Fanaroff AA, Wrage LA, Poole K; National Institutes of Child
Health and Human Development Neonatal Research
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consensus definition of bronchopulmonary dysplasia.
7. Narang A, Kumar P, Kumar R. Chronic Lung Disease in
Neonates: Emerging problem in India. Indian Pediatr 2002; 39:
158-162.
8. Kinsella JP, Greenough A, Abman SH. Bronchopulmonary
dysplasia. Lancet 2006; 29; 367 : 1421-1431.
9. Makri V, Hospes B, Stoll-Becker S, Borkhardt A, Gortner
L.Polymorphisms of surfactant protein B encoding gene:
modifi ers of the course of neonatal respiratory distress. Eur J
Pediatr 2002; 161 : 604-608.
10. Northway WH Jr, Rosan RC, Porter DY: Pulmonary disease
following respiratory therapy of hyaline-membrane disease.
Bronchopulmonary dysplasia. N Engl J Med 1967; 276 : 357.

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11. Jobe AH. The New BPD: an arrest of lung development.
Pediatr Res 1999; 46 : 641-643.
12. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis
of the randomized trials, 1972 to 1994. Am J Obstet Gynecol
1995; 173 : 322-335.
13. Crowther CA, Alfi revic Z, Haslam RR. Thyrotrophin
releasing hormone added to corticosteroids for women at risk
of preterm birth for preventing neonatal respiratory disease.
Cochrane Database Syst Rev 2004; 2: CD000019.
14. Avery ME, Tooley WH, Keller JB, Hurd SS, Bryan MH, Cotton
RB et al. Is chronic lung disease in low birth weight infants
preventable? A survey of eight centers. Pediatrics 1987; 79 : 26-
30.
15. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin
JB; COIN Trial Investigators. Nasal CPAP or intubation at
birth for very preterm infants. N Engl J Med 2008;14; 358 : 700-
708.
16. Davis PG, Lemyre B, De Paoli AG. Nasal intermittent positive
pressure ventilation (NIPPV) versus nasal continuous positive
airway pressure (NCPAP) for preterm neonates after
extubation. Cochrane Database of Systematic Reviews 2001; 3 :
CD003212.
17. Greenough A, Dimitriou G, Prendergast M, Milner AD.
Synchronized mechanical ventilation for respiratory support
in newborn infants. Cochrane Database of Systematic Reviews
2008; 3 : CD000456.
18. Thome UH, Carlo WA, Pohlandt F. Ventilation strategies and
outcome in Randomised Trials of High Frequency Ventilation.
Arch Dis Child 2005; 90 : F466-F473.
19. McCallionN, Davis PG, MorleyCJ. Volume-targeted versus
pressure-limited ventilation in the neonate. Cochrane Database
of Systematic Reviews 2005; 3: CD003666.
20. Carlo WA, Stark AR, Wright LL, Tyson JE, Papile LA,
Shankaran S et al. Minimal ventilation to prevent
bronchopulmonary dysplasia in extremely-low-birth-weight
infants. J Pediatr 2002; 141 : 370-374.
21. Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM.
Oxygen-saturation targets and outcomes in extremely preterm
infants. N Engl J Med 2003; 4; 349 : 959-967.
22. Supplemental Therapeutic Oxygen for Prethreshold
Retinopathy of Prematurity (STOP-ROP), a randomized,
controlled trial. I: primary outcomes. Pediatrics 2000; 105 : 295-
310.
23. Barrington KJ, Al-Hazzani FN. Fluid restriction for treatment
of preterm babies with chronic lung disease. (Protocol)
Cochrane Database of Systematic Reviews 2005; (3) : CD005389.
24. Biniwale MA, Ehrenkranz RA. The role of nutrition in the
prevention and management of bronchopulmonary dysplasia.
Semin Perinatol 2006; 30 : 200-208.
25. Engle WA; American Academy of Pediatrics Committee on
Fetus and Newborn. Surfactant-replacement therapy for
respiratory distress in the preterm and term neonate. Pediatrics
2008; 121 : 419-432.
26. Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L,
Ehrenkranz RA, Stoll BJ, Lemons JA, Stevenson DK, Bauer
CR, Korones SB, Fanaroff AA. Vitamin A supplementation
for extremely-low-birth-weight infants. National Institute of
Child Health and Human Development Neonatal Research
Network. N Engl J Med 1999; 340 : 1962-198.
27. Darlow BA, Graham PJ. Vitamin A supplementation for
preventing morbidity and mortality in very low birth weight
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28. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ,
Ohlsson A et al. Caffeine for Apnea of Prematurity Trial
Group. Caffeine therapy for apnoea of prematurity. N Engl J
Med 2006; 354 : 2112-2121.
29. Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS,
Saigal S et al. Trial of Indomethacin Prophylaxis in Preterms
(TIPP) Investigators. Long-term effects of indomethacin
prophylaxis in extremely-low-birth-weight infants. N Engl J
Med 2001; 344 : 1966-1972.
30. Shah SS, Ohlsson A. Ibuprofen for the prevention of patent
ductus arteriosus in preterm and/or low birth weight infants.
Cochrane Database Syst Rev 2006;(1):CD004213.
31. Clyman RI. Recommendations for the postnatal use of
indomethacin: an analysis of four separate treatment
strategies. J Pediatr 1996; 128 : 601-607.
32. Halliday HL, Ehrenkranz RA. Early postnatal (< 96 hours)
corticosteroids for preventing chronic lung disease in preterm
infants. Cochrane Database Syst Rev 2003; (1): CD001146.
33. Halliday HL, Ehrenkranz RA. Moderately early (714 days)
postnatal corticosteroids for preventing chronic lung disease
in preterm infants. Cochrane Database Syst Rev 2003; (1):
CD001144.
34. Barrington KJ. The adverse neuro-developmental effects of
postnatal steroids in the preterm infant: a systematic review of
RCTs. BMC Pediatrics 2001; 1: 114.
35. Sankar MJ, Deorari AK. Postnatal corticosteroids for chronic
lung disease (CLD). Indian Pediatr 2007; 44 : 531-539.
36. Shah V, Ohlsson A, Halliday HL, Dunn MS. Early
administration of inhaled corticosteroids for preventing
chronic lung disease in ventilated very low birth weight
preterm neonates (Cochrane Review). Cochrane Database Syst
Rev 2000; 2: CD001969.
37. Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory
failure in preterm infants. Cochrane Database Syst Rev 2006:
CD000509.
38. Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL et
al. Early inhaled nitric oxide therapy in premature newborns
with respiratory failure. N Engl J Med 2006; 355 : 354-364.
39. Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PJ et al.
Inhaled nitric oxide in preterm infants undergoing mechanical
ventilation. N Engl J Med 2006; 355 : 343-353.
40. Baveja R, Christou H. Pharmacological strategies in the
prevention and management of bronchopulmonary dysplasia.
Semin Perinatol 2006; 30 : 209-218.
41. Ng GY, Ohlsson A. Cromolyn sodium for the prevention of
chronic lung disease in preterm infants. Cochrane Database Syst
Rev 2001; (2) : CD003059.
42. Ng GY, da S, Ohlsson A. Bronchodilators for the prevention
and treatment of chronic lung disease in preterm infants.
Cochrane Database Syst Rev 2001; (3) : CD003214.A
43. Davis JM, Parad RB, Michele T et al. Pulmonary outcome at
one year corrected age in premature infants treated at birth
with recombinant CuZn superoxide dismutase. Pediatrics
2003; 111 : 469-476.
44. Ambalavanan N, Carlo WA. Ventilatory strategies in the
prevention and management of bronchopulmonary dysplasia.
Semin Perinatol 2006; 30 : 192-199.
45. Halliday HL, Ehrenkranz RA. Delayed (3 weeks) postnatal
corticosteroids for chronic lung disease in preterm infants.
Cochrane Database Syst Rev 2003; (1): CD001145.
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Symposium on AIIMS Protocols in Neonatology IV

Congenital Hypothyroidism
Vandana Jain1, Ramesh Agarwal2, Ashok K. Deorari2 and Vinod K. Paul2
1
Division of Pediatric Endocrinology, 2Division of Neonatology, Department of Pediatrics, All India Institute of
Medical Sciences Ansari Nagar, New Delhi, India

ABSTRACT
Congenital Hypothyroidism (CH) is one of the most common preventable causes of mental retardation with a worldwide
incidence of 1:4000 live births. Ideally universal screening at 3-4 days of age should be done for detecting CH. Abnormal
values on screening (T4 < 6.5 ug/dL, TSH > 20mu/L) should be confirmed by a venous sample (using age appropriate cut-
offs) before initiating treatment. Term as well as preterm infants with low T4 and elevated TSH should be started on L-thyroxine
at a dose of 10-15g/ kg/ day as soon as the diagnosis is made. Regular monitoring should be done to ensure that T4 is in
the upper half of normal range. The outcome of CH depends on the time of initiation of therapy and the dose of L-thyroxine
used with the best outcome in infants started on treatment before 2 weeks of age with a dose > 9.5g/ kg/ day. [Indian J
Pediatr 2008; 75 (4) : 363-367] Email: aranag@rediffmail.com

Key words : Congenital hypothyroidism; L-thyroxine; Newborn

Congenital Hypothyroidism (CH) is one of the most
common preventable causes of mental retardation. The
worldwide incidence is 1:4000 live births and the
estimated incidence in India is 1:2500-2800 live births.1
Thyroid dysgenesis is the commonest cause accounting
for 75-80% of all cases of CH.
Embryology and physiology of the thyroid in the fetus: The
thyroid gland originates as a proliferation of endodermal
epithelial cells at 3 to 4 weeks of gestation. Synthesis and
secretion of thyroxine (T4) and triiodothyronine (T3) starts
from 12 weeks of gestation. Hypothalamic-pituitary-
thyroid (HPT) axis begins to develop in the first trimester
and thyrotropin-releasing hormone (TRH) and thyroid
stimulating hormone (TSH) are also detectable by the end
of first trimester. However, the activity of HPT axis is low
with insufficient production of thyroid hormones by the
fetus until about 18-20 weeks of gestation. In the second
half of gestation, the T4 and TSH levels increase
progressively. In the first trimester, the fetus is dependent
on transplacental passage of thyroid hormones.
In the hypothyroid fetus, this transplacental passage of
maternal thyroid hormones is critical for neuroprotection
throughout the intra-uterine life. The cord blood T 4
concentration at birth in infants who are unable to
synthesize T4 is 30% of normal. In addition, there is
increased intracerebral conversion of T4 to T3, resulting in
Correspondence and Reprint requests : Dr. Ramesh Agarwal,
Assistant Professor, Department of Pediatrics, All India Institute of
Medical Sciences, Ansari Nagar, New Delhi 110029, India.
[Received March 17, 2008; Accepted March 17, 2008]
increased local availability of the physiologically more
important T3. Near normal cognitive outcome is possible
in even the most severely affected infants with CH as long
as postnatal therapy is initiated early in optimum doses
and maternal thyroid function is normal. In contrast,
when both maternal and fetal hypothyroidism are present
as in severe iodine deficiency, there is a significant
impairment in neuro-intellectual development despite
adequate therapy soon after birth.2
Neonatal physiology: After birth, the term baby
experiences a surge of TSH as a physiological response to
cold environment. The TSH concentration can rise to 80
mU/L and falls quickly in the first 24 hours, followed by
a slower decrease to below 10 mU/L after the first
postnatal week. The rise in TSH initiates increase of T4
and free T4(fT4) to 17 g/dL and 3.5 ng/dL, respectively
at 24 to 36 hours after birth with a slow decline to adult
values over 4-5 weeks. Preterm infants demonstrate a
similar but blunted response due to HPT axis immaturity.
ETIOLOGY OF CH
CH can be permanent or transient. Thyroid dysgenesis is the
commonest cause of permanent CH affecting 1 in 4000
live births. It is usually sporadic with a 2:1 female to male
preponderance. The cause is largely unknown but
maternal cytotoxic antibodies and genetic mutations
causing inactivation of thyroid receptor are sometimes
found (Table 1).
Thyroid hormone synthetic defects account for 10% of all

Indian Journal of Pediatrics, Volume 75April, 2008 363


V. Jain et al
cases. These are inherited as autosomal recessive
disorders. The defect can lie in iodide trapping or
organification, iodotyrosine coupling or deiodination and
thyroglobulin synthesis or secretion. The commonest of
these is a defect in the thyroid peroxidase (TPO) activity
leading to impaired oxidation and organification of iodide
to iodine. These disorders usually result in goitrous
hypothyroidism. Iodine deficiency is responsible for
endemic cretinism and hypothyroidism in some regions
of India.
TABLE 1. Etiology of CH
1. Permanent hypothyroidism.
b. Thyroid dysgenesis (aplasia, hypoplasia or ectopia).
c. Thyroid hormone biosynthetic defects.
d. Iodine deficiency (endemic cretinism).
e. Hypothalamic-pituitary hypothyroidism.
2. Transient hypothyroidism.
a. TSH binding inhibitory immunoglobulins
b. Exposure to goitrogens (iodides or antithyroid drugs).
c. Transient hypothyroxinemia of prematurity
d. Sick euthyroid syndrome
Hypothalamic- pituitary hypothyroidism has an incidence
of 1 in 100,000. It may be isolated or associated with
concomitant deficiency of other pituitary hormones and
present with hypoglycemia and microphallus. Transient
hypothyroidism due to transplacental transfer of TSH
binding inhibitory immunoglobulins (TBII) from mothers
with autoimmune thyroid disease is seen in 1: 50,000
births. Their effect wanes off by 3-6 months in the
majority but may last up to 9 months. Exposure to iodine in
sick preterm infants (e.g., application of povidone iodine
for skin disinfection) or intake of iodine containing
expectorants by pregnant mothers can lead to transient
hypothyroidism.
Transient hypothyroxinema of prematurity refers to low
serum concentration of thyroid hormones in up to 85% of
preterm infants in early postnatal life as compared to term
infants. The normal levels of fT4 and TSH in preterm
infants are presented in Table 2. 3 This reflects the
underdevelopment of the HPT axis, which cannot
compensate for the loss of maternal thyroid hormone in
preterm infants. There has been a concern that transient
hypothyroxinemia is associated with adverse
neurodevelopmental outcomes and decreased survival in
affected infants.4
Sick euthyroid syndrome reflects suppression of the
pituitarys response to TRH, with inappropriately low
TABLE 2. Reference Ranges for Serum Free T4 (fT4) and TSH in
Preterm Infants
Age in weeks Free T4 (ng/dl) TSH (mu/l)
25-27 06-2.2 0.2-30.3
28-30 0.6-3.4 0.2-20.6
31-33 1.0-3.8 0.7-20.9
34-36 1.2-4.4 1.2-21.6
364
57 35
TSH concentrations in the context of low T3 and in the
more severe cases, low T4 concentrations.
DIAGNOSIS
Newborn screening: Ideally universal screening at 3-4 days
of age should be done for detecting CH. Alternatively
cord blood can also be used if screening is being done
only for CH and not other inborn errors of metabolism.
Universal newborn screening is currently being done in
many parts of the world including Western Europe,
North America, Japan, Australia, and parts of Eastern
Europe, Asia, South America, and Central America. Three
approaches are being used for screening:
Primary TSH, back upT4
Primary T4, back up TSH
Concomitant T4 and TSH
In the first approach, TSH is measured first. T4 is
measured only if TSH is > 20mu/L. This approach is
likely to miss central hypothyroidism, thyroid binding
globulin deficiency and hypothyroxinema with delayed
elevation of TSH. In the second approach, T4 is checked
first and if low TSH is also checked. This is likely to miss
milder/ subclinical cases of CH in which T4 is initially
normal with elevated TSH. Concomitant measurement of
T4 and TSH is the most sensitive approach but incurs a
higher cost.5
Abnormal values on screening (T4 < 6.5 g/dL, TSH>
20mU/L) should always be confirmed by a venous
sample (using age appropriate cut-offs given in
Table 3)6, 7 before initiating treatment. Among infants with
proven CH, TSH is >50 mU/L in 90% and T4 is < 6.5 g/
dL in 75% of cases.
In the absence of universal screening, the newborns
with the following indications should be screened:
Family history of CH
History of thyroid disease or antithyroid medicine
intake in mother
Presence of other conditions like Downs syndrome,
trisomy 18, neural tube defects, congenital heart
disease, metabolic disorders, familial autoimmune
disorders and Pierre- Robbins syndrome which are
associated with higher prevalence of CH
Thyroid functions should be tested in any infant with
signs/ symptoms of hypothyroidism such as prolonged
jaundice, constipation, poor feeding, umbilical hernia,
macroglossia, wide open posterior fontanel and
edematous and dry skin. The test results should be
compared to the age related norms as presented in
table 3.
Once the diagnosis is established, further
Indian Journal of Pediatrics, Volume 75April, 2008

Congenital Hypothyroidism
TABLE 3. Reference Ranges for T4, fT4 and TSH in Term Infants
According to Age 6, 7
Age T4 (g/dl) fT4 (pg/ml) TSH (U/ml)
mean (range) mean (SD)/ range mean (range)
Cord blood 10.8 (6.6-15) 13.8 (3.5) 10.0 (1-20)
1-3 days 16.5 (11-21.5) * 5.6 (1-10)
4-7 days * 22.3 (3.9) * usually monitor with T4 (total) level. This assumes a
1-2 weeks 12.7 (8.2-17.2) * 2.3 (0.5-6.5)
2-6 weeks 6.5-16.3** 0.9-2.2 1.7-9.1**
6 weeks to 11.1 (5.9-1.3) * 2.3 (0.5-6.5)
12 months
*No data available ** data for median/mean not available
investigations to determine the etiology may be done.
These are considered optional because the initial
treatment is not altered by these. These investigations are
useful in infants with borderline thyroid function test
results and in determining whether CH is likely to be
transient or permanent. 8 A list of these diagnostic studies
is presented in table 4 and an algorithmic approach to
investigation in Fig. 1. If it is not possible to get the
investigations performed immediately, the therapy
should be started without any delay.9
TABLE 4. Diagnostic Studies for Evaluation of CH
1. Imaging Studies (will determine location and size)
a. Scintigraphy (99mTc or 123 I)
b. Sonography
2. Function Studies
a. 123 I uptake
b. Serum thyroglobulin
3. Suspected inborn error of T4 synthesis
a. 123I uptake and perchlorate discharge
4. Suspected autoimmune thyroid disease
a. Maternal and neonatal serum TBII measurement (not
routinely available)
5. Suspected iodine exposure or deficiency
a. Urinary iodine measurement
6.Ancillary test to determine severity of fetal hypothyroidism
a. Radiograph of knee for skeletal maturation
When should we ask for free T4 levels?
In most situations, T4 (total) levels are sufficient for
diagnosis of hypothyroidism and monitoring treatment.
Free T4 estimation is three times costlier and availability
of the test is limited. There are certain specific situations
when estimation of free T4 should be done6, 10:
In premature newborns, T4 (total) values may be low
because of abnormal protein binding or low levels of
thyroxine binding globulin (TBG) due to immaturity
of liver function or undernutrition. Therefore, free T4
values provide a better estimate of true thyroid
function in premature or sick newborns.
Free T4 should be asked for in case of finding a low
T4 with normal TSH. If free T4 is normal, it can be a
case of congenital partial (prevalence 1: 4000-12000
newborns) or complete (prevalence 1: 15000
Indian Journal of Pediatrics, Volume 75April, 2008
58 36
newborns) TBG deficiency. TBG levels should be
evaluated to confirm this but this test is not available
routinely. If free T4 is also low along with low T4
with normal TSH, central hypothyroidism should be
suspected.
During monitoring for adequacy of treatment, we
normal TBG level. This can be confirmed by
measuring free T4 or TBG levels once at the time of
the first post-treatment T4 measurement.
TREATMENT OF CH
Term as well as preterm infants with low T4 and elevated TSH
should be started on L-thyroxine as soon as the diagnosis
is made. The initial dose of L-thyroxine should be 10-
15g/ kg/ day with the aim to normalize the T4 level at
the earliest. Those infants with severe hypothyroidism
(very low T4, very high TSH and absence of distal femoral
and proximal tibial epiphyses on radiograph of knee)
should be started with the highest dose of 15g/ kg/
day.11
Monitoring of Therapy : T4 should be kept in the upper half
of normal range (10-16 g/dL) or free T4 in the 1.4 - 2.3
ng/dl range with the TSH suppressed in the normal
range. T4 and TSH levels should be checked according to
the following schedule:
0-6 months: every 6 weeks
6 months-3 years: every 3 months
> 3 years: 6 monthly
T4 and TSH should also be checked 6-8 weeks after any
dosage change.
It is equally important to avoid over treatment.
Adverse effects of over treatment include premature
fusion of cranial sutures, acceleration of skeletal
maturation and problems with temperament and
behavior.
Asymptomatic hyperthyrotropinemia: Elevated TSH with
normal T4 values are seen commonly. This
hyperthyrotropinemia can be transient or permanent.
Perinatal iodine exposure is the commonest cause of
transient elevation of TSH. Other causes of
hyperthyrotropinemia include defects in biological
activity of TSH or TSH receptor, a mild thyroid hormone
biosynthesis defect, subtle developmental defects or a
disturbance of the TSH feedback control system.
Hyperthyrotropinemia in newborns is usually treated but
in the presence of free T4 levels in upper half of normal
range, expectant management can be followed. In case of
starting treatment, a 6 week trial of putting the child off
therapy followed by measuring TSH and T4 levels should
be done at 3 years of age.
365
 59
V. Jain et al
Fig. 1. Approach to a newborn infant with positive screening test for CH
Preterm infants with low T4 and normal TSH levels
(Transient hypothyroxinemia of prematurity): Use of
levothyroxine in an attempt to normalize levels remains
controversial because there is insufficient evidence that
early treatment with thyroid hormone leads to improved
outcomes. Larger studies, especially in the extremely
preterm infants are needed to resolve this issue.12
Transient Hypothyroidism: Infants with presumed
transient hypothyroidism due to maternal goitrogenic
drugs need not be treated unless low T4 and elevated
TSH values persist beyond 2 weeks. Therapy can be
discontinued after 8-12 weeks. Intake of antithyroid drugs
366
37
can be continued by the hyperthyroid mothers during
breast feeding because concentration of these drugs is
very low in breast milk. If we have been able to document
the presence of TBII in an infant and are attributing
hypothyroidism to maternal autoimmune thyroiditis,
treatment should be started if T4 is low and continued for
3-6 months 6. However, when TBII estimation is not
available it is best to continue treatment till the age of 3
years and then give a trial off therapy for 6 weeks
followed by retesting of T4 and TSH to determine the
need for continuation of therapy.
The management has been summarized in Panel 1.
Indian Journal of Pediatrics, Volume 75April, 2008
 60
Congenital Hypothyroidism
PANEL 1. Management of Congenital Hypothyroidism
Abnormal values on screening (T4 < 6.5 ug/dL, TSH > 20mu/
L) should always be confirmed by a venous sample using age
appropriate cut-offs.
Investigations to determine the etiology such as scintigraphy
should be done as soon as the diagnosis is made. If it is not
possible, the therapy should be started without delay.
The initial dose of L-thyroxine should be 10-15g/ kg/ day
with the aim to normalize the T4 level at the earliest. T4 should
be kept in the upper half of normal range (10-16 g/dL) with
TSH level suppressed in the normal range.
Asymptomatic hyperthyrotropinemia should be treated unless
the free T4 levels are in upper half of normal range.
When treatment has been started in an infant with suspected
transient hypothyroidism or isolated increase in TSH or
borderline values of T4 and TSH, a 6 week trial of putting the
child off therapy followed by measuring TSH and T4 levels
should be done at 3 years of age.
OUTCOME
The best outcome occurs with L-thyroxine therapy started
by 2 weeks of age at 9.5g/kg or more per day, compared
with lower doses or later start of therapy. Residual defects
can include impaired visuospatial processing and
selective memory and sensorimotor defects. More than
80% of infants given replacement therapy before three
months of age have an IQ greater than 85 but show signs
of minimal brain damage, including impairment of
arithmetic ability, speech, or fine motor coordination in
later life.5 When treatment is started between 3-6 months,
the mean IQ is 71 and when delayed to beyond 6 months,
the mean IQ drops to 54.13
REFERENCES
1. Desai MP, Upadhye P, Colaco MP, Mehre M, Naik SP, Vaz FE
Indian Journal of Pediatrics, Volume 75April, 2008
38
et al. Neonatal screening for congenital hypothyroidism using
the filter paper thyroxine technique. Indian J Med Res 1994;
100: 36-42.
2. Fisher DA, Klein AH. Thyroid development and disorders of
thyroid function in the newborn. N Engl J Med 1981; 304 : 702
712.
3. Adams LM, Emery JR, Clark SJ, Carlton EI, Nelson JC.
Reference ranges for newer thyroid function tests in
premature infants. J Pediatr 1995; 126 : 122-127.
4. Nikta Forghani, Tandy Aye. Hypothyroxinemia and
prematurity. Neoreviews 2008; 9 : e66-e71.
5. American Academy of Pediatrics, Rose SR; Section on
Endocrinology and Committee on Genetics, American
Thyroid Association, Brown RS; Public Health Committee,
Lawson Wilkins Pediatric Endocrine Society, Foley T,
Kaplowitz PB, Kaye CI, Sundararajan S, Varma SK. Update of
newborn screening and therapy for congenital
hypothyroidism. Pediatrics 2006; 117 : 2290-303.
6. Fisher DA. Disorders of the thyroid in newborns and infants.
In Sperling MA, ed. Pediatric Endocrinology, 2 nd ed.
Philadelphia; Saunders, 2002; 161-186.
7. Fisher DA. Disorders of the thyroid in childhood and
adolescence. In Sperling MA, ed. Pediatric Endocrinology, 2nd
ed. Philadelphia; Saunders, 2002; 187-210.
8. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis
and management. Thyroid 1999; 9 : 735-740.
9. Fisher DA. Management of congenital hypothyroidism. J Clin
Endocrinol Metab 1991; 72 : 525-528.
10. Brown RS. The thyroid gland. In Brook CGD, Hindmarsh PC
eds. Clinical Pediatric Endocrinology, 4th ed. London; Blackwell
Science, 2001; 288-320.
11. LaFranchi SH, Austin J. How should we be treating children
with congenital hypothyroidism? J Pediatr Endocrinol Metab
2007; 20 : 559-578.
12. Postnatal thyroid hormones for preterm infants with transient
hypothyroxinaemia. Cochrane Database Syst Rev 2007:
CD005945.
13. Klien AH, Meltzer S, Kenny FM. Improved prognosis in
congenital hypothyroidism treated before age three months. J
Pediatr 1972; 81 : 912-915.
367
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 65 39

Symposium on AIIMS Protocols in Neonatology - V

Protocol for Administering Continuous Positive Airway

Pressure in Neonates
M. Jeeva Sankar, Jhuma Sankar, Ramesh Agarwal, Vinod K. Paul and Ashok K. Deorari

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi,
India

ABSTRACT

Continuous positive airway pressure (CPAP) is a simple, inexpensive and gentle mode of respiratory support in preterm
very low birth weight (VLBW) infants. It helps by preventing the alveolar collapse and increasing the functional residual
capacity of the lungs. Since it results in less ventilator induced lung injury than mechanical ventilation, it should theoretically
reduce the incidence of chronic lung disease in VLBW infants. Various devices have been used for CPAP generation and
delivery. The relative merits and demerits of these devices and the guidelines for CPAP therapy in neonates are discussed
in this protocol. [Indian J Pediatr 2008; 75 (5) : 471-478] Email: ashokdeorari_56@hotmail.com

Key words: Continuous positive airway pressure; Devices, Fixation; Treatment; Protocol

Continuous positive airway pressure (CPAP), often
thought to be the missing link between supplemental
oxygen and mechanical ventilation, is gaining immense
popularity in neonatal intensive care units. Being
technically simple, inexpensive and effective, it has
become the primary mode of respiratory support in
preterm very low birth weight (VLBW) infants. The
evidence, clinical studies, and the controversies
regarding its use have been extensively reviewed and
are not discussed here. 1, 2 This protocol deals mainly
with the practical aspects of CPAP administration in
neonates.
DEFINITION AND BACKGROUND
CPAP refers to the application of positive pressure to the
airway of a spontaneously breathing infant through out
the respiratory cycle.
The first clinical use of CPAP was reported by
Gregory et al in a landmark report in 1971. They
described the use of CPAP via endotracheal tube or a
head box in preterm infants with respiratory distress
syndrome (RDS).3 Shortly after this, Kattwinkel reported
Correspondence and Reprint requests : Prof Ashok K Deorari,
Professor, Department of Pediatrics, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi 110029, India.
[Received April 24, 2008; Accepted April 24, 2008]
successful use of nasal prongs to provide CPAP in these
infants. 4 After the initial enthusiasm, it gradually fell
out of favor in 1980s because of the advent of newer
modes of ventilation (such as high frequency
ventilation) and the perceived complications of CPAP
(such as air leak). However, reports of significantly
lower incidence of chronic lung disease (CLD) from
Columbia University unit that used more CPAP
(Hudson prongs) as compared to other North American
Centers have led to a resurgence of interest in CPAP
over the past 15 years.5
CPAP: HOW DOES IT WORK?
CPAP predominantly helps by preventing collapse of
the alveoli with marginal stability. This results in better
recruitment of alveoli thus increasing the functional
residual capacity (FRC). The physiologic effects of CPAP
are represented in fig. 1.
Components of CPAP system
The components of a CPAP system are:
Gas source: To provide continuous supply of warm
humidified and blended gases i.e., air and oxygen
Pressure generator: To create the positive pressure
in the circuit
Patient interface/delivery system: To connect the
CPAP circuit to the infants airway.

Indian Journal of Pediatrics, Volume 75May, 2008 471

 66 40

M.J. Sankar et al

CPAP

Fig. 1. Effects of CPAP

(FRC, functional residual capacity; V/Q, ventilation-perfusion ratio; PVR, pulmonary vascular resistance; PaCO 2 & PaO 2 ,
partial pressure of carbon-di-oxide and oxygen respectively in the arterial blood)

Devices used for pressure generation Bubble CPAP: A typical bubble CPAP setup is shown
in Panel 2. One has to remember that though classified
The pressure sources of CPAP can be broadly grouped
as a continuous flow device, flow may still need to be
into: 6
adjusted to maintain continuous bubbling in the water
Continuous flow devices
chamber and thus the required level of CPAP.
Variable flow devices (Fig. 2)

Fig. 2. Types of CPAP Devices

472 Indian Journal of Pediatrics, Volume 75May, 2008

 67 41

Protocol for Administering Continuous Positive Airway Pressure in Neonates

Variable flow CPAP: A typical example is the Infant flow Devices used for CPAP delivery (Patient interface)
driver (IFD). It uses the Bernoulli Effect via dual injector
Various devices used for CPAP delivery include:
jets directed towards each nasal prong to maintain a
constant pressure. If the infant requires more Nasal prongs (single/double or binasal)
inspiratory flow, the Venturi action of the injector jets
Long (or) nasopharyngeal prongs
entrains additional flow. When the infant makes a
spontaneous expiratory effort, there is a fluidic flip Nasal cannulae (Fig. 3)
that causes the flow to flip around and to leave the
generator chamber via the expiratory limb (Coanda Nasal masks
effect). So, unlike in the other methods of CPAP where Face mask, endotracheal, and head box are no longer
the infant has to exhale against the incoming gas flow, used for delivering CPAP in neonates.
the fluidic flip of the variable flow devices assist his
exhalation thus reducing the work of breathing. Endotracheal CPAP is not recommended because it
has been found to increase the work of breathing (infant
We use continuous flow CPAP by both conventional has to breathe through a straw).
ventilators and bubble CPAP device in our unit.
The advantages and disadvantages of each of these
The advantages and disadvantages of each of these methods have been summarized in table 2.
methods are given in table 1.
TABLE 1. A Comparison of CPAP Devices Used for Pressure Generation7

Device Examples Approximate Advantages Disadvantages Remarks

Cost (INR)

Conventional Bear Cub, Bird- 5 10 lakhs No need of Expensive Of practical utility in

ventilator VIP, Draeger separate Standard flow of units having ventilators
derived CPAP Baby log, equipment 5-8L/min may be but not so in a small
Newport, Can be easily insufficient in the hospital/nursing home
Sechrist, Siemens, switched over presence of high without a neonatal
SLE, etc. to mechanical leak ventilator.
ventilation, if Difficult to know
CPAP fails if the set flow is
sufficient or not
(insufficient flow
can lead to increased
WOB)

Stand-alone Lectromedik, 25,000 to Economical Most of them do Though inexpensive,

CPAP machines Meditrin, 80,000 Useful for small not have proper they have not been
(Indigenous Phoenix, hospitals blenders and/or tested adequately;
CPAP) Shreeyash, Zeal Can have bubble pressure niggling issues observed
CPAP option manometer during daily use

Bubble CPAP Indian: 50,000 to 80,000 Simple and Flow has to be It seems unlikely that
Mediserve, inexpensive altered to ensure oscillations delivered at
Meditrin Oscillations proper bubbling the nares are
Imported: 1,60,000 produced by It is difficult to transmitted up to the
Fisher & Paykel continuous detect high flow alveoli;
bubbling might which can lead Still, the stand-alone
contribute to gas to over distension option makes it an easy
exchange (akin to of the lungs and cost effective
HFV) proposition in
Can identify large developing countries
leaks at the nares
(bubbling stops)

Variable flow Arabella, IFD, 3 lakhs Maintains more Expensive On theoretical grounds,
devices Viasys SiPAP uniform pressure Requires more this device scores more
Might decrease the technical expertise than the other two;
WOB However the prohibitive
Recruits lung cost and the lack of
volume more evidence regarding its
effectively superiority preclude its
widespread use

(WOB, work of breathing; HFV, high frequency ventilation; IFD, infant flow driver)

Indian Journal of Pediatrics, Volume 75May, 2008 473


Fig. 3. CPAP Delivery Systems
T ABLE 2. Advantages and Disadvantages of Common CPAP delivery Systems
Delivery system
Nasal prongs
(single/binasal)
Example:
Argyle
Hudson
IFD prongs
Nasopharyngeal prongs
(e.g., using a cut
endotracheal tube)
Length is estimated by
measuring the distance from
the earlobe to the tip of the
chin or nose;
Tube placement is confirmed
by direct visualization of the
tip behind the uvula
Nasal cannulae
(with an outer diameter of
3mm and flows up to
2 L/min)
Nasal masks
(IFD, Infant flow driver)
In our unit, we use short bi-nasal prongs for delivering
CPAP (both ventilator and bubble CPAP).
Indications for CPAP
The common clinical indications of CPAP have been
474
68
M.J. Sankar et al
Advantages
Simple device
Lower resistance leads to
greater transmission
of pressure
Mouth leak acts like a
pop-off mechanism
Easy availability
Economical
More secure fixation
Ease of application
Minimal nasal trauma
42
listed in Panel 1.
Practically, CPAP is very useful in preterm (<35 weeks)
infants with respiratory distress/failure of any etiology.
Some of these indications have been briefly described
below:
RDS: The most common indication for CPAP is mild
to moderate RDS. It helps in this condition by
preventing collapse of alveoli with marginal stability.
The recruitment of more alveoli helps to increase the
FRC thus helping in better oxygenation (Fig. 1).
Numerous studies have proved its efficacy in
reducing the need for mechanical ventilation and
probably the incidence of chronic lung disease in
infants with RDS.10, 11
CPAP and surfactant: The beneficial effect of CPAP in
preterm infants (<29 to 30 weeks) could probably be
enhanced by administering surfactant. In this
approach, if respiratory distress progresses even
after initiating CPAP, the baby is intubated, given
Disadvantages Remarks
Relatively difficult to fix Studies have shown that they
Risk of trauma to nasal are more effective than
septum and turbinates nasopharyngeal prongs (in
Leak through mouth means post-extubation setting) 8
end expiration pressure
is variable
More easily blocked Though more economical and
by secretions easily available, they are found
Likely to get kinked to be inferior to short binasal
prongs8
Unreliable pressure delivery Mainly tried in apnea of
May need high flows to prematurity paucity of
generate pressure data in other conditions 9
if only oxygen is used Still experimental
(without air blender)
FiO2 delivered may be high
Large leaks around the
cannulae
Difficulty in obtaining an New generation masks are yet
adequate seal to be studied in detail
surfactant, and then extubated and put back on
CPAP again. Known as INSURE (Intubation-
Surfactant-Extubation), this approach might further
reduce the need for subsequent ventilation and
improve the outcome in extreme preterm infants.12
Indian Journal of Pediatrics, Volume 75May, 2008
 69
Protocol for Administering Continuous Positive Airway Pressure in Neonates
Panel 1. Indications for CPAP
Common indications
Respiratory distress syndrome (RDS)
Apnea of prematurity (especially obstructive apnea)
Post-extubation in preterm VLBW infants
Transient tachypnea of newborn (TTNB)/delayed
adaptation
Other indications
Pneumonia
Meconium aspiration/ other aspiration syndromes
Pulmonary edema/pulmonary hemorrhage
Laryngomalacia/ tracheomalacia/ bronchomalacia
However, clinical trials have not shown any
reduction in the incidence of CLD so far. More
studies are needed to confirm or refute its possible
beneficial effects. We do not routinely employ INSURE
technique at present.
Apnea of prematurity: The mechanism by which
CPAP helps in apnea of prematurity has been
explained before (Fig. 1). It is typically used when
clinically significant episodes persist despite optimal
methylxanthine therapy.
Post-extubation in VLBW infants: CPAP reduces the
incidence of apnea, respiratory acidosis, and
increased oxygen requirement in VLBW infants
extubated after a brief period of mechanical
ventilation.
Delayed adaptation/TTNB: In these conditions
associated with excess lung fluid, CPAP helps by
maintaining the lung expansion. Though useful in
premature infants, term and near-term neonates with
TTNB often do not tolerate this mode of respiratory
support.
Pneumonia: CPAP can be tried in stable infants with
mild to moderate respiratory distress due to
pneumonia. It helps in this condition by maintaining
the lung expansion preventing any collapse due to
fluids and secretions.
Meconium aspiration syndrome: Use of CPAP is a
contentious issue in this condition as most of the
infants would already have hyperexpanded lung
fields and CPAP might further aggravate it.
Moreover, these term infants are unlikely to tolerate
CPAP well. It is only indicated in a rare infant with
predominant collapse/atelectasis (preferably proven
by chest X-ray).
We use CPAP predominantly in preterm infants (<35
weeks and birth weight <1800g) with respiratory distress,
apnea of prematurity, delayed adaptation, and pneumonia;
also we extubate VLBW infants to CPAP routinely. We
occasionally use CPAP in near-term and term infants with
transient tachypnea and pneumonia.
Indian Journal of Pediatrics, Volume 75May, 2008
43
CONTRAINDICATIONS OF CPAP
The important contraindications for CPAP include:
Progressive respiratory failure with PaCO2 levels
>60 mmHg and/or inability to maintain
oxygenation (PaO2 <50 mmHg)
Certain congenital malformations of the airway
(choanal atresia, cleft palate, tracheo esophageal
fistula, congenital diaphragmatic hernia, etc.)
Severe cardiovascular instability (hypotension)
Poor respiratory drive (frequent apnea and
bradycardia) that is not improved by CPAP.
GUIDELINES FOR INITIATION OF CPAP THERAPY
When to initiate CPAP?
The timing of initiation of CPAP in preterm infants with
respiratory distress needs further elaboration.
Early CPAP: It is important to note that CPAP helps
mainly by preventing the alveolar collapse in infants
with surfactant deficiency. Once atelectasis and
collapse have occurred, CPAP might not help much.
Therefore, all preterm infants (<35 weeks) with any
sign of respiratory distress (tachypnea/chest in
drawing/grunting) should be started immediately on
CPAP.
Prophylactic CPAP: Extending this logic, some have
advocated use of prophylactic CPAP (before the onset
of respiratory distress) in preterm VLBW infants as
majority of them would eventually develop respiratory
distress. However, there is no evidence for any
additional benefit with this approach; indeed, there are
concerns regarding increased adverse effects such as
intraventricular hemorrhage. Hence, prophylactic
CPAP is NOT recommended at present.13
How to set up a CPAP apparatus?
The steps in setting-up a bubble CPAP are summarized
in Panel 2.
How to fix the CPAP delivery system (nasal cannula)
The most difficult aspect of using nasal CPAP is the
positioning and fixation of the patient interface. The
optimal technique of fixation depends on the type of
delivery system used; the exact technique used does not
matter as long as the device is secure and not
traumatizing.
Short binasal prongs: It is important to choose the
appropriate sized prong that snugly fits in the nasal
cavity to avoid a significant leak. However, to avoid
causing any injury, it should be fixed straight and not
pressed hard against the nasal septum.
We use a modified cap (made from adult cotton socks) and
475
 70 44

M.J. Sankar et al

Panel 2. Steps of Initiation and Nursing Care during CPAP7

A. How to set-up a bubble CPAP?

1. Connect the air and oxygen tubing (pressurized gases from either central manifold or from compressor and oxygen cylinder respectively)
2. Attach both to the air-oxygen blender
3. Set the flow using flow meter (usually at 5-8 L/min)
4. Set up the inspiratory limb:
a. From the flow meter to the humidifier and
b. From the humidifier to the patient end (e.g., nasal cannula); fill water in the humidifier and humidify the gases to 34-370C.
5. Set up the expiratory limb - from the patient end to a chamber filled with sterile water. Immerse it under the water up to the required depth
(which is determined by the intended pressure - e.g., to deliver 5 cm H20, immerse up to 5 cm mark in the tube).
6. Attach a pressure manometer at the patient end

7. Set required pressure and FiO2, low pressure alarm and apnea alarm
8. Occlude the patient end of the ventilator circuit with your palm and observe if:
a. Bubbling occurs in the water chamber - If there are no bubbles, look for any leak in the circuit; if no leak is found, increase the
flow by 1 L/min and recheck.
b. The set pressure is delivered (see the manometer reading) - If it is less than the set pressure, look for any leaks in the circuit/
around the cannula. If no leak is found, increase the flow and recheck.

B. Initiation of CPAP
1. Place a roll under infants shoulder to slightly extend the neck
2. Application of prongs:
a. Choose the correct size prong (the prongs should fill the nasal opening without stretching the skin)
b. Apply a thin strip of Tegaderm on overlying skin of septum
c. Place the prongs with the curve downwards and fix as shown in Fig. 4.
3. Attach the patient end of the ventilator circuit to the cannula
4. Attach a pulse-oximeter to the infant

C. Nursing Care
1. Monitor the infant frequently (see text); observe if the baby is comfortable
2. Pass an orogastric tube. Keep the proximal end of tube open. If the infant is being fed while on CPAP, close the tube for half an hour after
giving feeds and keep it open for the next 90 minutes (if fed 2 hourly).
3. Do regular but gentle nasal suction to clear the mucus 4 hourly or as and when required.
4. Clean the nasal cannula and check its patency once per shift.
5. Change the infants position regularly every 2-4 hours and check the skin condition frequently for redness and sores.

476 Indian Journal of Pediatrics, Volume 75May, 2008

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Protocol for Administering Continuous Positive Airway Pressure in Neonates

TABLE 3. Protocol for CPAP Therapy in Three Common Neonatal Conditions

Indications
RDS Apnea of prematurity Post extubation

How to initiate ?
Pressure Start at 5cm H 2 O Start at 4cm H 2 O Start at 4-5cm H 2O
FiO 2 0.5 (titrate based on SpO2 ) 0.21-0.4 (as decided by SpO 2 ) 0.05 to 0.1 above the
pre-extubation FiO2
What to do if there
is no improvement?
Pressure Increase in steps of 1-2cm H 2O to Increase up to 5cm H 2 O Increased in steps of 1-2cm
reach a maximum of 7-8 cm H2 O (further increase is not H 2 O to reach a maximum of
warranted usually in this 7-8cm H 2 O
condition - may lead to
hyperinflation)
FiO 2 Increase in steps of 0.05 (if FiO2 increase does not Increase in steps of 0.05 to a
oxygenation is still compromised) help much maximum of 0.8
up to a maximum of 0.8
Failure of CPAP Worsening respiratory distress (as Recurrent episodes of apnea
indicated by Silverman scoring) and/ requiring PPV
or hypoxemia (PaO 2 <50mmHg) /
hypercarbia (PaCO 2 >60mmHg)
despite CPAP pressure of 7-8 cm
H2 O and FiO 2 of 0.8
(Likely to occur in infants with severe (Likely to occur in infants (Likely to occur in ELBW infants
RDS, associated sepsis, and in ELBW with central apneas sepsis ) and in sepsis / pneumonia, PDA,
infants who have not received ANS) metabolic acidosis, and collapse)
Same as for RDS
Weaning from CPAP
When to wean When there is no respiratory distress No episodes of apnea/ Same as for RDS
and SpO 2 / blood gases are normal desaturation / bradycardia
for atleast 12-24 has hrs
How to wean Reduce FiO 2 in steps of 0.05 to 0.4, Same as for RDS
then decrease pressure in steps of
1-2cm H2O until 3-4 cm H 2 O
(infants clinical condition will guide
the speed of weaning)

tapes to secure the binasal prongs (Fig. 4). d. Abdominal girth

Steps of initiation and nursing care before and during Hazards/Complications of CPAP
CPAP
The steps of initiation and nursing care during CPAP CPAP though less invasive and generally safer than
therapy are given in Panel 2. IMV, is not free of side effects.
Pulmonary air leaks are probably the most
PROTOCOL FOR CPAP THERAPY important clinically significant adverse effect of
CPAP. 14 It occurs following over distension of the
lungs caused by inappropriately high pressures.
Protocol for CPAP therapy in the three most common They tend to occur when the lung compliance starts
clinical indications is given in table 3. improving and the oxygen requirements also show a
Monitoring while on CPAP reduction. One has to note that the two recent trials
on CPAP for RDS have shown either a trend or a
The following parameters need to be monitored while definite increase in the incidence of pneumothorax.15,
the infant is on CPAP: 16
Therefore, extra vigilance is required during CPAP
Continuous monitoring of respiratory rate, heart rate, therapy.
SpO2 Decreased cardiac output due to reduction in the
Serial monitoring of venous return, decreased right ventricular stroke
a. Severity of respiratory distress by using Downes or volume, and altered dispensability of left ventricle.17
Silverman score This effect can be minimized by using optimal CPAP
b. Arterial blood gases (ABGs) and achieving adequate intravascular volume.
c. Perfusion - CFT, BP, peripheral pulses, urine output Impedance of pulmonary blood flow with increased

Indian Journal of Pediatrics, Volume 75May, 2008 477

 72
M.J. Sankar et al
Fig. 4. Steps in Fixation of CPAP Nasal Cannula
pulmonary vascular resistance (with inappro-
priately high CPAP pressure)
Gastric distension and CPAP belly syndrome.
These complications are rarely seen nowadays. The
risk is further minimized by routine use of orogastric
tube.
Nasal irritation, damage to the septal mucosa, or
skin damage and necrosis from the fixing devices.
CONCLUSION
CPAP has been well established as the first line therapy
in the management of respiratory distress in preterm
VLBW infants. It helps by preventing alveolar collapse,
maintaining airway stability and stabilizing the chest
wall. Various devices, both for pressure generation and
for delivery of CPAP, are available for use in neonates.
The advantages and disadvantages of each device,
method of fixation of short binasal prongs, and a
protocol for initiation of CPAP have been discussed in
this protocol.
478
46
REFERENCES
1. Sankar MJ, Deorari AK. CPAP A gentler mode of
ventilation. J Neonatol 2007; 21 : 160-165.
2. Upadhyay A, Deorari AK. Continuous positive airway
pressure - a gentler approach to ventilation. Indian Pediatr
2004; 41 : 459-469.
3. Gregory GA, Kitterman JA, Phibbs RH et al. Treatment of
idiopathic respiratory distress syndrome with continuous
positive airway pressure. N Engl J Med 1971; 284 : 333-340.
4. Kattwinkel J, Nearman HS, Fanaroff AA, Katona PG, Klaus
MH. Apnea of prematurity. Comparative therapeutic
effects of cutaneous stimulation and nasal continuous
positive airway pressure. J Pediatr 1975; 86 : 588-592.
5. Avery ME, Tooley WH, Keller JP et al. Is chronic lung
disease in low birth weight infants preventable? A survey of
eight centers. Pediatrics 1987; 79 : 26-30.
6. Courtney SE, Barrington KJ.Continuous positive airway
pressure and noninvasive ventilation. Clin Perinatol 2007; 34:
73-92.
7. Anonymous. Continuous Positive Airway Pressure Machines.
In Deorari AK, Paul VK, eds. Neonatal Equipment. 3rd ed.
New Delhi, Sagar Publications; 2006, 129-137.
8. De Paoli AG, Davis PG, Faber B, Morley CJ. Devices and
pressure sources for administration of nasal continuous
positive airway pressure (NCPAP) in preterm neonates.
Cochrane Database of Syst Rev 2002: CD002977.
9. Sreenan C, Lemke RP, Hudson-Mason A et al. High-flow
nasal cannulae in the management of apnea of prematurity:
a comparison with conventional nasal continuous positive
airway pressure. Pediatrics 2001; 107 : 1081-1083.
10. Gittermann MK, Fusch C, Gittermann AR, Regazzoni BM,
Moessinger AC. Early nasal continuous positive airway
pressure treatment reduces need for intubation in very low
birth infants. Eur J Pediatr 1997; 156: 384-388.
11. Poets CF, Sens B. Changes in intubation rates and outcome
of VLBW -a population based study. Pediatrics 1996; 98:
24-27.
12. Verder H, Robertson B, Greisen G, Ebbesen F, Albertsen P,
Lundstron JT. Surfactant therapy and nasal continuous
positive airway pressure for newborns with respiratory
distress syndrome. Danish-Swedish Multicentre Study
Group. N Engl J Med 1994; 331: 1051-1055.
13. Subramaniam P, Henderson-Smart DJ, Davis PG.
Prophylactic nasal continuous positive airways pressure for
preventing morbidity and mortality in very preterm infants.
Cochrane Database of SystRev 2005: CD001243.
14. Hall RT, Rhodes PG. Pneumothorax and pneumome-
diastinum in infants with idiopathic respiratory distress
syndrome receiving CPAP. Pediatrics 1975; 55: 493.
15. Buckmaster AG, Arnolda G, Wright IM, Foster JP,
Henderson-Smart DJ. Continuous positive airway pressure
therapy for infants with respiratory distress in non tertiary
care centers: a randomized, controlled trial. Pediatrics 2007;
120 : 509-518.
16. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM,
Carlin JB; COIN Trial Investigators.Nasal CPAP or
intubation at birth for very preterm infants. N Engl J Med
2008; 358 : 700-708.
17. Tittley JG, Fremes SE, Weisel RD, Christakis GT, Evans PJ,
Madonik MM et al. Hemo-dynamic and myocardial
metabolic conse-quences of PEEP. Chest 1985; 88: 496-502.
Indian Journal of Pediatrics, Volume 75May, 2008
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Symposium on AIIMS Protocols in Neonatology V

Feeding of Low Birth Weight Infants

M. Jeeva Sankar, Ramesh Agarwal, Satish Mishra, Ashok K. Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar,
New Delhi, India

ABSTRACT
Optimal feeding of low birth weight (LBW) infants improves their immediate survival and subsequent growth and development.
Being a heterogeneous group comprising term and preterm neonates, their feeding abilities, fluid and nutritional requirements
are quite different from normal birth weight infants. A practical approach to feeding a LBW infant including choice of initial
feeding method, progression of oral feeds, and nutritional supplementation based on her oral feeding skills and nutritional
requirements is being discussed in this protocol. Growth monitoring, management of feed intolerance, and the essential skills
involved in feeding them have also been described in detail. [Indian J Pediatr 2008; 75 (5) : 459-469] Email: vinodpaul@
neonatalhealth.com

Key words : Low birth weight; Feeding; Expression of breast milk; Fortification; Growth monitoring

Globally, about 18 million infants are born with a birth
weight of <2500g every year.1 Though these low birth
weight (LBW) infants constitute only about 14% of the
total live births, they account for 60-80% of total neonatal
deaths.2 Most of these deaths can be prevented with extra
attention to warmth, prevention of infections and more
importantly, optimal feeding.
WHY IS IT IMPORTANT?
Nutritional management influences immediate survival
as well as subsequent growth and development of LBW
infants. Even simple interventions such as early initiation
of breastfeeding and avoidance of pre-lacteal feeding have
been shown to improve their survival in resource
restricted settings.3 Early nutrition could also influence the
long term neurodevelopmental outcomes; malnutrition at
a vulnerable period of brain development has been shown
to have deleterious effects in experimental animals.4
HOW IS IT DIFFERENT?
Term infants with normal birth weight require minimal
assistance for feeding in the immediate postnatal period -
they are able to feed directly from mothers breast. In
contrast, feeding of LBW infants is relatively difficult
because of the following limitations:
Though majority of them are born at term, a
significant proportion are born premature with
inadequate feeding skills. They might not be able to
breastfeed and would require other methods of
feeding such as spoon or gastric tube feeding.
These infants are prone to have significant illnesses in
the first few weeks of life; the underlying condition
often precludes enteral feeding.
Preterm very low birth infants (VLBW) infants have
higher fluid requirements in the first few days of life
due to excessive insensible water loss.
Since intrauterine accretion of nutrients occurs mainly
in the later part of the third trimester, VLBW infants
(usually born before 32 weeks gestation) have low
body stores at birth. Hence, they require
supplementation of various nutrients. Even term LBW
infants who are likely to be growth restricted need
higher calories for catch-up growth.
Because of the gut immaturity, they are more likely to
experience feed intolerance necessitating adequate
monitoring and treatment.
PROTOCOL FOR FEEDING LBW INFANTS

In this protocol, we address the following issues:

Correspondence and Reprint requests : Prof Vinod K. Paul,
Professor & Head, Department of Pediatrics, All India Institute of How to decide the initial method of feeding in a given
Medical Sciences, Ansari Nagar, New Delhi-110029, India LBW infant?
[Received April 23, 2008; Accepted April 23, 2008]

Indian Journal of Pediatrics, Volume 75May, 2008 459

 78
M.J. Sankar et al
For infants initiated on modes other than
breastfeeding:
a. How to progress to breastfeeding?
b. What milk to be given?
c. How much milk to be given?
What supplements are required?
How to assess the feeding adequacy and monitor the
growth?
How to identify and manage feed intolerance?
DECIDING THE INITIAL METHOD OF FEEDING
It is essential to categorize LBW infants into two major
groups sick and healthy - before deciding the method of
feeding.
Sick infants
This group constitutes infants with significant respiratory
distress requiring assisted ventilation, shock requiring
inotropic support, seizures, symptomatic hypoglycemia/
hypocalcemia, electrolyte abnormalities, renal/cardiac
failure, surgical conditions of gastrointestinal tract,
necrotizing enterocolitis (NEC), hydrops, etc. These
infants are usually started on intravenous (IV) fluids.
Enteral feeds should be initiated as soon as they are
hemodynamically stable with the choice of feeding
method based on the infants gestation and clinical
condition (see below).
It is important to realize that enteral feeding is
important even in sick neonates. Oral feeds should not be
delayed in them without any valid reason. Even infants
with respiratory distress and/or on assisted ventilation
can be started on enteral feeds once the initial acute phase
is over and the infants color, saturation and perfusion
have improved. Similarly, sepsis (unless associated with
shock/sclerema/NEC) is not a contraindication for
enteral feeding.
Healthy LBW infants
Enteral feeding should be initiated immediately after
TABLE 1. Maturation of Oral Feeding Skills and the Choice of Initial Feeding Method in LBW Infants5
Gestational age Maturation of feeding skills
< 28 weeks No proper sucking efforts
No propulsive motility in the gut
28-31 weeks Sucking bursts develop
No coordination between suck/swallow
and breathing
32-34 weeks Slightly mature sucking pattern
Coordination between breathing and
swallowing begins
>34 weeks Mature sucking pattern
More coordination between breathing and
swallowing
460
48
birth in healthy LBW infants with the appropriate feeding
method determined by their gestation and oral feeding
skills.
Maturation of oral feeding skills: Breastfeeding requires
effective sucking, swallowing and a proper coordination
between suck/swallow and breathing. These complex
skills mature with increasing gestation (Table 1).
The fetus is able to swallow amniotic fluid by as early
as 11 to 12 weeks gestation. Mouthing can be observed at
15 weeks but the coordinated sucking movements are not
usually present until about 28 weeks gestation. Single
sucks can be recorded manometrically at 28 weeks and
sucking bursts by 31 weeks gestation. A mature sucking
pattern that can adequately express milk from the breast
is not present until 32-34 weeks gestation.5 However, the
coordination between suck/swallow and breathing is not
fully achieved until 37 weeks of gestation.
The maturation of oral feeding skills and the choice of
initial feeding method at different gestational ages are
summarized in table 1.
THE INITIAL FEEDING METHOD
Traditionally, the initial feeding method in a LBW infant
is decided based on her birth weight. This is not an ideal
way because the feeding ability depends largely on
gestation rather than the birth weight.
However, it is important to remember that not all infants
born at a particular gestation would have same feeding
skills. Hence the ideal way in a given infant would be to
evaluate if the feeding skills expected for his/her
gestation are present and then decide accordingly (Fig. 1).
All stable LBW infants, irrespective of their initial
feeding method should be put on their mothers breast.
The immature sucking observed in preterm infants born
before 34 weeks might not meet their daily fluid and
nutritional requirements but helps in rapid maturation of
their feeding skills and also improves the milk secretion in
their mothers (Non-nutritive sucking).
Spoon/paladai feeding
In our unit, we use paladai feeding in LBW infants who
Initial feeding method
Intravenous fluids
Oro-gastric (or naso-gastric) tube feeding with occasional spoon/
paladai feeding
Feeding by spoon/paladai/cup
Breastfeeding
Indian Journal of Pediatrics, Volume 75May, 2008
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Feeding of Low Birth Weight Infants
are not able to feed directly from the breast. The steps of
paladai feeding are described in Panel 1.6
Intra-gastric tube feeding
The steps of intra-gastric tube feeding are given in Panel
2. Some of the controversial issues in gastric tube feeding
are discussed below:
Naso-gastric vs. oro-gastric feeding: Physiological studies
have shown that naso-gastric (NG) tube increases the
airway impedance and the work of breathing in very
preterm infants.7 Hence, oro-gastric tube feeding might be
preferable in these infants. We employ only oro-gastric tube
feeding in our unit.
Intermittent bolus vs. continuous intra-gastric feeding: There
are no differences in the time to reach full enteral feeding/
somatic growth/incidence of NEC between infants fed by
intermittent bolus or continuous intra-gastric feeding.8
Studies have shown that gastric emptying and duodenal
motor responses are enhanced in infants given continuous
intra-gastric feeding.9 But a major disadvantage of this
method is that the lipids in the milk tend to separate and
stick to the syringe and tubes during continuous infusion
Fig. 1. Deciding the Initial Feeding Method in LBW infants
Indian Journal of Pediatrics, Volume 75May, 2008
49
Panel 1. Steps of Paladai Feeding6
Place the infant in up-right posture on mothers lap
Keep a cotton napkin around the neck to mop the spillage.
Take the required amount of expressed breast milk by using
a clean syringe
Fill the paladai with milk little short of the brim;
Hold the paladai from the sides; DO NOT put your finger
Place it at the lips of the baby in the corner of the mouth
Tip the paladai to pour a small amount of milk into the
infants mouth
Feed the infant slowly; he/she will actively swallow the
milk
Repeat the process until the required amount has been fed
If the infant does not actively accept and swallow, try to
arouse him/her with gentle stimulation
While estimating the milk intake, deduct the amount of milk
left in the cup and the amount of estimated spillage
Wash the paladai with soap and water and then put in boiling
water for 20 minutes to sterilize before next feed
461

M.J. Sankar et al
Panel 2. Steps of Intra-gastric Tube Feeding6
Before starting a feed, check the position of the tube
Remove the plunger the syringe (ideally a sterile syringe
should be used)
Connect the barrel of the syringe to the end of the gastric tube
Pinch the tube and fill the barrel of the syringe with the
required volume of milk
Hold the tube with one hand, release the pinch and elevate the
syringe barrel
Let the milk run from the syringe through the gastric tube by
gravity; DO NOT force milk through the gastric tube by using
the plunger of the syringe
Control the flow by altering the height of the syringe.
Lowering the syringe slows the milk flow, raising the syringe
makes the milk flow faster
It should take about 10-15 minutes for the milk to flow into the
infants stomach
Observe the infant during the entire gastric tube feed. Do not
leave the infant unattended. Stop the tube feed if the infant
shows any of the following signs: breathing difficulty, change
in colour/ looks blue, becomes floppy, and vomiting
Cap the end of the gastric tube between feeds; if the infant is on
CPAP, the tube is preferably left open after about half an hour
Avoid flushing the tube with water or saline after giving feeds.
Fig. 2. Progression of Oral Feeding in Preterm LBW Infants
462
80 50
resulting in significant loss of energy and fat content. We
use intermittent bolus feeding in our unit.
Progression of Oral Feeds
All LBW infants, irrespective of their gestation and birth
weight, should ultimately be able to feed directly from the
mothers breast. For preterm LBW infants started on IV
fluids/OG tube/paladai feeding, the steps of progression
to direct and exclusive breastfeeding are summarized in
Fig. 2.
Term LBW infants started on IV fluids (because of their
sickness) can be put on the breast once they are
hemodynamically stable.
Special situations
Extremely low birth weight infants: They are usually
started on parenteral nutrition from day 1. Enteral feeds
in the form of trophic feeding or minimal enteral nutrition
(MEN) are initiated once the infant is hemodynamically
stable. Further advancement is based on the infants
ability to tolerate the feeds (See AIIMS protocol on
Minimal enteral nutrition).10
Severe IUGR with antenatally detected Doppler flow
abnormalities: Fetuses with abnormal Doppler flow such
Indian Journal of Pediatrics, Volume 75May, 2008
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Feeding of Low Birth Weight Infants
as absent/reversed end diastolic flow (A/REDF) in the
umbilical artery are likely to have had mesenteric
ischemia in utero. After birth, they have a significant risk
of developing feed intolerance and NEC.11 The timing of
initiation of oral feeds in these infants is controversial. We
usually delay feeding up to 48-72 hours in preterm (<35
weeks) infants with A/REDF.
Infants on CPAP/ventilation: These infants can be started
on OG tube feeds once they are hemodynamically stable.
But it is important to leave the tube open intermittently to
reduce gastric distension.
CHOICE OF MILK FOR LBW INFANTS
All LBW infants, irrespective of their initial feeding
method should receive ONLY breast milk. This can be
ensured even in those infants who are fed by paladai or
gastric tube by giving expressed breast milk (mothers
own milk or human donor milk).
Expressed breast milk (EBM): All preterm infants
mothers should be counseled and supported in expressing
their own milk for feeding their infants. Expression
should ideally be initiated within hours of delivery so that
the infant gets the benefits of feeding colostrum.
Thereafter, it should be done 2-3 hourly - this would
ensure that the infant is exclusively breastfed and also
helps in maintaining the lactation in the mother.
The steps of breast milk expression are given in Panel 3.
We counsel mothers for expression of breast milk soon
after delivery by demonstration and by using poster
(Annexure 1) & videos (available on our website:
www.newbornwhocc. org)
Expressed breast milk can be stored for about 6 hours at
room temperature and for 24 hours in refrigerator.
Donor human milk: In centers where optimal milk
banking facilities are available, donor human milk can be
used for feeding a LBW infant. At present, only a few
centers in India have standardized human milk banking
facilities. Hence, it is not a practical option in our country.
Special situations
Sick mothers/ contraindication to breastfeeding: In these rare
circumstances, the options available are
Formula feeds:
a. Preterm formula in VLBW infants and
b. Term formula in infants weighing >1500g at
birth
Animal milk: e.g., undiluted cows milk
Once the mothers condition becomes stable (or the
contraindication to breastfeeding no longer exists), these
infants should be started on exclusive breastfeeding.
Indian Journal of Pediatrics, Volume 75May, 2008
51
Panel 3. Steps of expression of breast milk6
The mother should wash her hands thoroughly.
She should hold a clean wide mouthed container near her
breast.
Ask her to gently massage the breast for 5-10 minutes
before expressing the milk (using the pulp of two fingers
or with knuckles of the fist in a circular motion towards
the nipple as if kneading dough). Massage should not
hurt her.
Ask her to put her thumb ABOVE the nipple and areola,
and her first finger BELOW the areola opposite the thumb.
She should support the breast with her other fingers.
Ask her to press her thumb and first finger slightly inward
towards the chest wall.
She should press her breast behind the nipple and areola
between her fingers and thumb. She must press on the
lactiferous sinuses beneath the areola.
Press and release, press and release. This should not hurt-
if it hurts, the technique is wrong. It may take some time
before milk starts coming.
Ask her to press the areola in the same way from the
SIDES, to make sure that milk is expressed from all
segments of the breast.
She should express one breast first till the milk flow slows;
then express the other side; and then repeat both sides.
Avoid rubbing or sliding her fingers along the skin.
Avoid squeezing the nipple itself. Pressing or pulling the
nipple cannot express the milk.
HOW MUCH MILK IS TO BE GIVEN?
It is essential to calculate the fluid requirements and feed
volumes for infants on paladai/gastric tube feeding.
Fluid requirement: The daily fluid requirement is
determined based on the estimated insensible water loss,
other losses, and urine output. Extreme preterm infants
need more fluids in the initial weeks of life because of the
high insensible water loss.
We usually start fluids at 80 mL and 60 mL/kg/day for
infants birth weights of <1500g and 1500-2500g
respectively. Further requirements are calculated by daily
estimation of weight loss/gain, serum sodium, urine
output and specific gravity. The usual daily increment
would be about 15-20 mL/kg/day so that by the end of
first week 150 mL/kg/day is reached in both the
categories. We usually reach a maximum of 180mL/kg/
day by day 14 (Refer to AIIMS protocol on Fluids and
electrolyte management in term and preterm neonates).12
Feed volume: After estimating the fluid requirements, the
individual feed volume to be given by OG tube or paladai
(2-hrly/3-hrly) should be determined.
463
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M.J. Sankar et al

multi-nutrient supplementation or fortification of breast

milk (cf. VLBW infants). However, vitamin D and iron
might still have to be supplemented in them. While iron
supplementation is mandatory for all infants, vitamin D is
contentious because of the paucity of the data regarding
its levels and deficiency status in different populations.
Some would argue that the daily requirement of vitamin
D is met usually by de novo synthesis in the skin
(following exposure to sun light) and hence no
supplementation is required. However, because LBW
infants are more at risk of orteopenia than healthy term
infants, most neonatal units tend to supplement vitamin
D in the dose of 200-400 IU/day.13, 14
One has to assess the mothers nutritional status, their
exposure to sun, and the infants exposure to sun before
adopting a policy for their respective unit(s).
We supplement both vitamin D and iron in infants with
birth weights of 1500-2499 grams; vitamin D (200 IU) is
started at 2 weeks and iron (2 mg/kg/day) at 2 months of
life; both are continued till 1 year of age (Table 2).
VLBW infants
These infants who are usually born before 32-34 weeks
gestation have inadequate body stores of most of the
nutrients. Expressed breast milk has inadequate amounts
of protein, energy, calcium, phosphorus, trace elements
(iron, zinc) and vitamins (D, E & K) that are unable to
meet their daily recommended intakes (Table 3). Hence,
these infants need multi-nutrient supplementation till
they reach term gestation (40 weeks postmenstrual age).
After this period, their requirements are similar to those
infants with birth weights of 1500-2499 grams.
Multi-nutrient supplementation can be ensured by one of
the following methods:

Annexure 1. Poster on the procedure of Expression of Breast Milk Supplementing individual nutrients e.g., calcium,
phosphorus, vitamins, etc.
NUTRITIONAL SUPPLEMENTATION By fortification of expressed breast milk:

LBW infants, especially those who are born preterm
require supplementation of various nutrients to meet their
high demands. Since the requirements of VLBW infants
differ significantly from those with birth weights of 1500-
2499 grams, they have been discussed separately.
Infants with birth weights of 1500-2500g
These infants are more likely to be born at term or near
term gestation (>34 weeks); hence, they do not require
Fortification with human milk fortifiers (HMF)
Fortification with preterm formula
Supplementing breast milk with minerals and vitamins:
The following nutrients have to be added to the expressed
breast milk to meet the VLBW infants high requirements:
Calcium1 and phosphorusa (140-160 mg/kg/d & 70-
80 mg/kg/d respectively for infants on EBM)

TABLE 2. Nutritional Supplements for Infants with Birth Weights of 1500-2499 g

Nutrients Method of supplementation Dose When to start Till when?

Vitamin D* Multivitamin drops/syrup 200-400 IU/day 2 weeks of life Till 1 year of age
Iron Iron drops/syrup 2 mg/kg/day (maximum 15mg/day) 6 8 weeks of age Till 1 year of age

*See text

464 Indian Journal of Pediatrics, Volume 75May, 2008

 83 53

Feeding of Low Birth Weight Infants

TABLE 3. Recommended Dietary Allowance in Preterm VLBW infants and the Estimated Intakes with Fortified/unfortified Human
Milk

At daily intake of 180 mL/kg

RDA* Only expressed EBM fortified with EBM fortified with Preterm
(Units/kg/day) breast milk# Lactodex-HMF formula (4g/100mL)
(4g/100mL)

Energy (kcal) 105-130 117 144 153

Protein (g) 3.5-4.0 2.46 3.2 3.4
Carbohydrates (g) 10-14 11.6 16.84 15.58
Fat (g) 5.4-7.2 6.8 7.1 9.06
Calcium (mg) 210 43.2 223 103
Phosphorus (mg) 110 22.2 112 52
Vitamin A (IU) 90-270 680 3308 980
Vitamin D (IU/day) 400 3.5 903 40
Vitamin E (IU) >1.3 1.9 6.3 3.6
Vitamin B1 (mcg) > 48 36.2 79.4 231
Vitamin B2 (mcg) > 72 84.2 156.2 564.2
Vitamin B6 (mcg) > 42 25.7 115.7 221
Folic acid (mcg) 39.6 6 150 36
Zinc (mg) >0.6 0.6 0.96 0.96
Remarks Deficient in protein, calcium, Deficient in protein Deficient in calcium,
phosphorus, and vitamins phosphorus, vitamin D,
B1, B6 and D; Zinc content and folic acid; protein is
is slightly less than the RDA slightly less.

* AAPCON 200415
#
Based on preterm mature milk (after 2 weeks of delivery)
(RDA, recommended dietary allowance; EBM, expressed breast milk)

Vitamin D 2 (400 IU/day), vitamin B complex and
zinc b (about 0.5mg/day) usually in the form of
multivitamin drops
Folate (about 50 mcg/kg/day) 3
Iron (2 mg/kg/day)4
a. Eg. Syr. Ostocalcium (Glaxo SmithKline Co.). Syr.
Ossopan-D (TTK Healthcare)
b. E.g. Dexvita drops (Tridoss Co.), Visyneral-zinc
drops (Lifeon Co.), Dexvita drops (Tridoss Co.)
c. E.g. Folium (Speciality Meditech Co.) Folvite
(Wyeth Lederie Co.)
d. E.g. Ferrochelate (Albert David Co.) Tonoferon
(East India Co.)
However, one has to remember that supplementation of
minerals and vitamins would not meet the high protein
requirements of these infants (Table 3). Hence, this
method is usually not preferred.
To avoid abnormal increase in the osmolality, these
supplements should be added at different times in the
day.
Fortification with HMF. Fortification of expressed breast
milk with HMF increases the nutrient content of the milk
with out compromising its other beneficial effects (such as
reduction of NEC, infections, etc.). Experimental studies
have shown that the use of fortified human milk results in
net nutrient retention that approaches or is greater than
expected intrauterine rates of accretion in preterm
infants.16 Though there are concerns about the increase in
osmolality, clinical studies have not shown any significant
adverse effects following fortification of human milk. The
Cochrane review on fortification found short term
improvement in weight gain, linear and head growth
with out any increase in adverse effects such as NEC.17
The standard preparations of human milk fortifiers
(HMF) used in developed countries are not available in
India. The only preparation available (Lactodex-HMF,
Raptakos, Brett & Co. Ltd; Rs. 10/- per sachet) has some
limitations: inappropriately high vitamin A, no iron, etc.
Short of other options, it may still have to be used in
VLBW infants. One study from Chandigarh has reported
better growth with its use.18
As seen from table 3, preterm VLBW infants on
expressed breast milk fortified with HMF do not require
any supplementation (except for iron).
Fortification with preterm formula: The other option
available for fortification is preterm formula (e.g., Dexolac
Special Care [Wockhardt Co.], Pre-Lactogen [Nestle Co.]).
The recommended concentration is 0.4g per 10mL of
breast milk. Though more economical than fortification by
HMF, this method has two major drawbacks - it is
difficult to measure such small amounts of formula
powder and the RDA of some minerals and vitamins (e.g.,
calcium, phosphorus, vitamin D, folic acid) are not met
even after fortification. While the former problem can be
managed to a certain extent by using a small scoop of 1g
size for 25mL of milk, the later is circumvented by
additional supplementation (Table 3).

Indian Journal of Pediatrics, Volume 75May, 2008 465

 84 54

M.J. Sankar et al

The recommended dietary allowances (RDA) and the
estimated intakes with fortified human milk are given in
table 3.
Fortification/supplementation in VLBW infants
Summary:
The protocol for nutritional supplementation in VLBW
infants until 40 weeks PMA and beyond is described in
tables 4 and 5.
We use HMF fortification for all preterm (<32 weeks) VLBW
infants. It is started once they reach 150 mL/kg/day of enteral
feeds in the dose recommended by the manufacturer (4g [2
sachets] /100mL of expressed breast milk). We start iron at 4-6
weeks in the dose of 2mg/kg/day.
If HMF is unavailable or parents could not afford it, we
fortify EBM with preterm formula (0.4g/10 mL). Since
calcium, phosphorus, and vitamin D intakes are low even
after fortification with formula, we supplement these
nutrients additionally (Table 4). We also add zinc and
iron as mentioned before.
We continue fortification till the infant reaches 40 weeks
PMA or attains 2 kg (whichever is later).
GROWTH MONITORING OF LBW INFANTS
Regular growth monitoring helps in assessing the
nutritional status and adequacy of feeding; it also
identifies those infants with inadequate weight gain.
All LBW infants should be weighed daily till the time
of discharge from the hospital. Other anthropometric
parameters such as length and head circumference should
be recorded weekly.
Both term and preterm LBW infants tend to lose
weight (about 10% and 15% respectively) in the first 7
days of life; they regain their birth weight by 10-14 days.
Thereafter, the weight gain should be at least 15-20g/kg/
day till a weight of 2-2.5 kg is reached. After this, a gain of
20 to 30 g/day is considered appropriate.19
Growth charts: Using a growth chart is a simple and
effective way to monitor the growth. Serial plotting of
weight and other anthropometric indicators in the growth
chart allows the individual infants growth to be
compared with a reference standard. It helps in early
identification of growth faltering in these infants.

TABLE 4. Nutritional Supplementation in VLBW Infants Till 40 Weeks PMA

Type of feeding

Nutrients Only expressed EBM fortified with EBM fortified with Preterm formula
breast milk* Lactodex-HMF*

Calcium Start calcium supplements
(140-160 mg/kg/day) once the infant is
on full enteral feeds
(e.g. Syr. Ostocalcium at 8-10mL/kg/d)
Phosphorus Start supplements (70-80 mg/kg/day)
once the infant is on full enteral feeds
(e.g., Syr. Ostocalcium at 8-10mL/kg/d)
Zinc and Start multivitamin supplements once the
vitamins infant is on full feeds
B1, B6 (e.g., ViSyneral zinc / Dexvita drops at
0.5mL/day)
Vitamin D (Usually obtained from multivitamin drops
and calcium supplements that contain
vitamin D)
Folic acid Start supplements once the infant is on
full feeds
(e.g., Folvite/folium drops at 0.3 mL/day)
Iron Start iron (2 mg/kg/d) at 4-6 weeks of life
(e.g., Tonoferon drops at 2 drops/kg/day)
Not needed Start calcium supplements to meet the RDA
once the infant is on full enteral feeds
(e.g., Syr. Ostocalcium at 5-6mL/kg/d)
Not needed Start supplements to meet the RDA once the infant
is on full enteral feeds (e.g., Syr. Ostocalcium at
5-6mL/kg/d)
Not needed Not needed
Not needed (Usually obtained from multivitamin drops and
calcium supplements that contain vitamin D)
Not needed Start supplements once the infant is on full feeds
(e.g., Folvite/folium at 0.1 mL/day)
Start iron (2 mg/kg/d) Start iron (2 mg/kg/d) at 4-6 weeks of life
at 4-6 weeks (e.g., Tonoferon drops at 2 drops/kg/day)
(e.g., Tonoferon drops
at 2 drops/kg/day)

(PMA, postmenstrual age; EBM, expressed breast milk; HMF, human milk fortifier)
Note: The examples quoted are only indicative; Readers are encouraged to use similar products of their choice.

TABLE 5. Nutritional Supplementation in VLBW Infants After 40 Weeks PMA

Nutrients Method of Dose Till when?

supplementation

Vitamin D Multivitamin drops/syrup 200-400 IU/ day Till 1 year of age

Iron Iron drops/syrup 2 mg/kg/day (maximum 15mg/day) Till 1 year of age

466 Indian Journal of Pediatrics, Volume 75May, 2008

 85
Feeding of Low Birth Weight Infants
Two types of growth charts are commonly used for
growth monitoring in preterm infants: intrauterine and
postnatal growth charts. Of these, the later chart is
preferred because it is a more realistic representation of
the true postnatal growth (than an intrauterine growth
chart) and also shows the initial weight loss that occurs in
the first two weeks of life. The two postnatal charts that
are most commonly used for growth monitoring of
preterm VLBW infants are: Wrights and Ehrenkranz
charts.20, 21 We use either of these in our unit.
Once the preterm LBW infants reach 40 weeks PMA,
WHO growth charts should be used for growth
monitoring.
When to Discharge?
After they reach 34 weeks gestation and are above
1400g
AND Show consistent weight gain for at least 3
consecutive days.
MANAGEMENT OF INADEQUATE WEIGHT GAIN
Inadequate weight gain is a common and pertinent
problem in LBW infants. It starts at the time of initial
admission and continues after discharge resulting in
failure to thrive and wasting in the first year of life. The
common causes are summarized in Panel 4.
Management of inadequate weight gain consists of the
following steps:
Proper counseling of mothers and ensuring adequate
support for breastfeeding their infants; includes
assessment of positioning/attachment, managing
sore/flat nipple etc.
Explaining the frequency and timing of both
breastfeeding and spoon/paladai feeds: Infrequent
feeding is one of the commonest causes of inadequate
weight gain. Mothers should be properly counseled
regarding the frequency and the importance of night
feeds. A time-table where mother can fill the timing
and amount of feeding is very helpful in ensuring
frequent feeding.
Giving EBM by spoon/paladai feeds after
breastfeeding also helps in preterm infants who tire
out easily while sucking from the breast.
Proper demonstration of the correct method of
expression of milk and paladai feeding: It is important
to observe how the mother gives paladai feeds; the
technique and amount of spillage should be noted.
This should be followed by a practical demonstration
of the proper procedure.
Initiating fortification of breast milk when indicated
Management of the underlying condition(s) such as
Indian Journal of Pediatrics, Volume 75May, 2008
55
anemia, feed intolerance,etc.
If these measures are not successful, increase either
the
Energy (calorie) content of milk by adding MCT oil,
corn starch, etc. Infants on formula feeds can be
given concentrated feeds (by reconstituting 1 scoop
in 25 mL of water) OR
Feed volume to 200 mL/kg/day.
Panel 4. Causes of inadequate weight gain
1. Inadequate intake
Breastfed infants:
Incorrect feeding method (improper positioning/
attachment)*
Less frequent breastfeeding, not feeding in the night hours*
Prematurely removing the baby from the breast (before the
infant completes feeds)
Infants on spoon /paladai feeds:
Incorrect method of feeding* (e.g., excess spilling)
Incorrect measurement/calculation
Infrequent feeding
Not fortifying the milk in VLBW infants
Energy expenditure in infants who have difficulty in
accepting spoon feeds
2. Increased demands
Illnesses such as hypothermia/cold stress*, bronchopulmonary
dysplasia
Medications such as corticosteroids
Underlying disease/pathological conditions
Anemia*, hyponatremia, late metabolic acidosis
Late onset sepsis
Feed intolerance and/or GER
* Common conditions
(EBM, expressed breast milk; GER, gastroesophageal reflux)
FEED INTOLERANCE
The inability to tolerate enteral feedings in extremely
premature infants is a major concern for the pediatrician
/neonatologist caring for such infants. Often, feed
intolerance is the predominant factor affecting the
duration of hospitalization in these infants.
There are no universally agreed-upon criteria to define
feed intolerance in preterm infants. 17 Various clinical
features that are usually considered to be the indicator(s)
of feed intolerance are summarized below (Panel 5):
Panel 5. Indicator(s) of feed intolerance17
Symptoms
1. Vomiting (altered milk/bile or blood-stained)*
2. Systemic features: lethargy, apnea
Signs
1. Abdominal distension (with or without visible bowel
loops)*
2. Increased gastric residuals: >2mL/kg or any change from
previous pattern
3. Abdominal tenderness
4. Reduced or absent bowel sounds
5. Systemic signs: cyanosis, bradycardia, etc.
* Common signs
467
 86
M.J. Sankar et al
Fig. 3. Approach to feed intolerance in LBW infants
Of these, vomiting, abdominal distension, and increased
gastric residual volume form the triad for defining feed
intolerance.
Vomiting: The characteristic of vomitus is important in
assessing the cause: while altered milk is usually
innocuous, bile- or blood-stained aspirate should be
thoroughly investigated.
Abdominal distension: It is essential to serially monitor
the abdominal girth in all preterm LBW infants admitted
in neonatal nursery. This helps in early identification of
feed intolerance and eliminates the need for routine
gastric aspirate.
Gastric residual volume: It indicates the rapidity of
468
56
gastric emptying. Since several factors (both systemic and
local) influence the gastric emptying, the residual volume
is a poor and non-specific indicator of fed intolerance.
Measures to enhance the specificity - by quantifying the
volume and by using different cut-offs for defining feed
intolerance - have not been found to be much useful.
Moreover, repeated gastric aspiration to look for residuals
could injure the delicate mucosa aggravating the local
pathology.
We monitor the abdominal girth every 2 hours in all preterm
LBW infants admitted in the nursery. We do not routinely
aspirate the gastric contents before giving next feed. It is done
only if there is an increase in abdominal girth by >2 cm from
the baseline.
Indian Journal of Pediatrics, Volume 75May, 2008
 87
Feeding of Low Birth Weight Infants
Management of feed intolerance
The common factors attributed to feed intolerance in
preterm infants are: immature intestinal motility,
immaturity of digestive enzymes, underlying medical
conditions such as sepsis, inappropriate feed volume, and
giving hyperosmolar medications/feedings, and
importantly, necrotizing enterocolitis (NEC).
While issues such as feed volume and osmolality can
be controlled to an extent, feed intolerance due to
immaturity is rarely amenable to any intervention;
conservative management till the gut attains full maturity
is often the only option left.
The steps in evaluation and management of an infant
with feed intolerance are given in fig. 3.
CONCLUSION
Optimal feeding of LBW infants is important for the
immediate survival as well as for subsequent growth.
Unlike their normal birth weight counterparts, these
infants have vastly different feeding abilities and
nutritional requirements. They are also prone to develop
feed intolerance in the immediate postnatal period. It is
important for all health care providers caring for such
infants to be well versant with the necessary skills
required for feeding them. It is equally important to have
a protocol based approach to manage various issues that
occur while feeding them.
REFERENCES
1. UNICEF. State of the Worlds Children 2005. New York:
UNICEF, 2004.
2. Bang A, Reddy MH, Deshmukh MD. Child mortality in
Maharashtra. Economic Political weekly 2002; 37 : 4947-4965.
3. Edmond KM, Kirkwood BR, Tawiah CA, Agyei SO. Impact of
early infant feeding practices on mortality in low birth weight
infants from rural Ghana. J Perinatol 2008; [Epub ahead of
print]
4. Levitsky DA, Strupp BJ. Malnutrition and the brain: changing
concepts, changing concerns. J Nutr 1995; 125 : 2212S2220S.
5. Omari TI, Rudolph CD. Gastrointestinal Motility. In: Polin RA
and Fox WW eds. Fetal and Neonatal Physiology, 2 nd ed.
Philadelphia, WB Saunders Co, 1998; 1125-1138.
6. Anonymous. Feeding. In Deorari AK, Paul VK, Scotland J,
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McMillan DD, Singhal N eds. Practical Procedures for the
Newborn Nursery, 2nd ed. New Delhi, Sagar Publishers, 2003:
71-78.
7. Stocks J. Effect of nasogastric tubes on nasal resistance during
infancy. Arch Dis Child 1980; 55 : 17-21.
8. Premji SS, Chessell L. Continuous nasogastric milk feeding
versus intermittent bolus milk feeding for premature infants
less than 1500 grams. Cochrane Database of Systematic Reviews
2001, Issue 1. Art. No.: CD001819.
9. DeVille KT, Shulman RJ, Berseth CL. Slow infusion feeding
enhances gastric emptying in preterm infants compared to
bolus feeding. Clin Res 1993; 41 : 787A.
10. Mishra S, Agarwal R, Jeevasankar M, Deorari AK, Paul VK.
Minimal enteral nutrition. Indian J Pediatr 2008; 75 : 267-269.
11. Dorling J, Kempley S, Leaf A. Feeding growth restricted
preterm infants with abnormal antenatal Doppler results. Arch
Dis Child Fetal Neonatal Ed 2005; 90 : F359-F363.
12. Chawla D, Agarwal R, Deorari AK, Paul VK. Fluid and
electrolyte management in term and preterm neonates. Indian
J Pediatr 2008; 75 : 255-259.
13. Annonymous. Nutrition. In Edmond K, Bahl R, eds. Optimal
feeding of law-birth weights infnats Technical Review. World
Health Organization 2006; 42.
14. Abrams SA. Abnormalities of serum calcium and magnesium.
In Cloherty JP, Eichenwald EC, Stark AR eds. Manual of
Neonatal Care. 6th ed. Philadelphia: Lippincott Williams &
Wilkins 2008; p558.
15. American Academy of Pediatrics Committee on Nutrition:
Nutritional needs of preterm infants. In Kleinman RE ed.
Pediatric Nutrition Handbook American Academy of Pediatrics. Elk
Grove Village, IL, American Academy of Pediatrics, 2004; 23-
54.
16. Schanler RJ, Garza C. Improved mineral balance in very low
birth weight infants fed fortified human milk. J Pediatr 1987;
112 : 452-456.
17. Kuschel CA, Harding JE. Multicomponent fortified human
milk for promoting growth in preterm infants. Cochrane
Database of Systematic Reviews 1998, Issue 4. Art. No.:
CD000343.
18. Mukhopadhyay K, Narnag A, Mahajan R. Effect of human
milk fortification in appropriate for gestation and small for
gestation preterm babies: a randomized controlled trial. Indian
Pediatr 2007; 44 : 286-290.
19. Schanler RJ. Enteral Nutrition for the High-Risk Neonate. In
Taeusch HW, Ballard RA, Gleason CA eds. Averys Diseases of
the Newborn, 8th ed. Philadelphia, Saunders, 2005; 1043-60.
20. Wright K, Dawson JP, Fallis D, Vogt E, Lorch V. New
postnatal growth grids for very low birth weight infants.
Pediatrics 1993; 91 : 922-926.
21. Ehrenkranz RA, Younes N, Lemons JA, Fanaroff AA,
Donovan EF, Wright LL et al. Longitudinal growth of
hospitalized very low birth weight infants. Pediatrics 1999; 104
: 280-289.
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 92 58

Symposium on AIIMS Protocols in Neonatology - V

Follow-up of High Risk Neonates

Pradeep Kumar, M. Jeeva Sankar, Savita Sapra, Ramesh Agarwal, Ashok K. Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New
Delhi, India

ABSTRACT
The improvement in perinatal care has led to increase in survival as well as reduction of morbidity in sick newborns. These
babies need to be followed up regularly to assess growth and neurodevelopmental outcome and for early stimulation and
rehabilitation. We present a protocol describing the various components of a follow up program, and services. [Indian J
Pediatr 2008; 75 (5) : 479-487] E-mail: aranag@rediffmail.com

Key words: Follow up; Neurodevelopmental; Outcome; Early Stimulation

Improving perinatal and neonatal care has led to be placed on these.

increased survival of infants who are at-risk for long-
term morbidities such as developmental delay and
visual/hearing problems 1, 2 Moreover, many of these
neonates (e.g., extremely low birth weight infants) tend
to have higher incidence of growth failure and ongoing
medical illnesses A proper and appropriate follow-up
program would help in early detection of these
problems thus paving way for early intervention.
IMPORTANCE OF FOLLOW-UP CARE
Numerous studies have shown that despite substantial
improvements in the neonatal mortality, the incidence
of chronic morbidities and adverse outcomes among
survivors has not declined much.3 This highlights the
need for a follow-up care service that would ensure
systematic monitoring of the general health and
neurodevelopmental outcomes after discharge from the
hospital. The monitoring would help the infants and
their families (early identification of problems and
hence early rehabilitation services) as well as the
physicians involved in their care (to improve the quality
of care provided and for research purposes). There is a
common perception that high risk follow-up mainly
concerns with detection and management of
neurosensory disability. Infact growth failure and
ongoing illnesses are equally, if not more important
issues in high risk follow-up. Adequate emphasis must
Correspondence and Reprint requests : Dr Ramesh Agarwal,
Assistant Professor, Department of Pediatrics, All India Institute
of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
[Received April 24, 2008; Accepted April 24, 2008]
However, a rigorous follow-up of all the neonates
discharged from a particular health facility would
neither be practical nor feasible. Therefore, it is
important to select a cohort of neonates who are at a
higher risk of developing these adverse outcomes at-
risk infants. Surprisingly, there are no standardized
guidelines for follow up of high risk infants even in
tertiary care centers. 4 We have devised a follow up
protocol which identifies the subset of neonates to be
followed up and outlines the optimal time for follow-up
visits and the appropriate assessment measures to be
adopted.
SETTING UP OF FOLLOW-UP SERVICES
High risk infants follow-up requires a multidisci-
plinary approach involving a team of pediatricians,
child psychologist, pediatric neurologist, ophthalmo-
logist, otorhinolaryngologist, physiotherapist, occupa-
tional therapist, medical social worker, and a dietician.
The respective role of each team member is summarized
in table 1.
Ideally, all the required personnel should be
available under one roof at a place earmarked for
follow-up care. If this is not feasible, at least the services
of pediatrician, clinical psychologist, dietician, medical
social worker, and physiotherapist should be ensured
in the follow-up clinic. Medical social worker is an
important member of the team liasoning with the
family and helps them to keep follow up visits. Infants
who need hearing/visual assessment or speech therapy
can be referred to the concerned specialist on fixed
days.

Indian Journal of Pediatrics, Volume 75May, 2008 479

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Pradeep Kumar et al

TABLE 1. Personnel Required for Follow-up Program and their Individual Roles

S. No Team member Role(s)

1. Pediatrician(s) / neonatologist(s) Serves as the nodal person of the team

To assess growth and screen for developmental delay
To manage intercurrent illnesses
2. Child psychologist(s) For formal neurodevelopmental assessment

Screening for behavioral problems and their management
3. Pediatric neurologist Long-term management of neurological illnesses such as seizures
4. Ophthalmologist Follow-up of ROP screening/treatment

Assessment of visual acuity and screening for problems such as
strabismus, nystagmus, refractory errors, etc.
5. Otorhinolaryngologist Hearing assessment (BERA, OAE, etc.)

Management of hearing impairment, if any
6. Dietician Dietary advice regarding complementary feeding

Management of infants with failure to thrive and those with special
needs (e.g. galactosemia)
7. Medical social worker To take care of the social issues to help improve follow up rates

8. Physiotherapist Assessment and grading of muscle tone and power

Plan an appropriate training program for each infant with tone
abnormalities
To teach the parents for continuing the prescribed exercises at home
9. Speech / occupational therapist Rehabilitation of infants with impairment/disability

WHO NEEDS FOLLOW-UP CARE? The developing brain of premature babies is

Selection of high-risk infants should be based on the
gestational age, birth weight, occurrence and severity of
perinatal/neonatal illnesses, interventions received in
the neonatal intensive care unit (NICU), presence of
malformations, etc. It can further be modified for each
unit based on their admission and outcome profiles.
Panel 1 lists the cohort of high risk infants whom we
follow-up in our unit.
Panel 1. High Risk Neonates Who Need Follow-up Care
(customize as per local policy)
Babies with <1800g birth weight and/or gestation <35
weeks
Small for date (<3 rd centile) and large for date (>97th
centile)
Perinatal asphyxia - Apgar score 3 or less at 5 min and/or
hypoxic ischemic encephalopathy
Mechanical ventilation for more than 24 hours
Metabolic problems Symptomatic hypoglycemia and
hypocalcemia
Seizures
Infections meningitis and/or culture positive sepsis
Shock requiring inotropic/vasopressor support
Major morbidities such as chronic lung disease,
intraventricular hemorrhage, and periventricular
leucomalacia
Infants born to HIV-positive mothers
Twin with intrauterine death of co-twin
Twin to twin transfusion
Hyperbilirubinemia > 20mg/dL or requirement of
exchange transfusion
Rh hemolytic disease of newborn
Major malformations
Inborn errors of metabolism / other genetic disorders
Abnormal neurological examination at discharge
extremely vulnerable to injury; the risk for
neurodevelopmental deficit increases with decreasing
gestational age and birth weight resulting in relatively
high risk of cerebral palsy, developmental delay,
hearing and vision impairment and subnormal
academic achievement 5 . Similarly, small for date
infants (birth weight < 3rd centile) are also at significant
risk of poor long term outcomes. Those who required
mechanical ventilation for more than 24hours, babies
with metabolic problems symptomatic hypoglycemia
as half of them have abnormal neurodevelopmental
outcome, symptomatic hypocalcemia, birth asphyxia
Apgar score 3 or less at 5 min, abnormal neurological
examination at discharge, seizures, hyperbilirubinemia
> 20mg/dL or requirement of exchange transfusion, Rh
hemolytic disease of newborn as they have anemia
presenting till three to six months age, infections
culture positive sepsis or meningitis, babies born to HIV
infected mothers, twin with intrauterine death of co-
twin due to increased incidence of cerebral venous
thromboembolic phenomenon, twin to twin transfusion
or major malformation. All infants cared for in the
NICU should have periodic preventive assessment by
their primary care physicians which should include
regular assessment of growth, sensory function,
behavior and neurodevelopment. Infants with suspect
findings should be referred for more comprehensive
evaluation to a center with experience in follow up of
high risk neonates.
PRE-REQUISITES FOR FOLLOW-UP
To ensure proper follow-up of the high risk infants,

480 Indian Journal of Pediatrics, Volume 75May, 2008

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Follow-up of High Risk Neonates
parents (especially mother) and other family members
should be counseled even before discharge from the
hospital. Discharge should be planned well in advance
so that the mother can be counseled adequately.
Discharge planning: Discharge planning should ideally
begin as soon as the baby is admitted in the nursery.
This gives adequate time for the caretakers to ask
questions and practice skills. The following criteria
should be fulfilled before discharging a high risk infant:
Hemodynamically stable; able to maintain body
temperature in open crib
On full enteral feeds (either breast feeding or by
paladai/spoon)
Parents confident enough to take care of the baby at
home
Has crossed birth weight and showing a stable
weight gain for at least three consecutive days; in
case of very low birth weight infants, weight should
be at least 1400 grams before considering for
discharge and should have crossed birth weight.
Not on any medications (except for vitamins and
iron supplementation). Ideally preterm babies on
theophylline therapy for apnea of prematurity should
be off therapy for at least five days to make sure that
there is no recurrence.
Received vaccination as per schedule (based on
postnatal age).
These criteria can be individualized to meet the infant
and family needs.
Counseling prior to discharge: Counseling plays an
important role in the care of these babies at home;
regular counseling sessions should be done before
discharge. Parents should be given advice regarding:
Temperature regulation proper clothing, cap, socks,
Kangaroo mother care etc.
Feeding type and amount of milk, method of
administration, and nutritional supplementation, if
any.
Prevention of infections hand washing, avoidance
of visitors, etc.
Follow-up visits where and when (Table 2)
Danger signs recognition and where to report if
signs are present
Vaccination schedule, next visit, etc.
Special needs e.g., next visits for ROP screening.
If possible the family should be provided with the
telephone number of the health care provider e.g., on-
duty doctor in case the family needs to consult for
infants illness.
Indian Journal of Pediatrics, Volume 75May, 2008
60
PROCEDURE FOR FOLLOW-UP
Venue: A specified site should be earmarked for follow
up services. The parents should be properly
communicated about the venue and it should also be
mentioned in the discharge summary. Registration
procedure at the follow-up clinic should be simplified
to avoid any undue delay. Ongoing illness is common
problem among these infants. If the infant develops any
illness requiring admission, priority should be given for
the same.
Record maintenance: There should be a separate but
uniform file for each high risk infant . We have separate
files for male and female babies. Male babies get blue
and female babies get pink files. Addresses and
telephone numbers should be entered clearly in the file.
If possible, an alternate address and telephone number
should also be recorded. It may be good idea to enquire
an important landmark for locating the house in case
one needs to make a home visit. The family should also
be given a booklet containing follow-up information.
Schedule: The follow up schedule should be explained
to the parents (see below). Timings should be fixed and
adhoc visits should be discouraged.
Corrected age: Age of the child since the expected date
of delivery. The correction for gestational immaturity at
birth should be done till 24 months age. All
developmental milestones are assessed according to
corrected age to compensate for the prematurity. The
addition of complementary feeds is also according to
corrected age.
Postnatal age: Age of the child since birth.
Immunization is done according to postnatal age.
WHEN TO FOLLOW-UP
For the purpose of follow-up visits, at-risk infants can
be grouped under two major categories: (1) preterm/
LBW infants and (2) infants with other conditions. The
follow-up schedule for both these categories has been
summarized in table 2. This schedule represents
minimum number of visits of high risk neonates. If the
baby has ongoing issues or illness, more frequent visits
are recommended. Please note that first contact of the
infant with the health providers after discharge is
important and helps in identification of adjustment
problems at home. Ideally this contact should be
achieved by the home visit.
The selection of age of assessment depends on
developmental acquisitions available at a given age,
availability and applicability of appropriate test
instruments at specific ages and the cost and feasibility
of long-term tracking in the population in question. The
481
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Pradeep Kumar et al

TABLE 2. Follow-up Schedule of At-risk Infants

Cohort Schedule for follow-up

Infants with <1800g birth weight and/or After 3-7 days of discharge to check if the baby has been adjusted well in
gestation <35 weeks the home environment. Every 2 weeks until a weight of 3 kg
(immunization schedule until 10-14 weeks to be covered in these visits)
At 3, 6, 9, 12 and 18months of corrected age and then every 6 months
until age of 8years
All other conditions 2 weeks after discharge
At 6, 10, 14 weeks of postnatal age
At 3, 6, 9, 12 and 18months of corrected age and then every 6 months
until age of 8years

Note: If a preterm infant (< 35 weeks) develop any other morbidity covered in other conditions, he should be followed up as per
the schedule outlined for the first group of cohort

long term follow up of complete cohorts is optimal for
determining the outcome of high risk neonates and the
safety of antenatal and perinatal interventions. Very
low birth weight babies or those born at less than 33
weeks gestation should be followed up for eye check up
for retinopathy of prematurity till the postnatal age of
44 weeks.
Some neurological abnormalities that are identified
in the first year of life are transient or improve whereas
findings in other children may worsen over time.6 By 12
months corrected age the cognitive and language
assessment can be done. By 18-24 months corrected age
there is improved prediction to early school age
performance.7, 8, 9, 10 The importance of long term follow
up lies in the fact that minor neurological disabilities
may not be detected early and become apparent only
with increasing age. Standard follow-up for many
multicenter networks is currently at 18-24 months
corrected age.
WHAT SHOULD BE DONE AT FOLLOW-UP?
Table 3 summarizes the plan for follow-up.
Assessment of feeding and dietary counseling
Parents should be asked about the infants diet and
offered dietary counseling at each visit. Breast feeding
frequency and adequacy should be assessed. The
amount, dilution and mode of feeding should be noted
if supplemental feeding is given. It is a good idea to
enquire about source of milk as milk supplied by local
vendors is often diluted (dilution has the same impact
on the infant whether done by the family or the
vendor!). It is also important to record the duration of
exclusive breast feeding. If a baby is not gaining
adequate weight on exclusive breast feeding take care
of any illness, maternal problems which may interfere
with feeding and milk output. If poor weight gain
persists despite all measures to improve breast milk
output, supplementation can be considered.
Complementary feeding should be started at 6
months corrected age. Initially, semisolids should be
advised in accordance with the local cultural practices.
Spend adequate time on explaining what to give and
how to give. The common practice of giving too little or
too dilute complementary food such as rice-water, dal-
water, too much of juice, etc should be discouraged. The
recommended meal frequencies assuming a diet with
energy density of 0.8 kcal per gram or above and low
breast milk intake are: 2-3 meals per day for infants
aged 6-8 months; 3-4 meals per day for infants aged 9-
11 months and children 12-24 months; additional
nutritious snacks may be offered 1-2 times a day, as
desired. Complementary foods should be varied and
include adequate quantities of meat, poultry, fish or
eggs, as well as vitamin A-rich fruits and vegetables
every day. Where this is not possible, the use of fortified

TABLE 3. Follow-up Plan for High Risk Infants

Assessment Age in months

Assessment of feeding and dietary counseling 1 2 3 6 9 12 15 18 24 ......8years

Growth monitoring All visits
Immunization As per schedule (based on postnatal age)
Neurological examination
Developmental assessment and DQ
Hearing (BERA)
Ophthalmic evaluation
USG/CT brain As indicated
if previous test abnormal

482 Indian Journal of Pediatrics, Volume 75May, 2008

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Follow-up of High Risk Neonates
complementary foods and vitamin mineral
supplements may be necessary to ensure adequacy of
particular nutrient intakes. As infants grow, the
consistency of complementary foods should change
from semisolid to solid foods and the variety of foods
offered should increase. By eight months, infants can
eat finger foods and by 12 months, most children can
eat the same types of food as the rest of the family. The
major problem with the family food is that it is not
nutrient-rich.10
Growth monitoring
Growth (including weight, head circumference, mid-
arm circumference and length) should be monitored
and plotted on an appropriate growth chart at each
visit. We use Wrights charts (till 40 weeks PMA) and
WHO growth charts (for preterm infants after 40 weeks
PMA and for term infants) for growth monitoring . The
infants growth pattern (slope of the curve) is compared
with the standard curve; any deviation should be noted
and appropriate remedial action taken. Weight should
be taken on an electronic weighing scale. Length should
be measured with an infantometer. The infant should be
held supine and legs fully extended. The feet should be
pressed against the movable foot piece with the ankles
fixed to 90. Head circumference should be measured
with nonstretchable fiberglass tape.11
Developmental assessment
Assessment of developmental milestones should be
done according to the corrected age. The milestones
should be assessed in four domains- gross motor, fine
motor, language, and personal-social. The date of
assessment and the infants corrected age should be
mentioned against each milestone. Based on the date of
achievement of milestones in a particular domain and
the expected age of achieving them, the developmental
age can be calculated.
Infants who lag behind in any domain should
undergo a formal developmental evaluation by a
clinical psychologist using tests such as Developmental
assessment of Indian Infant II (DASII II).12 This scale
consists of 67 items for assessment of motor
development and 163 items for assessment of mental
development. Motor scale assesses control of gross and
fine motor muscle groups. Mental scale assesses
cognitive, personal and social skills development. Both
mental development index and psychomotor
development index can be calculated by DASII. The age
placement of the item at the total score rank of the scale
is noted as the child developmental age. This converts
the child total scores to his motor age (MoA) and
mental age(MeA). The respective ages are used to
calculate his motor and mental development quotients
respectively by comparing them with his chronological
age and multiplying it by 100. (DMoQ = MoA/CA x 100
Indian Journal of Pediatrics, Volume 75May, 2008
62
and DMeQ = MeA/CA x 100). The composite DQ is
derived as an average of DMoQ and DMeQ.
The Vineland Social Maturity Scale measures social
competence, self-help skills, and adaptive behavior
from infancy to adulthood. The Vineland scale consists
of a 117-item interview with a parent or other primary
caregiver.
It is emphasized here that developmental
stimulation of the child should not be delayed if the
above mentioned tests are not available. Age
appropriate stimulation should be provided to these
babies. Mental development index and Psychomotor
development index at 3, 12,18 and 24 months and
every 3 months if abnormal.
Immunization
Immunization should be ensured according to
chronological age . Parents should be offered the option
of using additional vaccines such as Hemophilus
influenzae B, typhoid and MMR.
Ongoing problems
They should be mentioned in the follow up notes . The
management of ongoing illnesses is an integral part of
any high risk follow up program. The hospital
admission of the child should be prioritized, if
required.
Neurological assessment
Evaluation of muscle tone is an integral part of the
neurological examination. A waxing and waning
pattern of neuromotor development from 28 weeks of
gestation to the end of first year of life was reported by
Amiel-Tison. From 28 to 40 weeks gestation, the
acquisition of muscle tone and motor function spreads
from lower extremities towards the head. After full term,
the process is reversed so that relaxation and the motor
control proceed downwards for the next 12 to 18
months. So the upper limbs begin to relax and acquire
skills before the lower limbs. The axial tone follows a
similar pattern. Head control appears first followed by
the ability to sit, stand and walk. Hypertonia or
hypotonia should be looked for by measuring the
following angles: adductor angle, popliteal angle, ankle
dorsiflexion, and scarf sign; any asymmetry between
the extremities should also be recorded. Any history of
seizures or involuntary movements should also be
recorded.
Hypertonia in lower limbs is defined as when either
adductor angle is restricted to less than the age specific
norms as per Amiel-Tison or if there is scissoring or
tight tendo-achilles or restriction of ankle dorsiflexion
on extension of knee. Hypertonia in upper limbs is
defined as when scarf sign does not cross midline at
one year corrected age. Hypertonia of the neck
483
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Pradeep Kumar et al

TABLE 4. Muscle Tone Norms

Age Adductor Popliteal Dorsiflexion Scarf sign

(months) angle angle angle

0-3 40 -80 80 -100 60 -70 Elbow does not cross midline

4-6 70 -110 90 -120 60 -70 Elbow crosses midline
7-9 110 -140 110 -160 60 -70 Elbow goes beyond axillary line
10-12 140 -160 150 -170 60 -70

Fig. 1. Amiel-Tison Method oa assessment of tone in infants

484 Indian Journal of Pediatrics, Volume 75May, 2008

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Follow-up of High Risk Neonates
extensors can be inferred by an increased gap between
the nape of the neck and examination table with the
infant lying in supine position.
The following angles should be measured to assess
tone as shown in fig 1, table 4.
Truncal extensor hypertonia: there is a tendency of body
to go into hyperextension or opisthotonus.
Cerebral palsy: Definitely abnormal neurological
examination with upper motor neuron signs with
motor developmental delay.
Spastic hypertonia syndromes
Hemiplegia- only one half of body involved
Diplegia- paresis of lower limbs more than upper limbs
Quadriplegia- Paresis of all four limbs with upper limb
involvement equal to or more than lower limbs.
Abnormal neurological examination should be defined
as definite abnormalities In the form of:
a) Brisk reflexes with hypertonia or
b) Brisk reflexes with hypotonia or
c) Definitely and consistently elicited asymmetrical
signs or
d) Persistent abnormal posturing or abnormal
movements
The tone abnormalities should be taken care by regular
physiotherapy. This improves mobility of joints and
locomotion of the child. The child should be provided
with special shoes if required. Orthopedic evaluation
should be done and corrective surgery for contractures
should be done as required. All possible efforts should
be made to improve mobility of these children and make
them functionally less dependent and independent if
possible.
Eye evaluation
The check-up for retinopathy of prematurity starts in
the NICU and continues till 44 weeks postconceptional
age or till the retinal vessels have matured. Refer to
protocol on Retinopathy of prematurity.13
At 9 months corrected age the ophthalmologist
should evaluate the baby for vision, squint, cataract and
optic atrophy. Subjective visual assessment can be
made from clinical clues as inability to fixate eyes,
roving eye movements and nystagmus. Objective visual
assessment should be done with the Teller Acuity Card.
It has seventeen 25.5 51 cm cards. Fifteen of these
contain 12.5 12.5 cm patches of square-wave gratings(
vertical black and white strips) ranging in spatial
frequency from 38.0 cycles/cm to 0.32 cycles/cm. The
range is in half octave steps. A cycle consists of one
black and one white stripe and an octave is a halving or
doubling of spatial frequency. In Snellens terms it is an
halving or doubling of the denominator e.g. 6/6, 612, 6/
24. Half octave steps would be 6/6, 6/9, 6/12, 6/18, 6/
Indian Journal of Pediatrics, Volume 75May, 2008
64
24 and so on. There is a low vision card containing 25.5
23 cm patch of 0.23 cm cycle/cm( 2.2 cm wide black or
white stripes). The seventeenth card is a blank grey card
with no grating pattern. The gratings have 82 84%
contrast and are matched to the surrounding grey card
to within 1% in space average luminance. This
minimizes the chance of a patient fixating because of
brightness difference. Detection of pattern alone
determines the fixating preference. Proper illumination
without any shadows should be ensured (10 candelas /
sqm). Testing distance from patients eyes to the cards
should be maintained constant as it determines the
visual acuity. Children from 7m to 3y should be tested at
55 cm and later at 84 cm.
Rehabilitation for visual impairment should be early
so that the child gets appropriate stimulation. If delayed
the restoration of the vision may not be possible
because of continuous sensory deprivation of the optic
nerve. The child should be provided with glasses or
corrective surgery as appropriate. It should be
emphasized that a good high risk follow up program
does not only pick up handicaps early but also ensures
early corrective measures and rehabilitation. This
emphasizes the multidisciplinary and well coordinated
approach to such babies
Hearing evaluation
High risk infants have higher incidence of moderate to
profound hearing loss (2.5-5% vs 1%). Since clinical
screening is often unreliable, brainstem auditory
evoked responses (BAER/BERA) should be performed
between 40 weeks PMA and 3 months postnatal age. A
screening BERA is usually done initially. If this is
abnormal, a diagnostic BERA should be done within 2
weeks of the initial test. Infants with unilateral
abnormal results should have follow-up testing within
three months. The test should be carried out in a sound-
proof room and the infant should be sedated with oral
triclofos 50mg/kg 30 min before the procedure. To
measure the electrical pulses, small monitoring
electrodes are placed on the scalp. Earphones provide a
clicking noise to the ear and the response from the
brainstem is measured time-locked to the clicks. The
clicks may become louder or softer, faster or slower, to
see how the auditory responds to these different
stimulus parameters. The other method of assessment
for hearing is oto-acoustic emission (OAE). This
records acoustic feedback from the cochlea through the
ossicles to the tympanic membrane and ear canal
following a click stimulus. It is quicker to perform than
BERA but is more likely to be affected by debris or fluid
in the external and middle ear. It is unable to detect
some form of sensorineural hearing loss including
auditory dyssynchrony.
The severity of hearing loss is profound (70 dB or
more of hearing loss), severe (50 dB - 70 dB), moderate
485
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Pradeep Kumar et al
(30 dB - 50 dB) and mild (15 dB - 30 dB).
The audiological testing should be done at 3 months
of age. Infants with true hearing loss should be referred
for early intervention to enhance the childs acquisition
of developmentally appropriate language skills. The
child should be provided with hearing aids and if
severe to profound hearing loss cochlear implants
should be considered by 12 months age. Fitting of
hearing aids by the age of 6 months has been associated
with improved speech outcome. Initiation of early
intervention services before three months age has been
associated with improved cognitive development at 3
years age.14
EARLY STIMULATION
The high risk baby requires more attention of the family
members. Parents and family members need to aid the
development process in an age appropriate way
spending quality time with children. Such interactions
improve parent child relationship and bring about
positive parental attitudinal change. Effective parents
supervise their children in an age appropriate way, use
consistent positive discipline, communicate clearly and
supportively, and show warmth, affection,
encouragement, and approval. The actions of the child
should be appreciated. This makes him happy and
encourages doing more activities.
0-2 months:
Activities
Maintain eye to eye contact
Talk and sing to the baby while bathing, dressing
and feeding
Help the baby to turn his head to sound and light
Auditory
Provide different sounds to the child like rattle, bell,
squeezing a toy. Make the child listen to music, high
pitched and low pitched human sounds
Humming in a soft low voice
Visual
Keep the baby in a well lighted room
Shine mobile, color balls and hang bright clothes
Tactile
Put the baby on different surfaces like soft clothes,
mattresses, rubber mat and mothers lap
Change the childs position frequently like putting
on his back, sides and tummy
Kinesthetic
Support the head and gently rock the child avoiding
sudden jerky movements
486
65
2-4 months
General stimulation
Hold the baby at the shoulder
Place things just out of the reach of the baby.
Stimulate him to reach out and grasp the object
Auditory
Give sound producing toys
Talk to the child more frequently
Point out the names of objects shown to the child
Visual
Hang bright objects about 30cm above the crib
Maintain eye contact while talking to the child
Tactile
Give the child paper to crumble and things to bite
and suck
Place the child on a rubber mat on the ground
allowing him to move freely
4-6 months:
General activities:
Sit the baby in the mothers lap and ask her to gently
bounce her knees singing songs.
Place the child flat on the back on the ground over a
soft surface. Show him a colorful toy. Slowly turn him
by flexing the far away leg. Assist him to turn over
the tummy.
Show an attractive toy and encourage the child to
reach out to it.
Put your hands under the childs feet and move his
legs up and down like pedaling a cycle.
Auditory
Shake a bell or a squeaky toy over the head of the
baby. Encourage him to turn his head and locate the
sound
6-8 months
Call the child by his name
Make the child sit as long as possible. Give support
to his pelvis.
Give him pieces of paper to tear
Encourage him to roll over his tummy by showing
him colorful toys on one side.
8-10 months
Make the child stand by holding onto the furniture
Encourage the child to clap hands
Give him a small container and ask to drop small
thing into it.
Encourage him to produce monosyllables.
Show him picture books and assist to turn the pages.
Indian Journal of Pediatrics, Volume 75May, 2008
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Follow-up of High Risk Neonates
10-12 months:
Let the child play with other children
Name the body parts while bathing him
Take the child on a walk and show him different
animals and birds
Do simple actions like clapping, bye-bye and
encourage copying these actions.
Encourage him to pull to stand by holding the
furniture
Make the child sit in front of a mirror so that he can
see himself
12-15 months:
Give picture books to the child. Talk about what you
see and let him turn the pages
Ask him to put cubes one over the other
Ask him to put things into the container and then
take out things out of the container.
Hide a small toy under a cloth. Encourage the baby to
find the hidden toy.
Ask the child to scribble by drawing a few lines.
First demonstrate what he is supposed to do.
How to ensure a good follow up rate
The importance of follow up should be emphasized
frequently to the parents. The permanent and present
addresses along with phone numbers should be kept to
ensure follow up. If the parents do not turn up for follow
up they should be telephoned and letters should be
posted to ensure good follow up rates. There should be
a dedicated person who can adjust the timing with the
parents. If possible home visits should be arranged for
those who do not turn up. There should be a
comprehensive assessment of the child under one roof
to minimize the hassles of roaming from one corner of
the hospital to the other.
REFERENCES
1. Narayan S, Aggarwal R, Upadhyay A, Deorari AK, Singh
Indian Journal of Pediatrics, Volume 75May, 2008
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M, Paul VK. Survival and morbidity in Extremely Low Birth
Weight (ELBW) infants. Indian Pediatr 2003; 40: 130-135.
2. Costello D, Friedman H, Minich N, Siner B, Taylor G,
Schuchlter M, Hack M. Improved neurodevelopmental
outcomes for extremely low birth weight infants in 2000-
2002. Pediatrics 2007; 119: 37-45.
3. Escobar G, Littenberg B, Petitti DB Outcome among
surviving very low birthweight infants: a meta-analysis.
Arch Dis Child Feb1991; 66: 204 - 211.
4. Wang CJ, McGlynn EA, Brook RH et al. Quality-of-care
indicators for the neuro-developmental follow-up of very
low birth weight children: results of an expert panel
process. Pediatrics 2006; 117 : 2080-2092.
5. Vohr BR, Wright L, Anna M, Perritt R, Poole WK, Tyson JE
et al. Center for the Neonatal Research Network Center
differences and outcomes of exteremely low birth weight
infants. Pediatrics 2004; 113 : 781-789.
6. Drillien C. Abnormal neurological signs in the first year of
life in low birth weight infants: possible prognostic
significance. Dev Med Child Neurol 1997; 14 : 575-84.
7. Weisglas-Kuperus N, Baerts W, Smrkovsky M, Sauer PJ.
Effects of biological and social factors on the cognitive
development of very low birth weight children. Pediatrics
1993; 92 : 658-665.
8. Dezoete JA, MacArthur BA, Tuck B. Prediction of Bayley
and Stanford-Binet scores with a group of very low
birthweight children. Child Care Health Dev 2003; 29 : 367-
372.
9. Lee H, Barratt MS. Cognitive development of preterm low
birth weight children at 5 to 8 years old. J Dev Behav Pediatr
1993; 14 : 242-249.
10. Report of the global consultation, and summary of guiding
principles for complementary feeding of the breastfed child
Authors: World Health Organization
11. Implementation of the WHO Multicenter Growth Reference
Study in India N. Bhandari, S. Taneja, T. Rongsen, J.
Chetia, P. Sharma, R. Bahl, D. K. Kashyap, and M. K. Bhan,
for the WHO Multicenter Growth Reference Study Group
12. Phatak B. Mental and motor growth of Indian babies (1-30
months). Final report. Department of Child Development,
MSUB, Baroda, 1970.
13. Chawla D, Agarwal R., Deorari AK, Paul VK. Retinopathy
of Prematurity. Indian J Pediatr 2008; 75 : 73-76.
14. NIH Joint Committee on Infant Hearing. Year 2000
position statement: Principles and guidelines for early
hearing detection and intervention programmes. Pediatrics
2000; 106 : 798-817.
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Indian J Pediatr (2010) 77:11231128
DOI 10.1007/s12098-010-0176-0
SYMPOSIUM ON AIIMS PROTOCOLS IN NEONATOLOGY-I
Hypocalcemia in the Newborn
Ashish Jain & Ramesh Agarwal & M. Jeeva Sankar &
Ashok Deorari & Vinod K. Paul
Received: 27 July 2010 / Accepted: 2 August 2010 / Published online: 25 August 2010
# Dr. K C Chaudhuri Foundation 2010
Abstract Hypocalcemia is a frequently observed clinical
and laboratory abnormality in neonates. Ionic calcium is
crucial for many biochemical processes including blood
coagulation, neuromuscular excitability, cell membrane
integrity, and many of the cellular enzymatic activities.
Healthy term infants undergo a physiological nadir in
serum calcium levels by 24-48 h of age. This nadir may
drop to hypocalcemic levels in high-risk neonates including
infants of diabetic mothers, preterm infants and infants with
perinatal asphyxia. The early onset hypocalcemia which
presents within 72 h requires treatment with calcium
supplementation for at least 72 h. In contrast, late onset
hypocalcemia usually presents after 7 days and requires
longer term therapy.
Keywords Hypocalcemia . Newborn . Therapy
During the last trimester, calcium is actively transferred from
mother to the fetus as demonstrated by a significantly high
level of total calcium concentration in cord blood compared
to maternal serum [1]. Parathyroid hormone (PTH) and
calcitonin (CT) do not cross the placental barrier. The PTH
related peptide (PTHrP) is the main regulator of the positive
calcium balance across the placenta. Serum calcium (SCa)
in the fetus is 10-11 mg/dL at term (1-2 mg higher as
compared to mother).
After birth the SCa levels in newborns depend on the
PTH secretion, dietary calcium intake, renal calcium
A. Jain : R. Agarwal : M. J. Sankar : A. Deorari (*) : V. K. Paul
Division of Neonatology, Department of Pediatrics,
All India Institute of Medical Sciences,
Ansari Nagar,
New Delhi 110029, India
e-mail: sdeorari@yahoo.com
67
reabsorbtion, skeletal calcium stores, and vitamin D status.
Hence, after delivery, calcium levels start decreasing (the
rate and extent of decrease is inversely proportional to the
gestation) and reaches a nadir of 7.5-8.5 mg/dL in healthy
term babies by day 2 of life. This drop in postnatal SCa
may be related to hypoparathyroidism, end organ unre-
sponsiveness to parathyroid hormone [2], abnormalities of
vitamin D metabolism, hyperphosphatemia, hypomagnese-
mia, and hypercalcitonemia [3] which occurs by 12-24 h of
age. PTH levels increase gradually in the first 48 h of life
and normal levels of SCa are regained by 3rd day of life
[4]. The efficacy of the intestinal absorption of calcium and
the renal handling matures by 24 wks. This transition
phase is responsible for the increased risk of early onset
hypocalcemia in high-risk neonates.
Calcium homeostasis in newborn
Body calcium exists in two major compartments: skeleton
(99%) and extracellular fluid (1%). Calcium in the
extracellular fluid is present in three forms: (a) bound to
albumin (40%) (b) bound to anions like phosphorus, citrate,
sulfate and lactate (10%) and (c) free ionized form (50%)
[5]. Ionized calcium is crucial for many biochemical
processes including blood coagulation, neuromuscular
excitability, cell membrane integrity and function, and
cellular enzymatic and secretory activity.
Measurement of the total serum Ca concentration alone
can be misleading because the relationship between total
and ionized Ca is not always linear. Correlation is poor
when the serum albumin concentration is low or, to a lesser
degree, with disturbances in acid-base status, both of which
occur frequently in premature or sick infants. With
hypoalbuminemia, the total Ca concentration will be low
 106
1124
while the ionized fraction will be normal unless some other
factor is affecting Ca metabolism. More so, falsely low
ionic calcium levels may be recorded in alkalosis and with
heparin use.
In general, the plasma calcium concentration falls by
0.8 mg/dL (0.2 mmol/L) for every 1.0 g/dL fall in the
plasma albumin concentration.
Therefore, estimation of total calcium levels is a poor
substitute for measuring the ionized levels.
Definition
Hypocalcemia is defined as total serum calcium of less than
7 mg/dL (1.75 mmol/L) or ionized calcium less than 4 mg/dL
(1 mmol/L) in preterm infants and less than 8 mg/dL
(2 mmol/L; total) or <1.2 mmol/L (ionic) in term neonates [6].
The SCa concentration is usually reported in different ways
viz. mg/dL, meq/L and mmol/L The relationship between
these units is related to the following equations: mmol=L
mg=dL  10  molecular wt; meq=L mmol=L  valency.
Since the molecular weight of calcium is 40 and the valence
is +2, 1 mg/dL is equivalent to 0.25 mmol/L and to 0.5 meq/L.
Thus, values in mg/dl may be converted to molar units
(mmol/L) by dividing by 4.
Early onset neonatal hypocalcemia (ENH) (Table 1)
This condition is fairly common and seen within the first
3-4 days of life in following clinical settings:
Prematurity This may be related to premature termination
of trans-placental supply, exaggeration of the postnatal drop
to hypocalcemic levels, increased calcitonin and diminished
target organ responsiveness to parathyroid hormone.
Infant of diabetic mother (gestational and insulin dependent)
This may be related to increased calcium demands of a
macrosomic baby [7]. Magnesium depletion in mothers with
Table 1 Causes of early onset hypocalcemia
Prematurity
Preeclampsia
Infant of Diabetic mother
Perinatal stress/ asphyxia
Maternal intake of anticonvulsants (phenobarbitone,
phenytoin sodium)
Maternal hyperparathyroidism
Iatrogenic (alkalosis, use of blood products,
diuretics, phototherapy, lipid infusions etc)
68
Indian J Pediatr (2010) 77:11231128
diabetes mellitus causes hypomagnesemic state in the fetus.
This hypomagnesemia induces functional hypoparathyroidism
and hypocalcemia in the infant. A high incidence of birth
asphyxia and prematurity in infants of diabetic mothers are
also contributing factors.
Perinatal asphyxia Delayed introduction of feeds, in-
creased calcitonin production, increased endogenous
phosphate load, renal insufficiency, and diminished
parathyroid hormone secretion all may contribute to
hypocalcemia.
Maternal hyperparathyroidism This causes intrauterine
hypercalcemia suppressing the parathyroid activity in the
fetus resulting in impaired parathyroid responsiveness to
hypocalcaemia after birth. Hypocalcaemia may be severe
and prolonged.
Intrauterine growth restriction (IUGR) Infants with IUGR
may have hypocalcemia if they are born preterm and/or
have had perinatal asphyxia. Small for gestational age is not
an independent risk factor for ENH.
Iatrogenic Any condition causing alkalosis increases the
binding of the calcium with albumin and causes decrease in
ionic calcium levels
Screening is recommended in at risk neonates (if facilities
exist)
1. Preterm infants born before 32 wks
2. Infants of diabetic mothers on IV fluids
3. Infants born after severe perinatal asphyxia defined as
Apgar score <4 at 1 min of age
Time schedule for screening
At 24 and 48 hrs of age in at risk babies.
Clinical presentation
1. Asymptomatic: ENH is usually asymptomatic unlike
the late onset variety and is incidentally detected.
2. Symptomatic: The symptoms may be of neuromuscular
irritability - myoclonic jerks, jitteriness, exaggerated startle,
and seizures. They may represent the cardiac involvement
like- tachycardia, heart failure, prolonged QT interval,
decreased contractibility. More often they are non-specific
and not related to the severity of hypocalcemia. Apnea,
cyanosis, tachypnoea, vomiting and laryngospasm are
other symptoms that are noted.
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Indian J Pediatr (2010) 77:11231128 1125

Diagnosis Treatment of early onset hypocalcemia

1. Laboratory: Total or ionized serum calcium (total
<7 mg/dL or ionized <4.0 mg/dL). Ionized calcium is
the preferred mode for diagnosis of hypocalcemia.
2. ECG: QoTc >0.22 s or QTc >0.45 s
QT interval in seconds
QTc p
R  R interval in seconds
QoT interval in seconds
QoTc p for this practice. Infants tolerating oral feeds may receive
R  R interval in seconds
(QT interval is measured from origin of q wave to end of
T wave on ECG; QoT is measured from origin of q wave to
origin of T wave).
A diagnosis of hypocalcemia based only on ECG criteria
is likely to yield a high false positive rate. Although these
parameters have good correlation with hypocalcemia in low
birth weight infants (sensitivity of 77% and specificity of
94.7%) [8], neonates suspected to have hypocalcemia by
ECG criteria should have the diagnosis confirmed by
measurement of serum calcium levels.
(1 ml of calcium gluconate (10%) gives 9 mg of elemental
calcium)
1. Patients at increased risk of hypocalcemia (prophylactic):
Preterm infants (32 wks), sick infants of diabetic
mothers and those with severe perinatal asphyxia should
receive 40 mg/kg/day of elemental calcium (4 mL/kg/day
of 10% calcium gluconate) for prevention of early onset
hypocalcemia. However, there is not sufficient evidence
this calcium orally q 6 hourly. Therapy should be con-
tinued for 3 days. Oral calcium preparations have high
osmolality and should be avoided in babies at higher risk
of necrotizing enterocolitis.
2. Patients diagnosed to have asymptomatic hypocalcemia
(on screening): Infants detected to have hypocalcemia
on screening and who are otherwise asymptomatic
should receive 80-mg/kg/day elemental calcium
(8 mL/kg/day of 10% calcium gluconate) for 48 hrs.
This may be tapered to 50% dose for another 24 hrs
and then discontinued. Neonates tolerating oral feeds

Fig. 1 Management of early

Hypocalcemia
neonatal hypocalcemia Total serum Cal <7 mg/dl

Asymptomatic
80 mg/kg/day for 48 hrs
(8 mL/kg/day of 10% calcium gluconate )

Taper to 40 mg/kg/day for one day

Then stop

Symptomatic
Bolus of 2 mL/kg calcium gluconate 1:1 diluted with 5 % dextrose over 10 minutes
under cardiac monitoring

Followed by continuous infusion 80 mg/kg/day for 48 hrs

(8 mL/kg/day of 10% calcium gluconate )
Document normal calcium at 48 hrs

Then taper to 40 mg/kg/day for one day

Then stop

Prophylactic
Preterm< 32 wk, sick IDM,severe asphyxia
40 mg/kg/day for 3 days
(4ml/kg/day of 10% calcium gluconate )
IV or oral if can tolerate per oral

Treatment is for 72 hrs

Continuous infusion is better than bolus
Symptomatic babies treatment is 48 hrs continuous infusion
In case the hypocalcemia does not correct with the above by 72 hrs then investigate for
causes of late hypocalcemia.- Refer Table 2
 108 70
1126 Indian J Pediatr (2010) 77:11231128

may be treated with oral calcium (IV preparation may Late onset neonatal hypocalcemia (LNH)
be used orally).
3. Patients diagnosed to have symptomatic hypocalcemia: This condition is rare as compared to ENH. It usually
These patients should receive a bolus dose of 2 mL/kg/dose presents at the end of the first wk of life. It is usually
diluted 1:1 with 5% dextrose over 10 min under cardiac symptomatic in the form of neonatal tetany or seizures.
monitoring. When there is severe hypocalcaemia with poor This is usually caused by high phosphate intake (iatrogenic).
cardiac function, calcium chloride 20 mg/kg may be given The causes are listed in Table 2.
through a central line over 10-30 min (as chloride in
comparison to gluconate does not require the metabolism Examination
by the liver for the release of free calcium). This should be
followed by a continuous IV infusion of 80 mg/kg/day Such babies should have an examination with special
elemental calcium for 48 h. Continuous infusion is emphasis on cataracts, hearing problems, and any evidence
preferred to IV bolus doses (1 mL/kg/dose q 6 hrly). of basal ganglia involvement (movement disorder).
Calcium infusion should be dropped to 50% of the original
dose for the next 24 h and then discontinued. The infusion Investigations
may be replaced with oral calcium therapy on the last day.
Normal calcium values should be documented at 48 h These should be considered in LNH or if the hypocalcemia
before weaning the infusion. does not respond to adequate doses of calcium. The work
All categories of hypocalcemia should be treated for at Table 2 Causes of Late Onset Hypocalcemia
least 72 h. Continuous infusion is preferred to IV bolus
doses. Symptomatic hypocalcemia should be treated with a Increased phosphate load
continuous infusion for at least 48 h (Fig. 1). Cow milk, renal insufficiency
Hypomagnesemia
Vitamin D deficiency
Precautions and side effects
Maternal vitamin D deficiency
Malabsorption
Bradycardia and arrhythmia are known side effects of bolus
Renal insufficiency
IV calcium administration. Hence, bolus doses of calcium
Hepatobiliary disease
should be diluted 1:1 with 5% dextrose and given slowly (over
PTH resistence
10 to 30 min) under cardiac monitoring. An umbilical venous
Transient neonatal pseudohypoparathyroidism
catheter (UVC) may be used for administration of calcium
Hypoparathyroidism
only after ensuring that the tip is positioned in the inferior vena
Primary
cava. Hepatic necrosis may occur if the tip of the UVC lies in a
branch of the portal vein. Umbilical artery catheter (UAC) Hypoplasia, aplasia of parathyroid glands - (Di Georges
syndrome), CATCH 22 syndrome (cardiac anomaly,
should never be used for giving calcium injections. Accidental abnormal facies, thymic aplasia, cleft palate, hypocalcaemia
injection into the UAC may result in arterial spasms and with deletion on chromosome 22)
intestinal necrosis. Skin and subcutaneous tissue necrosis may Activating mutations of the calcium sensing receptor (CSR)
occur due to extravasation. Secondary
Hence, IV sites where calcium is being infused should Maternal hyperparathyroidism
be checked at least q 2 hrly to monitor for extravasation and Metabolic Syndromes
avoid subcutaneous tissue necrosis. Kenny-caffey syndrome
Long-chain fatty acyl CoA dehydrogenase deficiency
Prolonged or resistant hypocalcemia Kearns-sayre syndrome
Iatrogenic
This condition should be considered in the following Citrated blood products
situations: Lipid infusions
Bicrbonate therepy
& Symptomatic hypocalcemia unresponsive to adequate
Diueretics (loop diuretics0
doses of calcium therapy
Glucocorticosteriods
& Infants needing calcium supplements beyond 72 h of age
Phosphate therepy
& Hypocalcemia presenting at the end of the first wk.
Alkalosis
These infants should be investigated for causes of LNH Phototherapy
(see below) Table 3.
 109 71
Indian J Pediatr (2010) 77:11231128 1127

up of such a case is very important to determine the
etiology. The same can be planned as per the Table 3.
If hypocalcemia is present with hyperphosphatemia and
a normal renal function, hypoparathyroidism should be
strongly suspected
Treatment of LNH
The treatment of LNH is specific to etiology and may in
certain diseases be life-long.
1. Hypomagnesemia: Symptomatic hypocalcemia unre-
sponsive to adequate doses of IV calcium therapy is
usually due to hypomagnesemia. It may present either as
ENH or later as LNH. The neonate should receive 2 doses
of 0.2 mL/kg of 50% MgSO4 injection, 12 h apart, deep
IM followed by a maintenance dose of 0.2 mL/kg/day of
50% MgSO4, PO for 3 days.
2. High phosphate load: These infants have hyperphos-
phatemia with near normal calcium levels. Exclusive
breast-feeding should be encouraged and top feeding
with cows milk should be discontinued. Phosphate
binding gels should be avoided.
3. Hypoparathyroidism [9] These infants tend to be
hyperphosphatemic and hypocalcemic with normal
renal function. Elevated phosphate levels in the
absence of exogenous phosphate load (cows milk)
and presence of normal renal functions indicates
parathormone inefficiency. It is important to realize
that if the phosphate level is very high, then adding
calcium will lead to calcium deposition and tissue
damage. Thus, attempts should be made to reduce the
phosphate (so as to keep the calcium and the
phosphate product less than 55) [10]. These neonates
need supplementation with calcium (50 mg/kg/day in 3
divided doses) and 1,25(OH)2 Vitamin D3 (0.5-1 g/day).
Syrups with 125 mg and 250 mg per 5 ml of calcium are
available.1,25(OH)2 vitamin D3 (calcitriol) is available as
0.25 g capsules. Therapy may be stopped in hypocal-
cemia secondary to maternal hyperparathyroidism after
6 wks.
4. Vitamin D deficiency states: These babies have
hypocalcemia associated with hypophosphatemia due
to an intact parathormone response on the kidneys.
They benefit from Vitamin D3 supplementation in a
dose of 30-60 ng/kg/day

Table 3 Investigations required in infants with persistent / late onset hypocalcemia

Investigations required

First line Second line Others

Serum phosphate Serum magnesium CT brain for calcification
Serum alkaline phosphatase (SAP) Serum parathormone levels (PTH) Echocardiography
Liver function tests Urine calcium creatinine ratio Vitamin D levels (1,25 D3)
Renal function tests Maternal calcium, phosphate, and Hearing evaluation
alkaline phosphatase
X ray chest/ wrist Serum cortisol
Arterial pH Thyroid function tests
S No Disorder causing hypocalcaemia Findings
1 Hypoparathyroidism High : Phosphate
Low : SAP, PTH, 1,25 D3
2 Pseudo Hypoparathyroidim High : SAP, PTH, Phosphate
Low : 1,25 D3
3 Chronic renal failure High : phosphate, SAP, PTH, pH
(acidotic), deranged RFT
Low : 1,25 D3
4 Hypomagnesemia High : PTH
Low : Phosphate, Mg,1,25 D3
5 VDDR1 High : SAP, PTH
Low : Phosphate, 1,25 D3
6 VDDR II High : SAP, 1, 25 D3, PTH
Low : Phosphate

(VDDR; vitamin D dependent rickets)

 110
1128
Monitoring
The baby is monitored for the SCa, and phosphate, 24 h
urinary calcium, and calcium creatinine ratio. Try to keep the
calcium in the lower range as defective distal tubular
absorption leads to hypercalciuria and nephrocalcinosis [11].
Prognosis and outcome
Most cases of early neonatal hypocalcemia resolve within
48-72 h without any clinically significant sequelae.
Late neonatal hypocalcemia secondary to exogenous
phosphate load and magnesium deficiency also responds
well to phosphate restriction and magnesium repletion.
When caused by hypoparathyroidism, hypocalcemia
requires continued therapy with vitamin D metabolites
and calcium salts. The period of therapy depends on the
nature of the hypoparathyroidism which can be transient,
last several wks to months, or be permanent.
References
1. Schauberger CW, Pitkin RM. Maternal-perinatal calcium relation-
ships. Obstet Gynecol. 1979;53:746.
Indian J Pediatr (2010) 77:11231128
2. Linarelli LG, Bobik J, Bobik C. Newborn urinary cyclic AMP and
developmental responsiveness to parathyroid harmone. Pediatrics.
1972;50:1423.
3. Hillman L, Rajanasathit S, Slatopolsky E, Haddad JG. Serial
measurements of serum calcium, magnesium, parathyroid hor-
mone, calcitonin, and 25-hydroxy-vitamin D in premature and
term infants during the first week of life. Pediatr Res.
1977;11:789844.
4. Salle BL, Delvin EE, Lapillonne A, Bishop NJ, Glorieux FH.
Perinatal metabolism of vitamin D. Am J Clin Nutr. 2000;71:1317S
24S.
5. Singh J, Moghal N, Pearce SH, Cheetham T. The investigation of
hypocalcaemia and rickets. Arch Dis Child. 2003;88:4037.
6. Oden J, Bourgeois M. Neonatal endocrinology. Indian J Pediatr.
2000;67:21723.
7. Schwartz R, Teramo KA. Effects of diabetic pregnancy on the
fetus and newborn. Semin Perinatol. 2000;24:12035.
8. Nekvasil R, Stejskal J, Tuma A. Detection of early onset neonatal
hypocalcemia in low birth weight infants by Q-Tc and Q-oTc
interval measurement. Acta Paediatr Acad Sci Hung.
1980;21:20310.
9. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N
Engl J Med. 2000;343:186375.
10. Sharma J, Bajpai A, Kabra M, Menon PSN. Hypocalcemia
clinical, biochemical, radiological profile and follow-up in a
tertiary hospital in India. Indian Pediatr. 2002;39:27682.
11. Rigo J, Curtis MD. Disorders of calcium, phosphorus and
magnesium metabolism. In: Martin RJ, Fanaroff AA, Walsh
MC, editors. Neonatal Perinatal Medicine- Diseases of the
fetus and infant. 8th ed. Pihladelphia: Elsevier; 2006. p. 1508
14.
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113
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 115
Indian J Pediatr (2010) 77:11371142
DOI 10.1007/s12098-010-0175-1
SYMPOSIUM ON AIIMS PROTOCOLS IN NEONATOLOGY-I
Hypoglycemia in the Newborn
Ashish Jain & Rajiv Aggarwal & M. Jeeva Sankar &
Ramesh Agarwal & Ashok K. Deorari & Vinod K. Paul
Received: 27 July 2010 / Accepted: 2 August 2010 / Published online: 7 September 2010
# Dr. K C Chaudhuri Foundation 2010
Abstract Hypoglycemia in a neonate is defined as blood
sugar value below 40 mg/dL. It is commonly associated
with a variety of neonatal conditions like prematurity,
intrauterine growth restriction and maternal diabetes.
Screening for hypoglycemia in high-risk situations is
recommended. Supervised breast-feeding may be an initial
treatment option in asymptomatic hypoglycemia. However,
symptomatic hypoglycemia should always be treated with
a continuous infusion of parenteral dextrose. Neonates
needing dextrose infusion rates above 12 mg/kg/min should
be investigated for a definite cause of hypoglycemia.
Hypoglycemia has been linked to poor neuro-developmental
outcome, and hence aggressive screening and treatment is
recommended.
Keywords Hypoglycemia . Screening . Newborn . Therapy
A. Jain
Department of Pediatrics, Hindu Rao Hospital,
New Delhi, India
R. Aggarwal
Department of Pediatrics, Narayana Hrudayalaya,
Bangalore, India
R. Aggarwal
Division of Neonatology, Department of Pediatrics, AIIMS,
New Delhi, India
M. Jeeva Sankar : R. Agarwal (*) : A. K. Deorari : V. K. Paul
Department of Pediatrics, All India Institute of Medical Sciences,
Ansari Nagar,
New Delhi 110029, India
e-mail: aranag@rediffmail.com
72
Hypoglycemia is a common disorder.in neonates [1].
There is, however, no universal definition for this
condition [2]. Currently there is insufficient evidence with
respect to what constitutes hypoglycemia. The issue is
further complicated by the fact that low blood glucose
levels (BGLs) are associated with increased cerebral blood
flow as a compensatory mechanism. Brain is able to utilize
alternative energy substrates to maintain its cerebral
energy milieu. Various investigators have empirically
recommended different blood glucose levels that should
be maintained in neonatal period to prevent injury to the
developing brain [3, 4]. The normal range of blood
glucose is variable and depends upon factors like birth-
weight, gestational age, body stores, feeding status,
availability of energy sources as well as the presence or
absence of disease [5, 6]. Thus, the definition of
hypoglycemia should be flexible and encompass all these
aspects. Further, there is no concrete evidence to show the
causation of adverse long-term outcomes by a particular
level or duration of hypoglycemia [7]. Hence, a consensus
has been to evolve an operational threshold.
Definition
The operational threshold for hypoglycemia is defined as
that concentration of plasma or whole blood glucose at
which clinicians should consider intervention, based on
the evidence currently available in literature [8]. This
so-called operational threshold values are useful guide-
lines for clinicians to take appropriate actions. Till proper
evidence is generated, this value is currently believed to
be a blood glucose value of less than 40 mg/dL (plasma
glucose less than 45 mg/dL) [9].
 116 73
1138 Indian J Pediatr (2010) 77:11371142

Screening for Hypoglycemia When Should be Screening is Stopped?

Normal blood glucose levels are maintained by glyco-
genolysis and by gluconeogenesis from a variety of non-
carbohydrate energy sources. Neonatal hypoglycemia
often occurs in infants with impaired gluconeogenesis,
brought about by increased insulin production, altered
counter-regulatory hormone production or an inadequate
substrate supply.
Screening for hypoglycemia is recommended in high
risk infants (Table 1).
Time Schedule for Screening
There is a paucity of the literature that looks into optimal
timing and the intervals of glucose monitoring. Lowest blood
sugar values are seen at 2 h of life. IDMs frequently
experience asymptomatic hypoglycemia very early viz. 1 to
2 h and rarely beyond 12 h (range 0.8 to 8.5 h), supporting
early screening for this population [11]. However, preterm
and SGA may be at risk up to 36 h (range 0.8 to 34.2 h) [12].
Some SGA and preterm infants may develop hypoglycemia
when feeding is not established. Based on these assumptions
and current knowledge, Table 2 elaborates the schedule and
frequency of monitoring in different situations.
Education and Counseling of Caregivers Regarding
the Screening
Parents should be made aware that their infant is at-risk
and therefore requires blood tests at regular intervals.
This will ensure appropriate parental participation in
monitoring and allay fears if further interventions are
required.
& At risk infants (Table 1): At the end of 72 h.
& In an infant on IV fluids: Has two consecutive values
>50 mg/dL on total oral feeds after stopping of the IV fluids.
& Infant whose blood sugar normalized on oral feed:
Consider at risk and monitor for 48 h
Infants in Whom Screening is not Required
Screening for hypoglycemia is not recommended in term
healthy breast-fed appropriate-for-gestational age (AGA)
infants. However, term infants with poor feeding, presence
of inadequate lactation or presence of cold stress may be
considered for screening.
Method of Glucose Estimation
a. Bed side reagent strips (Glucose oxidase): Though
widely used and an important point of care method,
glucose estimation by this method is unreliable, especially
at levels where therapeutic intervention is required such as
BGL 4050 mg/dL. They are useful for screening purpose
but low values should be always confirmed by formal
laboratory analysis. However, treatment may be initiated
based on the results of the reagent strips. It is important to
also consider the variations between capillary and venous,
blood and plasma, and immediate and stored samples
(whole blood sugar is 1015% less than the plasma sugar,
the glucose levels can fall by 1418 mg/dL per hr in blood
samples that await the analysis [13].) Arterial samples
have slightly higher value compared to venous and
capillary samples.

Table 1 High risk situations where screening is recommended [10]

1 Low birth weight infants (<2000 gm)

2 Preterm infants (35 wks)
3 Small for gestational age infants (SGA) : birth weight <10th percentile
4 Infant of diabetic mothers (IDM) - insulin dependent and gestational diabetes
5 Large for gestational age (LGA) infants: birth weight >90th percentilea
6 Infants with Rh-hemolytic disease
7 Infants born to mothers receiving therapy with terbutaline/propranolol/lebatolol/oral hypoglycemic agents
8 Infants with morphological IUGR. This group includes neonates with birth weight between 10th25th and
possibly up to 50th percentile with features of fetal under-nutrition such as three or more loose skin folds in gluteal region,
decreased overall subcutaneous fat, and head circumference to chest circumference difference greater than 3 cm
9 Any sick neonate such as those with perinatal asphyxia, polycythemia, sepsis, shock etc,
when they are in active phase of illness. The screening may be discontinued once their condition gets stabilized.
10 Infants on total parenteral nutrition
a
LGA infants because of constitutional reasons such as infants of constitutionally large parents may also be exempted from routine screening
 117 74
Indian J Pediatr (2010) 77:11371142 1139

Table 2 Schedule of blood glucose monitoring

Symptomatology of infants Time schedule for screening

At risk neonates (S. No 1-8 in Table 1) 2, 6, 12, 24, 48, and 72 hrs
Sick infants Sepsis, asphyxia, shock in the active phase of illness Every 68 hrs (individualize as needed)
Stable VLBW infants on parenteral nutrition Initial 72 hrs: every 6 to 8 hrs; after 72 hrs in stable babies: once a day

Infants exhibiting signs compatible with hypoglycemia at any time also need to be investigated

The first generation strips focused on change in color of cyanosis, convulsions, intermittent apneic spells or
of enzyme on application of blood drop. The color can tachypnea, weak and high pitched cry, limpness and
be read by naked eye or more recently by reflectance lethargy, difficulty in feeding, and eye rolling. Episodes of
meters. The readings tend to get affected by hematocrit sweating, sudden pallor, hypothermia and cardiac arrest
values, acidosis, presence of bilirubin, presence of edema have also been reported.
etc. The newer generation glucose reagent strips generate
a current on reaction of glucose with enzymes such
glucose oxidase or glucose dehydrogenase. The amount
Diagnosis
of current is proportional to amount of sugar present in
plasma. Though these second generation glucose readers
a. Asymptomatic hypoglycemia: It is said to be present
are more accurate than the previous version, they are still
when the blood glucose level is less than 40 mg/dl (to
not entirely reliable. Any abnormal BGLs by this
be confirmed by laboratory estimation) and the infant
technique must be confirmed by standard laboratory
does not manifest any clinical features
methods.
b. Symptomatic hypoglycemia: This diagnosis should be
b. Laboratory diagnosis: This is the most accurate made if hypoglycemia coexists with clinical symp-
method. In the laboratory (lab), glucose can be tomatology. Neonates generally present with nonspe-
measured by either the glucose oxidase (calorimetric) cific signs that result from a variety of illnesses.
method or by the glucose electrode method (as used in Therefore, careful evaluation should be done to look
blood gas and electrolyte analyzer machine). Blood for all possible causes especially those that can be
samples should be analyzed quickly to avoid errone- attributed to hypoglycemia.
ously low glucose levels.
If clinical signs attributable to hypoglycemia persist
despite intravenous glucose, then other causes of persistent /
resistant hypoglycemia should be explored.
Clinical Signs Associated with Hypoglycemia

a. Asymptomatic: It is well known that low BGL may not
manifest clinically and be totally asymptomatic. These
infants should also be treated in view of the possible
adverse long term effects [14, 15]. However, there is
considerable controversy with regards to if asymptom-
atic hypoglycemia results in a neuronal damage.
b. Symptomatic: Clinical signs of hypoglycemia in order of
frequency are stupor, jitteriness, tremors, apathy, episodes
Management of Asymptomatic Hypoglycemia
Table 3
Oral FeedsIssues
Direct breast-feeding is the best option for trial of an oral
feed. If the infant is unable to suck, expressed breast milk

Table 3 Management plan of infants with asymptomatic hypoglycemia on screening

Blood sugar 2040 mg/dL
Blood sugar levels <20 mg/dL
Trial of oral feeds (expressed breast milk or formula) and repeat blood test after 1 hr. If repeat blood
sugar is more than 50 mg/dL, two hrly feeds is ensured with 6 hrly monitoring for 48 hrs
If repeat blood sugar is <40 mg/dL, IV Dextrose is started and further management is
as for symptomatic hypoglycemia
IV Dextrose is started at 6 mg/kg/min of glucose;further management is as for symptomatic hypoglycemia
 118
1140
may be used. Breast milk promotes ketogenesis (ketoacids
are important alternate sources for the brain along with less
important pyruvate, free fatty acids, glycerol, and amino
acids). If breast milk is not available, then formula feeds
may be given in at-risk neonates. If oral feeds are contra-
indicated, start glucose infusion.
Some of the randomized clinical trials in SGA [16] and
appropriate-for-gestational age [17] infants found that the
sugar or sucrose fortified milk (5 g sugar per 100 mL milk)
raises blood glucose and prevents hypoglycemia. Such
supplementation may be tried in the asymptomatic neonates
with blood sugar levels between 20 to 40 mg/dL. However,
this practice carries a potential to compromise breast feeding
rates, and therefore one should be prudent in exercising this
option.
All symptomatic infants should be treated with IV fluids.
Management of Symptomatic Hypoglycemia
For symptomatic hypoglycemia including seizures, a bolus
of 2 mL/kg of 10% dextrose (200 mg/kg) should be given.
This mini-bolus helps to rapidly achieve the steady state
levels of blood glucose [15]. Immediately after the bolus, a
glucose infusion at an initial rate of 68 mg/kg/min should
be started. Check blood sugar after 30 to 60 min and then
every 6 h until blood sugar is >50 mg/dL.
Repeat subsequent hypoglycemic episodes may be treated
by increasing the glucose infusion rate by 2 mg/kg/min until
a maximum of 12 mg/kg/min. After 24 h of IV glucose
therapy, once two or more consecutive blood glucose values
are >50 mg/dL, the infusion can be tapered off at the rate of
2 mg/kg/min every 6 h with BGL monitoring. Tapering has
to be accompanied by concomitant increase in oral feeds.
Once a rate of 4 mg/kg/min of glucose infusion is reached
and oral intake is adequate and the blood sugar values are
consistently >50 mg/dL, the infusion can be stopped without
further tapering. Ensure continuous glucose infusion without
any interruption preferably using infusion pump.
Table 4 Important causes of
resistant hypoglycemia and Important causes of resistant hypoglycemia
investigations
Congenital hypopitutarism
Adrenal insufficiency
Hyperinsulinemic states
Galactosemia
Glycogen storage disorders
Maple syrup urine disease
Mitochondrial disorders
Fatty acid oxidation defect
75
Indian J Pediatr (2010) 77:11371142
Do not stop an IV infusion of glucose abruptly; severe
rebound hypoglycemia may occur. Avoid using >12.5%
dextrose infusion through a peripheral vein due to the risk
of thrombophlebitis.
Recurrent / Resistant Hypoglycemia
This condition should be considered when there is a
failure to maintain normal blood sugar levels despite a
glucose infusion of 12 mg/kg/min or when stabilization
is not achieved by 7 days of therapy. High levels of
glucose infusion may be needed in the infants to achieve
euglycemia.
Besides increasing the rate of glucose infusion, drugs
may also be tried in the treatment of resistant hypoglyce-
mia. Before administration of the drugs, take the samples to
investigate the cause (Table 4). Drugs that are used include
the following:
(1) Hydrocortisone 5 mg/kg/day IV or PO in two divided
doses for 24 to 48 h
(2) Diazoxide 1025 mg/kg/day in three divided doses
PO. Diazoxide acts by keeping the KATP channels of
the -cells of the pancreas open, thereby reducing the
secretion of insulin. It is therefore useful in states of
unregulated insulin secretion like in insulinomas.
(3) Glucagon 100 g/kg subcutaneous or intramuscular
(max 300 g)maximum of three doses. Glucagon acts
by mobilizing hepatic glycogen stores, enhancing
gluconeogenesis and promoting ketogenesis. These
effects are not consistently seen in small-for-gestational
age infants. Side effects of glucagon include vomiting,
diarrhea and hypokalemia and at high doses it may
stimulate insulin release.
(4) Octreotide (synthetic somatostatin in dose of 210 g/kg/
day subcutaneously two to three times a day.
Do not use diazoxide and glucagon in small for
gestational age infants.
Investigations to be considered
Serum insulin levels
Serum cortisol levels
Growth hormone levels
Blood ammonia
Blood lactate levels
Urine ketones and reducing substances
Urine and sugar aminoacidogram
Free fatty acid levels
Galactose 1 phosphate uridyl transferase levels
 119 76
Indian J Pediatr (2010) 77:11371142 1141

Useful Formulae similar relationship of lower head circumference and

developmental scores was highlighted by Duvanel et al.
a Infusion rate % of dextrose being infused  rate mL=hr [18] Further, a systematic review of 18 studies on neuro-

mg=kg=min body weight in kg  6 development after hypoglycemia showed poor methodo-
b Infusion rate IV rate mL=kg=day  % of dextrose logical quality of all but two studies. None of the studies

mg=kg=min 144 provided a valid estimate of the effect of neonatal
c Infusion rate mg=kg=min Fluid rate mL=kg=day hypoglycemia on neurodevelopment [19]. Though these
 0:007 x % of dextrose infused studies have major limitations, it would seem prudent to
follow up all infants who had confirmed hypoglycemia in the
high-risk category, till a future optimal study is performed
Follow-up and Outcome [19]. The outcome of hypoglycemia is determined by
factors like, duration, degree of hypoglycemia, rate of
Lucas in 1988 linked hypoglycemia to long term adverse cerebral blood flow, and cerebral utilization of glucose.
outcomes in a retrospective multicentric study. Later, a Special attention should be paid to neuro-developmental

Fig. 1 Algorithm for manage-

Hypoglycemia
ment of neonatal hypoglycemia Blood sugar < 40 mg/dL

Symptomatic including
Asymptomatic seizures

Bolus of 2 mL/kg 10%

20-40 mg/dL <20 mg/dL glucose

IV glucose infusion @ 6 mg/kg/min

Monitor hourly till euglycemic and
Trial of oral / fortified feeds
then 6 hrly
(5g/100mL of sugar)

Blood sugar >50 mg/dL Blood sugar >50 mg/dL

Monitor the blood sugar after 1 hr

Stable for 24 hrs on IV fluids; 2

glucose @ 2
values of blood sugar >50 mg/dL mg/kg/min till
euglycemia
> 40 mg/dL < 40 mg/dL

Weaning at 2 mg/kg/min every

6 hrs; Increase till the glucose
Frequent feeds oral feeds; infusion rate is >12
Monitoring to continue 6 hrly mg/kg/min

Stop IV fluids when

Monitor blood sugar the rate is 4 mg/kg/min Send
and the infant is stable Serum insulin. cortisol ,
and growth hormone
Stop after 48 hrs levels
Blood ammonia
Stop monitoring when 2
Blood lactate levels
values are more than 50 on
Before discharge ensure that Free fatty acid levels
full oral feeds
there is no feeding difficulty Urine ketones and
reducing substances
Urine aminoacidogram
Before discharge ensure
that there is no feeding
difficulty Hydrocortisone
Diazoxide (not in SGA)
Glucagon (not in SGA)
Octreotide

Refer to Specialist center

Pancreatic diagnosis
PET Scan, Pancreatic Biopsy
 120
1142
outcome, overall IQ, reading ability, arithmetic proficiency
and motor performance (Fig. 1).
The infants can be assessed at 1 month corrected age
for vision / eye evaluation. At 3, 6, 9, 12 and 18 months
corrected age they can be followed up for growth,
neurodevelopment, vision and hearing loss. Vision can
be assessed with Teller acuity card and hearing should be
assessed by Brainstem evoked auditory responses. Neu-
rodevelopment will be assessed by the clinical psychol-
ogist using DASII 2. MRI at 46 weeks provides a good
estimate of hypoglycemic injury and therefore should
be considered in follow up of such infants subject to
affordability.
References
1. Cornblath M. Neonatal hypoglycemia 30 years later: does it injure
the brain? Historical summary and present challenges. Acta
Paediatr Jpn. 1997;39:S7S11.
2. Cornblath M, Hawdon JM, Williams AF, et al. Controversies
regarding definition of neonatal hypoglycemia: suggested opera-
tional thresholds. Pediatrics. 2000;105:11415.
3. Termote B, Verswijvel G, Gelin G, Palmers Y. Neonatal
hypoglycemic brain injury. JBR-BTR. 2008;91:1167.
4. Inder T. How low can I go? The impact of hypoglycemia on the
immature brain. Pediatrics. 2008;122:4401.
5. Mitanchez D. Glucose regulation in preterm newborn infants.
Horm Res. 2007;68:26571.
6. Cornblath M, Ichord R. Hypoglycemia in the neonate. Semin
Perinatol. 2000;24:13649.
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7. Rozance PJ, Hay Jr WW. Hypoglycemia in newborn infants:
features associated with adverse outcomes. Biol Neonate.
2006;90:7486.
8. Cornblath M, Schwartz R. Outcome of neonatal hypoglycemia. Br
Med J. 1999;318:194.
9. Hay Jr WW, Raju TNK, Higgins RD, et al. Knowledge gaps and
research needs for understanding and treating neonatal hypogly-
cemia: workshop report from Eunice Kennedy Shriver National
Institute of Child Health and Human Development. J Pediatr.
2009;155:6127.
10. Kalhan S, Parimi P. Gluconeogenesis in the fetus and neonate.
Semin Perinatal. 2000;24:94106.
11. Srinivasan G, Pilades RS, Cattamanchi G, et al. Plasma glucose
values in normal neonates: a new look. J Pediatr. 1986;109:1147.
12. Holtrop PC. The frequency of hypoglycemia in full term and small
for gestational age newborns. Am J Perinatol. 1993;10:1504.
13. Cowett RM, Damico LB. Capillary (heelstick) versus venous
blood sampling for determination of glucose concentration in
neonate. Biol Neonate. 1992;62:326.
14. Lucas A, Morley R. Outcome of neonatal hypoglycemia. Br Med
J. 1999;318:194.
15. Filan PM, Inder TE, Cameron FJ, et al. Neonatal hypoglycemia
and occipital cerebral injury. J Pediatr. 2006;148:5525.
16. Singhal PK, Singh M, Paul VK. Prevention of hypoglycemia: a
controlled evaluation of sugar fortified milk feeding in small- for-
date infants. Indian Pediatr. 1992;29:13659.
17. Singhal PK, Singh M, Paul VK, Malhotra AK, Deorari AK,
Ghorpade MD. A controlled study of sugar fortified milk feeding
in prevention of neonatal hypoglycemia. Indian J Med Res.
1991;94:3425.
18. Duvanel CB, Fawer CL, Cotting J, Hothfield P, Matthieu JM.
Long term effects of neonatal hypoglycemia on brain growth and
psychomotor development in small-for-gestational age preterm
infants. J Pediatr. 1999;134:4928.
19. Boluyt N, van Kempen A. Martin offringa. Neurodevelopment
after neonatal hypoglycemia: a systematic review and design of an
optimal future study. Pediatrics. 2006;117:223143.
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 125 77

Symposium on AIIMS Protocols in Neonatology II

Management of Infants with Intra-uterine Growth

Restriction
Ashok K. Deorari, Ramesh Agarwal and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New
Delhi, India

ABSTRACT
Intra-uterine growth restriction (IUGR) contributes to almost two-thirds of LBW infants born in India. Poor nutritional status and
frequent pregnancies are common pre-disposing conditions in addition to obstetric and medical problems during pregnancy.
Growth restriction may be symmetrical or asymmetrical depending on the time of insult during pregnancy. The pathological
insult in an asymmetrical IUGR occurs during the later part of the pregnancy and has a brain-sparing effect. Common
morbidities are more frequent in <3rd percentile group as compared to 3rd10th percentile group. Guidelines for management
of IUGR neonates in these two groups have been provided in the protocol. [Indian J Pediatr 2008; 75 (2) : 171-174] E-mail:
sdeorari@yahoo.com

Key words : IUGR; LBW; Postnatal management

Nearly one third of neonates born in India are low birth
weight (LBW), weighing less than 2500 grams at birth. A
babys low birth weight is either the result of preterm
birth (before 37 completed weeks of gestation) or due to
intrauterine growth restriction (IUGR). Later condition is
akin to malnutrition and may be present in both term and
preterm infants. Neonates affected by IUGR are usually
undernourished, undersized and therefore, low birth
weight. Two-third LBW neonates born in India fall in
this category.1 Since, IUGR neonates are more likely to
suffer complications including cold stress and
hypoglycemia, it is important that these infants are
identified and managed appropriately at birth.2 Even after
recovering from neonatal complications, they remain
more prone to poor physical growth, poor
neurodevelopmental outcome, recurrent infection and
chronic diseases (hypertension, hyperlipidemia, diabetes
mellitus, coronary heart disease) later in life3.
the terminology. SGA a statistical definition, is used for
neonates whose birth weight is lower than (less than 10th
percentile for that particular gestational age) population
norms. IUGR is a clinical definition and includes neonates
with clinical evidence of malnutrition. This may be in the
form of loose skin folds on the face and in the gluteal
region, absence of subcutaneous fat and peeling of skin.
Although most IUGR infants would also be SGA, it is
possible that a small minority of IUGR infants may have
birth weights above the 10 th percentile. These
morphological IUGR infants would behave like SGA
infants and should be managed along the same lines as
SGA infants. For purposes of discussion in this paper, the
term IUGR would include both the groups of infants .
ETIOLOGY

Poor nutritional status of the mother and frequent

IUGR AND SGA (SMALL-FOR-GESTATIONAL AGE)
Although both the terms are used inter-changeably and
both denote malnutrition, there is a minor difference in
Correspondence and Reprint requests : Dr Ashok K. Deorari,
Professor, Department of Pediatrics, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi 110029, India.
[Received January 11, 2008; Accepted January 11, 2008]
pregnancies are the major cause of IUGR. Mothers with a
weight of less than 40 Kg and a height of less than 145 cm
often give birth to SGA infants. Insufficient nutritional
intake during pregnancy also has an adverse effect on
fetal weight. Maternal hypertension, pre-eclampsia, post-
maturity, frequent pregnancies, multiple pregnancy,
anemia, malaria and tobacco use are other causes of
IUGR. 4-6 Chronic maternal diseases of heart, kidneys,
lungs or liver may also lead to IUGR.

Indian Journal of Pediatrics, Volume 75February, 2008 171

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Ashok K. Deorari et al

TYPES OF IUGR TABLE 1. Common Morbidities in SGA Neonates

Period: Jan 1999 to Period: Aug 04 to

Infants with IUGR are often classified as having Dec 00 (n=156) Jul 05 (n=144)
symmetrical (head circumference, length and weight
Weight <3rd Weight 3rd-10th Weight <10th
equally affected) or asymmetrical (with relative head
percentile percentile (n=109)
growth sparing) growth restriction. Infants with (n=47) percentile (n=144)
symmetric IUGR often have an earlier onset and are
associated with causes that affect total fetal cell number Birth asphyxia
including chromosomal, genetic, teratogenic, intra-uterine Total 4(8.5%) 10 (9.2%) 25 (17%)
Moderate 2 8
infections and severe hypertensive etiologies. Asymmetric Severe 2 2 -
IUGR is often of a later onset, demonstrates preservation Hypoglycemia
of blood flow to brain and is associated with poor Total 12 (25.5%) 14 (12.8%) 24 (17%)
maternal nutrition or late onset exacerbation of maternal Symptomatic 6 3 3
vascular disease (pre-eclampsia, chronic hypertension).7 Asymptomatic 6 11 21
Polycythemia
Total 14 (29.8%) 17 (15.6%) 14 (10%)
CLINICAL FEATURES Symptomatic 3 8 3
Asymptomatic 11 9 11
Hypothermia 0 4 (3.7%) (13.2%)
IUGR or SGA infants are often term or near-term in *Includes 1 baby with hypothermia and 18 babies with cold stress
gestation. Their birth weight usually falls below the 10th
percentile.8 The neonate has an emaciated look and loose and only 7% at 24 h of life. No cases of polycythemia were
skin because of lack of subcutaneous tissue. These are detected at 48 and 72 h of life.
particularly prominent over the buttocks and the thighs.
They look alert and are often plethoric. Comparison of the
head circumference with chest circumference is helpful in MANAGEMENT
the identification of a SGA infant. In infants with
appropriate growth, the head size is usually bigger than
the chest by about 2-cm. In SGA infants, the head Early delivery is indicated if there is arrest of fetal growth
circumference usually exceeds the chest circumference by and pulmonary maturity is satisfactory. Fetal hypoxia
more than 3 cm. A preterm SGA infant would have a may necessitate emergency cesarean section and one
combination of clinical features suggestive of both, should be prepared to receive an asphyxiated infant. If
prematurity and IUGR.9 liquor is meconium stained and the neonate is depressed,
endotracheal suctioning is essential.10 Infant should be
screened for any congenital malformations. Based on
PROBLEMS OF SGA INFANTS initial assessment, decision is taken to either keep the
infant in nursery or with mother (Fig. 1).
Common neonatal morbidities encountered in SGA Birth weight 3 rd 10 th percentile : In the absence of
infants born in our hospital are given in Table 1. The complications including perinatal asphyxia and
common morbidities encountered in IUGR neonates respiratory distress, these neonates may be managed with
include: (a) perinatal asphyxia, (b) hypothermia, (c) the mother (Table 2). Skin-to-skin care helps in
hypoglycemia and (d) polycythemia. These morbidities maintaining temperature and facilitates breast-feeding.
are commoner in the more severely growth restricted Early initiation of breastfeeding and/ or assisted feeding
babies (<3rd percentile) as compared to babies in the 3rd to helps in averting hypoglycemia. Term SGA infants
10th percentile category. usually do not pose any serious difficulties because they
have no problems in direct breast-feeding. To avoid
From August 2004 to July 2005, 144 SGA babies were
hypoglycemia, they should be put to breast within one
born in our hospital. 24 (17%) developed hypoglycemia
hour of birth. However, these infants are at risk of
and 14 (10%) had polycythemia requiring partial
morbidities and should be monitored regularly for
exchange transfusion. Amongst 24 babies with
hypoglycemia and polycythemia in the first 48-72 hours.
hypoglycemia 50% of the total episodes occurred at 2 h,
22% at 48 h, 11% each at 6 and 12 h and only 4% each at 24 Neonates with asymptomatic hypoglycemia should be
and 72 h of age. 12 (50%) had multiple episodes of supplemented with sugar fortified formula feeds. This
hypoglycemia. 3 babies were symptomatic and required may be given with the help of a cup and spoon/ paladai.
intravenous fluid therapy. Rest were managed with Neonates with normoglycemia on regular feeds should be
supplementary oral feeds. Of 14 babies with gradually weaned to exclusive breast-feeding within the
polycythemia, only 3 were symptomatic. Polycythemia next 3-4 days. Failure to maintain normoglycemia despite
was detected at 2 h in 50%, at 6 h in 29%, at 12 h in 14% regular oral feeds should be treated with IV fluids.

172 Indian Journal of Pediatrics, Volume 75February, 2008

 127 79

Management of Infants with Intra-uterine Growth Restriction

TABLE 2. Management of SGA Infants neonatal intensive care unit.11

Criteria for admission to Nursery
All SGA infants < 2 SD (3rd percentile)
- Infants with gestational age < 35 wks
- Infants with birth asphyxia, respiratory distress etc.
Care of SGA infants with mothers (birth weight between 3rd and
10th percentile, gestation >35 wks)
Early initiation of breast feeding (within 1 hour)
Skin-to-skin care to maintain temperature, monitoring of
cold stress by mother and health professionals.
Monitor blood sugar, hematocrit
Prevent infections
Care of SGA infants in Nursery (birth weight <3rd percentile or
gestation <35 wks)
Nurse in thermo neutral environment
It stable, early initiation of feeds ( EBM).
Feed by orogastric tube or katori-spoon /paladai if gestation
>32 wks
Initial intravenous fluids followed by orogastric or katori-
spoon /paladai if gestation <32 wks
Monitor blood sugar, hematocrit
Care of SGA infants with absent or reversed en-diastolic blood
flow
At higher risk of development of NEC
If preterm (gestation <32 weeks): Nil per oral or on minimal
enteral nutrition for first 48-72 h of life followed by gradual
advancement of feed volume
Neonates with symptomatic hypoglycemia should be
shifted to a special care nursery and managed
appropriately with a glucose bolus followed by a
continuous glucose infusion at 6-8 mg/Kg/min.
Neonates with asymptomatic polycythemia and a
hematocrit <75 maybe managed conservatively by
increasing fluid intake. The infant should receive regular
(2-3 hourly) breast feeds with extra supplementation.
Infants with symptomatic polycythemia or hematocrit >75
should be managed by partial exchange transfusion in the
Birth weight <3 rd percentile, gestation <35 weeks :
Neonates with severe growth restriction (<3rd percentile)
or with presence of complications should be managed in
the intensive care unit (Table 2). This group would
include infants with perinatal asphyxia, symptomatic
hypoglycemia, symptomatic polycythemia, prematurity
(<35 weeks), respiratory distress and hypothermia. They
should be monitored for hypoglycemia, polycythemia
and feed intolerance in the initial few days.
Infants with gestation <30 weeks (birth weight <1200
grams) should be started on IV fluids initially and
gradually weaned to oral feeds over the next few days. In
the absence of other complications, oro-gastric feeds
should be started for neonates >30 weeks (>1200 grams)
and gradually shifted to katori-spoon/ paladai feeding. An
infant on full oral feeds with spoon-feeding may be tried
on direct breast-feeding. These high-risk infants need to
be observed for a minimum of 72 hours for hypoglycemia.
Infants on full katori-spoon feeding and/ or breast-
feeding may be shifted to the mother after 72 hours if she
is confident of on going-care.
Paladai/spoon feeding : Feeding with a spoon (or a
similar device such as paladai) and katori (or any other
receptacle such as cup) has been found to be safe in SGA
infants.8 This mode of feeding is a bridge between gavage
feeding and direct breast-feeding. It is based on the
premise that neonates with a gestation of 30-32 weeks or
more are in a position to swallow the feeds satisfactorily
even though they may not be good at sucking or
coordinated sucking and swallowing. A medium sized
katori and a small (1-2 ml size) spoon should be used. The
spoon should be filled just short of the brim with

SGA*

Term (borderline)
<35 wk

<3rd percentile 3rd 10th percentile

Admit nursery Monitor with mother Admit nursery

Breastfeeding or katori-spoon Breastfeeding <30 wk initial on IV

30 34 wk orogastric or katori-spoon
*Blood sugar, hematocrit, temperature monitoring
Fig. 1. Algorithm for management of SGA infants

Indian Journal of Pediatrics, Volume 75February, 2008 173

 128
Ashok K. Deorari et al
expressed milk, should be placed at the corner of mouth
and milk should be allowed to flow into the infants
mouth slowly, avoiding any spillage. The infant would
actively swallow the milk. This process should be
repeated till the required amount has been fed. If the
infant does not actively accept and swallow the feed, an
attempt should be made to wake the infant with gentle
stimulation. If he is still sluggish, do not insist on this
method. It is better to switch back to gavage feeds till the
infant is ready.
SGA/IUGR BABIES WITH ABSENT OR REVERSED
END-DIASTOLIC FLOW (AREDF) IN UMBILICAL
ARTERY
In the IUGR fetus, hypoxemia produces circulatory
redistribution towards the brain and away from the
viscera and placenta, culminating in umbilical artery or
aortic AREDF in the most severely affected fetuses. The
combination of antenatal and persisting postnatal
disturbances of gut perfusion, interacting with the
metabolic demands of feeding, may adversely affect
intestinal tissue oxygenation, combining with stasis and
immunological factors to contribute to the development
of NEC. A review by Dorling et al including 14 studies
and 1178 neonates found higher risk of NEC in IUGR
babies with AREDF (odds ratio: 2.13; 95% CI: 1.49 to
3.03).12 Although evidence for feeding strategy to be
adopted in these babies is limited, it may be prudent to
start and persist with minimal enteral nutrition for first
48-72 h of life.
LONG-TERM OUTCOME AND FOLLOW-UP
IUGR babies are at risk for poor growth and neuro-
developmental outcome.3 We routinely follow IUGR
babies with birthweight below <3rd percentile and those
with birthweight 3-10 th percentile if they develop
174
80
significant morbidities (e.g., hypoglycemia, polycythemia,
birth asphyxia) during hospital stay.
REFERENCES
1. United Nations Childrens Fund and World Health
Organization, Low Birthweight: Country,regional and global
estimates. UNICEF, New York, 2004.
2. Arora NK, Paul VK, Singh M. Morbidity and mortality in
term infants with intrauterine growth retardation. J Trop
Pediatr 1987; 33 : 186-189.
3. Teberg AJ, Walther FJ, Pena IC. Mortality, morbidity, and
outcome of the small-for-gestational-age preterm infant. Semin
Perinatol 1988; 12 : 84-94.
4. Mavalankar DV, Gray RH, Trivedi CR, Parikh VC. Risk
factors for small for gestational age births in Ahmedabad,
India. J Trop Pediatr 1994; 40 : 285-290.
5. Arora NK, Singh M, Paul VK, Bhargava VL. Etiology of fetal
growth retardation in hospital born infants. Indian J Med Res
1987; 85 : 395-400.
6. Bhatia BD, Agarwal KN, Jain NP, Bhargava V. Growth
pattern of intrauterine growth retarded (IUGR) infants in first
nine months of life. Acta Pediatr Scand 1984; 73 : 189-196.
7. Singh M. Disorders of weight and gestation. In Singh M, ed.
Care of the Newborn, 5th ed. New Delhi; Sagar Publications,
1999; 224-245.
8. Singh M, Giri SK, Ramachandran K. Intrauterine growth
curves of live-born infants. Indian Pediatr 1974; 11: 475-479.
9. Paul VK. Management of LBW babies. In Deorari AK, ed.
NNF Teaching Aids on Newborn Care. 2nd ed, New Delhi; Noble
Vision, 1998; 25-36 .
10. Niermayer S, Kattwinkel J, Van Reempts P, Nadkarni V,
Phillips B, Zideman D et al. International guidelines for
neonatal resuscitation. An excerpt from the guidelines 2000
for cardiopulmonary resuscitation and emergency
cardiovascular care. International consensus on Science.
Contributors and reviewers for the neonatal resuscitation
guiidelines. Pediatrics 2000; 106 : E29.
11. Deorari AK, Paul VK, Shrestha L, Singh M. Symptomatic
neonatal polycythemia: comparison of partial exchange
transfusion with saline versus plasma. Indian Pediatr 1995; 32:
1167-1171.
12. Dorling J, Kempley S, Leaf A. Feeding growth restricted
preterm infants with abnormal antenatal Doppler results. Arch
Dis Child Fetal Neonatal Ed 2005; 90 : F359-F363.
Indian Journal of Pediatrics, Volume 75February, 2008
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 133 81

Symposium on AIIMS Protocols in Neonatology II

Jaundice in the Newborns

Satish Mishra, Ramesh Agarwal, Ashok K. Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi,
India

ABSTRACT
Hyperbilirubinemia is the commonest morbidity in the neonatal period and 5-10% of all newborns require intervention for
pathological jaundice. Neonates on exclusive breast- feeding have a different pattern and degree of jaundice as compared
to artificially fed babies.. Latest guidelines from American Academy of Pediatrics (AAP) for management of jaundice in a normal
term newborn have been included in the protocol. Separate guidelines have been provided for the management of jaundice
in sick term babies, preterm and low birth weight babies, for hemolytic jaundice and prolonged hyperbilirubinemia. [Indian
J Pediatr 2008; 75 (2) : 157-163] E-mail: sdeorari@yahoo.com

Key words : Jaundice; Newborns; Guidelines; Phototherapy; Exchange

Jaundice is an important problem in the first week of life. PATHOLOGICAL JAUNDICE

It is a cause of concern for the physician and a source of
anxiety for the parents. High bilirubin levels may be toxic
to the developing central nervous system and may cause
neurological impairment even in term newborns. Nearly
60% of term newborn becomes visibly jaundiced in the
first week of life.1 In most cases, it is benign and no
intervention is required. Approximately 5-10 % of them
have clinically significant hyperbilirubinemia mandating
the use of phototherapy.2-3
PHYSIOLOGICAL JAUNDICE
This is attributable to physiological immaturity of
neonates to handle increased bilirubin production. Visible
jaundice usually appears between 24-72 hours of age.
Total serum bilirubin (TSB) level usually rises in full-term
TSB concentrations have been defined as non-physiologic
if concentration exceeds 5 mg/dl on first day of life in
term neonate, 10 mg/dL on second day, or 12-13
thereafter. 6 Any TSB elevation exceeding 17 mg/dL
should be presumed pathologic and warrants
investigation for a cause and possible intervention, such
as phototherapy. 7 Appearance of jaundice within 24
hours, peak TSB levels above the expected normal range
(Fig. 1)8, presence of clinical jaundice beyond 3 weeks and
conjugated bilirubin (dark urine staining the clothes and
light colored stool) would be categorized under
pathological jaundice.
Serum Bilirubin (mg/dl)

High Risk Zone

infants to a peak of 6 to 8 mg/dL by 3 days of age and Zon
e
isk
eR
then falls. A rise to 12mg/dL is in the physiologic range. med
iat
k Zo
ne
mol/L

ter
h In te Ris
In premature infants, the peak may be 10 to 12 mg/dL on Hig
In term
edia
Low
the fifth day of life, possibly rising over 15 mg/dL
without any specific abnormality of bilirubin metabolism. Low Risk Zone

Levels under 2 mg/dL may not be seen until one month

of age in both full term and premature infants.4 Safe
bilirubin levels in preterms vary according to gestational
age. 5 Postnatal Age (hours)

Fig. 1. Nomogram for designation of risk in 2840 well newborns at

Correspondence and Reprint requests : Dr Ashok K. Deorari,
Professor, Department of Pediatrics, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi 110029, India.
[Received January 1, 2008; Accepted January 1, 2008]
36 or more weeks gestational age with birth weight of 2000
g or more or 35 or more weeks gestational age and birth
weight of 2500 g or more based on the hour-specific serum
bilirubin values 8

Indian Journal of Pediatrics, Volume 75February, 2008 157

 134
S. Mishra et al
BREAST-FEEDING AND JAUNDICE
Exclusively breast-fed infants have a different pattern of
physiological jaundice as compared to artificially fed
babies. 7,9,10 Jaundice in breast-fed babies usually appears
between 24-72 hours of age, peaks by 5-15 days of life and
disappears by the third week of life. They have also been
reported to have higher bilirubin levels. Schneiders meta-
analysis of 25 studies has shown that 13% of breast-fed
babies had peak TSB levels of 12 mg/dL or higher as
compared to 4% of artificially fed babies.11 One third of all
breast-fed babies are detected to have mild clinical
jaundice in the third week of life, which may persist into
the 2nd to 3rd month of life in a few babies.
Authors have stated that this increased frequency is
not related to characteristics of breast milk but rather to
the pattern of breast-feeding. Decreased frequency of
breast-feeding is associated with exaggeration of
physiological jaundice. Encouraging a mother to breast-
feed her baby at least 10-12 times per day would be
helpful in the management of jaundice in a term healthy
baby.
BREAST MILK JAUNDICE
Approximately 2-4% of exclusively breast-fed term babies
have jaundice in excess of 10 mg/dL in the third week of
life.12,13 These babies with TSB beyond 10 mg/dL after the
third week of life should be investigated for prolonged
jaundice. A diagnosis of breast milk jaundice should be
considered if the TSB is predominantly unconjugated,
other causes of prolonged jaundice have been excluded
and the infant is in good health. Mothers should be
advised to continue breast-feeding frequently intervals
and TSB levels usually decline over a period of time.
Interruption of breast-feeding is not recommended unless
TSB level exceeds 20 mg/dl.
CLINICAL EXAMINATION
Originally described by Kramer,14 dermal staining of
bilirubin may be used as a clinical guide to the level of
jaundice. Dermal staining in newborn progresses in a
cephalo-caudal direction. The newborn should be
examined in good daylight. The skin should be blanched
with digital pressure and the underlying color of skin and
subcutaneous tissue should be noted. A rough guide for
level of dermal staining with level of bilirubin is included
in Table 1.
Newborns detected to have yellow discoloration of the
skin beyond the legs should have an urgent laboratory
confirmation for levels of TSB. Clinical assessment is not
very reliable if a newborn has been receiving
158
82
TABLE 1. Guide to Dermal Staining with Level of Bilirubin
(Modified from Kramers Original Article)14
Area of body Level of bilirubin
Face 4-6 mg/dl
Chest, upper abdomen 8-10 mg/dl
Lower abdomen, thighs 12-14 mg/dl
Arms, lower legs 15-18 mg/dl
Palms, soles 15-20 mg/dl
phototherapy and if the baby has dark skin.
MEASUREMENT OF TSB LEVELS
Biochemical: Laboratory estimation of TSB based on High
Performance Liquid Chromatography (HPLC) remains
the gold standard for TSB estimation. However, this test
is not universally available and laboratory estimation of
TSB usually done in labs is based on Vanden Bergh
reaction. It usually have marked interlaboratory
variability with coefficient of variation up to 10 to 12
percent for TSB and over 20 percent for conjugated
fraction.15
Micro method for bilirubin estimation: It is based on
spectro-photometry and estimates TSB on a micro blood
sample. It is useful in neonates, as bilirubin is
predominantly unconjugated.
Transcutaneous bilirubinometer: This method is non
invasive and based based on reflectance data of multiple
wavelengths from the bilirubin stained skin. It averages
the spectra of five replicate measurements at one site to
give bilirubin estimation in mmol/l (or mg/dl).
Transcutaneous bilimeter (TcB) has a linear correlation to
TSB and may be useful as a screening device to detect
clinically significant jaundice and decrease the need for
frequent TSB determinations.16
CLINICAL APPROACH TO JAUNDICE
Is the newborn term or preterm? : Basic pathophysiology
of jaundice is same in term and preterm neonates but at
lower gestation babies are at higher risk of developing
hyperbilirubinemia and require closer surveillance and
monitoring. TSB values for intervention also vary in term,
near-term, and preterm neonates less than 35 weeks
period of gestation.
Management of hyperbilirubinemia in preterm infants
is still in grey zone for lack of enough objective evidences.
Clinical practice guidelines from American Academy of
Pediatrics (AAP) applies to the newborn infants of 35 or
more weeks of gestation.17
Is there evidence of hemolysis?: Setting of Rh or less
frequently ABO incompatibility, onset of jaundice within
24 hours, presence of pallor and hydrops, presence of
Indian Journal of Pediatrics, Volume 75February, 2008
 135
Jaundice in the Newborns
hepato-splenomegaly, presence of hemolysis on the
peripheral blood smear, raised reticulocyte count (>8%),
rapid rise of bilirubin (>5 mg/dl in 24 hours or >0.5 mg/
dl/hr) or a suggestive family history of significant
jaundice should raise a suspicion of hemolytic jaundice.
However, end-tidal carbon monoxide corrected for
ambient carbon monoxide (ETCOc) levels can confirm the
presence or absence of hemolysis, and measurement of
ETCO c is the only clinical test that provides a direct
measurement of the rate of heme catabolism and the rate
of bilirubin production.17
Does the infant have an underlying serious disease?
(sepsis, galactosemia) : Presence of lethargy, poor
feeding, failure to thrive, hepato-splenomegaly,
temperature instability or apnea may be a marker of an
underlying serious disease.
Does the infant have cholestatic jaundice? Presence of
jaundice (>10 mg/dl) beyond 3 weeks, presence of dark
urine (staining the clothes) or pale colored stools would
suggest cholestatic jaundice.
JAUNDICE IN A TERM HEALTHY BABY
Advise for physiological jaundice: The parents should be
explained about the benign nature of jaundice. The
mother should be encouraged to breast-feed frequently.
The newborn should be exclusively breast-fed with no top
feeds, water or dextrose water. Mother should be told to
bring the baby to the hospital if the baby looks too yellow
or yellow discoloration of the skin beyond the legs .
Any newborn discharged prior to 72 hours of life
should be evaluated again in the next 48 hours for
adequacy of breast-feeding and progression of jaundice.
Clinical judgment should be used in determining
follow-up. Earlier or more frequent follow-up should be
provided for those who have risk factors for
hyperbilirubinemia (Table 2).17
Management of pathological jaundice: Any term or near-
term newborn noted to have yellow staining of the skin
beyond the legs/estimated clinical or TcB in the high risk
zone of nomogram should have a confirmatory serum
bilirubin level. The American Academy of Pediatrics
(AAP)17 has laid down criteria for managing babies with
bilirubin in the pathological range (Fig. 2). Jaundice
appearing within 24 hours should be managed as
hemolytic jaundice.
All infants with bilirubin levels in the phototherapy
range should have the following investigations: blood
type and Coombs test, if not obtained with cord blood (if
mother is Rh negative or O group); complete blood count
and smear for hemolysis and red blood cell morphology;
reticulocyte count and G6PD estimation. These
investigations are done to exclude any hemolytic cause of
Indian Journal of Pediatrics, Volume 75February, 2008
83
Total Serum Bilirubin (mg/dl)
mol/L
38 wk and well)
Infants at lower risk (
Infants at medium risk ( 38 wk+risk factors or 35-37 6/7 wk. and well
Infants at higher risk (35-37 6/7 wk. + risk factors)
Age
Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin
Risk factors isoimmune hemolytic disease GGPD deficiency, asphyxia, significant lethargy, temperature,
instability, sepsis, acidosis, albumin < 3.0 g/dL (If measured).
For well infants 35-37 6/7 wk can adjust TSB levels for intervention around the medium risk line. It is an options
to intervene at lower TSB level for infant closer to 35 wk and at higher TSB levels for those closer to 37 6/7 wk
It is an option to provide conventional phtotherapy in hospital or at home at TSB levels 2-3 mg/dL (35-50 mol/
L) below those shown but home phototherapy should not be used in any infants with risk factor
Fig. 2. Guidelines for phototherapy in hospitalized infants of 35 or
more weeks gestation17
jaundice. Repeat TSB in 424 h depending on infants age
and TSB level.
We usually do repeat TSB within 4 to 6 hr if initial TSB
was in or near the exchange transfusion range. Meanwhile
blood is arranged for the exchange transfusion, so that
exchange can be done if there is no significant fall in the
TSB. In a healthy neonate without setting for hemolytic
jaundice and TSB not near exchange range we repeat TSB
after 12 to 24 hr. In Rh isoimmunization we do repeat TSB
at 8 to 12 hr interval for first 48 hr and 12 to 24 hourly
afterwards when probability of unexpected rise in TSB
usually decrease.
We follow guidelines of the American Academy of
Pediatrics (AAP)s for initiating phototherapy in term and
TABLE 2. Risk Factors for Development of Severe Hyperbiliru-
binemia in Infants of 35 or More Weeks Gestation (in
Approximate Order of Importance)17
Major risk factors
Predischarge TSB or TcB level in the high-risk zone (Fig. 2)
Jaundice observed in the first 24 h
Blood group incompatibility with positive direct antiglobulin test,
other known hemolytic disease (e.g., G6PD deficiency)
Gestational age 3536 wk
Previous sibling received phototherapy
Cephalohematoma or significant bruising
If breastfeeding is not going well and weight loss is excessive
Minor risk factors
Predischarge TSB or TcB level in the high intermediate-risk zone
Gestational age 3738 wk
Jaundice observed before discharge
Previous sibling with jaundice
Macrosomic infant of a diabetic mother
Male gender
Decreased risk (these factors are associated with decreased risk of
significant jaundice, listed in order of decreasing importance)
TSB or TcB level in the low-risk zone (Fig. 2)
Gestational age 41 wk
Discharge from hospital after 72 h
159
 136 84

S. Mishra et al

38 wk and well)
Infants at lower risk (
age are mentioned in Table 4. Intervention for Rh
Infants at medium risk ( 38 wk+risk factors or 35-37 6/7 wk. and well hemolytic disease in preterm babies is indicated at lower
Infants at higher risk (35-37 6/7 wk. + risk factors)
values. A level greater than 0.5% and 1% birth weight
Total Serum Bilirubin (mg/dl)

(Kg) can be used as a rough guide for phototherapy and

exchange blood transfusion respectively.

mol/L
TABLE 4. Indications for Exchange Transfusion in Rh
Isoimmunization 6

An exchange transfusion soon after birth is indicated if:

Cord bilirubin is 5mg/dl
Cord Hb is 10 mg/dl, PCV <30
Age
The dashed lines for the first 24 hours indicate uncertaintity due to a wide range of clinical circumstances and Previous sibling history and positive DCT.
a range of responses to phototherapy
Immediate exchange transfusion is recommended if infant shows signs of acute bilirubin encephalopathy Subsequent exchange transfusions are indicated if:
(hypertonia, arching, retrocollis fever, high pitched cry) or if TSB is 5 mg/dl (85 mol/L) above these lines.
Risk factor- Isoimmune hemolytic disease G6PD deficiency, asphyxia, significant lethargy, temperature,
1. Bilirubin 10 mg/dl within 24 hours of age
instability, sepsis, acidosis. 2. Bilirubin 15 mg/dl between 25-48 hours of age
Measure serum albumin and calculate B/A ratio (see legend)
Use total bilirubin do not subtract direct reacting or conjugeted bilirubin. 3. Bilirubin 20 mg/dl after 48 hours of age.
Infant is well and 35-37 6/7 wk (medium risk) can individualize TSB levels for exchange based on actual
gestational age. Rate of rise of bilirubin is 0.5 mg/dl/hr.

Fig. 3. Guidelines for exchange transfusion in infants 35 or more

weeks gestation17 Intravenous immunoglobulin (IVIG) is an alternative
therapy which may be effective in treating isoimmune
near term infants (Fig. 2).17 For preterm and VLBW infants haemolytic jaundice. In isoimmune haemolysis red blood
guidelines for phototherapy are not so clear for lack of cells are probably destroyed by an antibody-dependent
data. We follow the ranges given in Table 3. cytotoxic mechanism mediated by Fc receptor bearing
cells of the neonatal reticuloendothelial system. The
TABLE 3. Management of Neonatal Hyperbilirubinemia in Low putative mechanism of IVIG action is non-specific
Birth Weight Babies Based on Bilirubin Levels (mg/dl)5
blockade of Fc receptors. IVIG may be used in a dose of
Weight (gm) Phototherapy Consider exchange 0.5g to 1g/Kg (single dose) after the first ET/as early as
transfusion possible if ET not indicated. Phenobarbitone 5 mg/Kg/
day x 5 days may be started after the first ET/with in 12
500-750 5-8 12-15
750-1000 6-10 >15
hrs if ET not indicated
1000-1250 8-10 15-18 ABO Incompatibility: Babies born to women with O
1250-1500 10-12 17-20 blood group should be closely monitored for jaundice and
1500-2500 15-18 20-25
discharged after 72 hours. If the maternal blood is group
O, Rh-positive, it is an option to test the cord blood for the
For paucity of evidence these phototherapy guidelines infants blood type and direct antibody test, but it is not
are given only for first week of life. We follows the same required provided that there is appropriate surveillance,
guidelines for neonates with hyperbilirubinemia post first risk assessment before discharge, and follow-up. Jaundice
week of life, however, these babies are probably less prone due to ABO incompatibility usually appears in the first 24
for bilirubin induced brain damage with similar TSB. hours. In the presence of significant jaundice or jaundice
appearing within 24 hours, the work up for pathological
HEMOLYTIC JAUNDICE jaundice should be done. An approach to phototherapy
and ET has been outlined in section 15.

The common causes of hemolytic jaundice include Rh Other hemolytic states: G6PD deficiency, hereditary
hemolytic disease, ABO incompatibility, G-6-PD spherocytosis, minor group incompatibilities should be
deficiency and minor blood group incompatibility. managed similar to ABO incompatibility. Investigations
for G-6-PD deficiency should be considered in all term
Rh hemolytic disease: A baby born to an Rh-negative and near-term infants with jaundice requiring
mother (and Rh-positive father) should have Rh typing phototherapy, with a family history of significant jaundice
and a Direct Coombs test (DCT) on cord blood. or a geographic origin associated with G-6-PD deficiency.
Newborns suspected to have Rh isoimmunization should
have a blood group and Rh typing, DCT, PCV and serum
bilirubin on cord blood to facilitate early treatment. A JAUNDICE IN PRETERM BABIES
reticulocyte count should be sent prior to the first
exchange transfusion (ET). Intensive phototherapy should
be started at birth and continued till two consecutive In premature infants, the term physiologic jaundice is of
readings are below phototherapy range. Indications for little value. In VLBW infants, TSB levels well within the
exchange transfusion at birth and subsequently at a later physiologic range might be hazardous and sometimes

160 Indian Journal of Pediatrics, Volume 75February, 2008

 137
Jaundice in the Newborns
need to be treated with phototherapy.18
Clinicians should ensure that all premature infants are
routinely monitored for the development of jaundice.
Serum bilirubin should be measured at 24 hours of age
with follow up estimations every 12-24 hours until the
levels stabilize. Recommendations for starting
phototherapy in VLBW infants have been mentioned in
Table 3. Bilirubin should be repeated within 24-48 hours
of stopping phototherapy or sooner if clinical jaundice
reappears. Direct bilirubin should be measured weekly in
infants on parentral nutrition.
As a rough guide in healthy low birth weight infants
phototherapy should be started at a bilirubin level of 1%
of the birth weight (in grams) e.g., a baby weighing 1000
grams should receive phototherapy if the bilirubin levels
exceed 10 mg/dl. An exchange transfusion should be
considered at a value of 5 mg/dl higher than that for
phototherapy (1% of birth weight + 5 mg/dl). A sick
VLBW baby requires intervention at lower levels.
SMALL FOR GESTATIONAL AGE (SGA) BABIES
Bilirubin handling in newborn is related to maturity of
liver, which is dependent upon gestational age.
Gestational age and corresponding appropriate weight
may be a better guide for intervention as compared to
actual birth weight in SGA infants.
JAUNDICE IN A SICK NEWBORN
At high bilirubin levels sick neonates are more prone for
bilirubin induces brain damage than the healthy neonate
of similar gestation and weight. Intervention for jaundice
in this group should start at lower levels of TSB (at a
centile line below the expected for that gestation in Fig. 2
and 3).
Additional investigations in a sick newborn include
direct bilirubin, septic screen, blood and urine culture and
urine for reducing substances
PROLONGED JAUNDICE BEYOND 3 WEEKS
This is defined as persistence of significant jaundice (10
mg/dl) beyond three weeks in a term baby. The common
causes include breast milk jaundice, extravasated blood
(cephalhematoma), ongoing hemolytic disease, G-6PD
deficiency and hypothyroidism. One should rule out
cholestasis by noting the urine and stool color and
checking the level of direct bilirubin. The diagnostic work
up in such a newborn includes:
Investigations to rule out cholestasis (stool color, urine
color, direct and indirect bilirubin levels)
Investigations to rule out ongoing hemolysis, G-6PD
Indian Journal of Pediatrics, Volume 75February, 2008
85
screen
Investigations to rule out hypothyroidism
Investigations to rule out urinary tract infection.
TREATMENT OPTIONS
Phototherapy
Factors That Affect the Dose and Efficacy of
phototherapy17
(a) Spectrum of light emitted: Blue-green spectrum is most
effective. At these wavelengths, light penetrates skin
well and is absorbed maximally by bilirubin. Use
special blue tubes or LED light source with output in
blue-green spectrum for intensive PT.
(b) Spectral irradiance (irradiance in certain wavelength
band) delivered to surface of infant: If special blue
fluorescent tubes are used, bring tubes as close to
infant as possible to increase irradiance. Special blue
tubes 1015 cm above the infant will produce an
irradiance of at least 35 W/cm2 per nm.
(c) Spectral power (average spectral irradiance across surface
area) For intensive PT, expose maximum surface area
of infant to PT. Double surface phototherapy may be
more effective than single surface phototherapy.
(d) Cause of jaundice: PT is likely to be less effective if
jaundice is due to hemolysis or if cholestasis is
present. When hemolysis is present, start PT at
lower TSB levels. Use intensive PT. Failure of PT
suggests that hemolysis is the cause of jaundice.
(e) TSB level at start of PT: The higher the TSB, the more
rapid the decline in TSB with PT. Use intensive PT
for higher TSB levels. Anticipate a more rapid
decrease in TSB when TSB >20 mg/dL (342 mol/L).
Continuous phototherapy : Is better than intermittent
phototherapy. Phototherapy should be interrupted in a
newborn only during breast-feeding and nappy changes.
Conventional phototherapy: If jaundice is non-hemolytic
or rate of rise of jaundice is slow then one can use either
conventional or fibre-optic phototherapy units.
Intensive phototherapy: In case of hemolytic or rapidly
rising bilirubin or when a conventional unit is not
effective, use of intensive phototherapy is warranted. This
can be achieved by placing the infant on bili-blanket and
using additional overhead phototherapy units with
special blue lights and lowering the phototherapy units to
within a distance of 15-20 cm. Intensive phototherapy
implies irradiance in the blue-green spectrum
(wavelengths of approximately 430490 nm) of at least 30
W/cm2 per nm (measured at the infants skin directly
below the center of the phototherapy unit) and delivered
to as much of the infants surface area as possible.
161
 138
S. Mishra et al
Measurements should be made with a radiometer
specified by the manufacturer of the phototherapy
system.17
Hydration: Maintaining adequate hydration and good
urine output should help to improve the efficacy of
phototherapy.
Failure of phototherapy: Failure of phototherapy has
been defined as an inability to observe a decline in
bilirubin of 1-2 mg/dl after 4-6 hours and/ or to keep the
bilirubin below the exchange transfusion level. Exchange
transfusion is recommended if the TSB rises to these levels
despite intensive phototherapy. For readmitted infants, if
the TSB level is above the exchange level, repeat TSB
measurement every 2 to 3 hours and consider exchange if
the TSB remains above the levels indicated after intensive
phototherapy for 6 hours. The recommended levels for
exchange transfusion have been given in Fig. 3. However,
an exchange transfusion (ET) may be performed at the
slightest suspicion of bilirubin encephalopathy
irrespective of the bilirubin value.
When Should Phototherapy Be Stopped?: There is no
standard for discontinuing phototherapy. For infants who
are readmitted after their birth hospitalization (usually for
TSB levels of 18 mg/dL or higher), phototherapy may be
discontinued when the serum bilirubin level falls below
13 to 14 mg/dL. Discharge from the hospital need not be
delayed to observe the infant for rebound. If phototherapy
is used for infants with hemolytic diseases or is initiated
early and discontinued before the infant is 3 to 4 days old,
a follow-up bilirubin measurement within 24 hours after
discharge is recommended. For infants who are
readmitted with hyperbilirubinemia and then discharged,
significant rebound is rare, but a repeat TSB measurement
or clinical follow-up 24 hours after discharge is a clinical
option.
Sunlight Exposure: Although sunlight provides sufficient
irradiance in the 425- to 475-nm band to provide
phototherapy, the practical difficulties involved in safely
exposing a naked newborn to the sun either inside or
outside (and avoiding sunburn) preclude the use of
sunlight as a reliable therapeutic tool, and it therefore is
not recommended.
Exchange transfusion
Rh isoimmunization: Blood used for exchange
transfusion in neonates with Rh isoimmunization should
always have Rh negative blood group. The best choice
would be O (Rh) negative packed cells suspended in AB
plasma. O (Rh) negative whole blood or cross-matched
babys blood group (Rh negative) may also be used in an
emergency.
ABO incompatibility: Only O group blood should be
used for exchange transfusion in neonates with ABO
incompatibility. The best choice would be O group (Rh
162
86
compatible) packed cells suspended in AB plasma or O
group whole blood (Rh compatible with baby).
Other situations: Cross-matched with babys blood
group.
Blood volume used
Partial exchange done at birth in Rh hemolytic disease
with severe anemia / hydrops (aims at increasing the
oxygen carrying capacity of blood): 50 ml/ kg of
packed cells
Double volume exchange: 2 x (80-100 ml/kg) x birth
weight in Kg (arrange 70% PRBC and 30% FFP, so that
PCV of whole arranged blood ~ 50-55)
Pharmacological Treatment
Phenobarbitone: It improves hepatic uptake, conjugation
and excretion of bilirubin thus helps in lowering of
bilirubin. However, its effect takes time. When used
prophylactically in a dose of 5 mg/Kg for 3-5 days after
birth, it has shown to effective in babies with hemolytic
disease, extravasated blood and in preterms without any
significant side effects.
Intravenous Immunoglobulins (IVIG): High dose
intravenous g-globulin (IVIG) (0.5 to 1 gm/Kg) has been
shown to reduce the need for exchange transfusions in Rh
and ABO hemolytic disease.17
Pharmacologic Therapy: There is now evidence that
hyperbilirubinemia can be effectively prevented or treated
with tin-mesoporphyrin, a drug that inhibits the
production of heme oxygenase. Tin-mesoporphyrin is not
approved by the US Food and Drug Administration. If
approved, tin-mesoporphyrin could find immediate
application in preventing the need for exchange
transfusion in infants who are not responding to
phototherapy.
FOLLOW-UP
Babies with serum bilirubin 20 mg/dl and those who
require exchange transfusion should be kept under
follow-up in the high- risk clinic for neuro-developmental
outcome. Hearing assessment (BERA) should be done at
0-3 months of corrected age. With prompt treatment, even
very elevated serum bilirubin levels within the range of
25 to 29 mg/dl are not likely to result in long-term
adverse effects on neurodevelopment. 19 Provisional
committee for quality improvement and subcommittee on
hyperbilirubinemia.
REFERENCES
1. American Academy of Pediatrics. Practice parameter:
management of hyperbilirubinemia in the healthy term
newborn. Pediatrics 1994; 94 : 558-565.
2. Maisels MJ, Gifford K, Antle CE, Lab GR. Jaundice in the
Indian Journal of Pediatrics, Volume 75February, 2008
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Jaundice in the Newborns
healthy newborn infant: a new approach to an old problem.
Pediatrics 1988; 81 : 505-511.
3. Kiviahan C, Jams EJ. The natural history of neonatal jaundice.
Pediatrics 1984; 74 : 364-370.
4. Martin CR, Cloherty JP. Neonatal hyperbilirubinemia. In
Cloherty JP, Eichenwald EC, Stark AR, eds. Manual of Neonatal
Care, 15th ed. Philadelphia: Lippincott Williams & Wilkins,
2004; 185-221.
5. Cashore WJ. Bilirubin and jaundice in the micropremie. Clin
Perinatol 2000; 27 : 171-179.
6. Madan A, Mac Mohan JR, Stevenson DK. Neonatal
Hyperbilirubinemia. In Taeush HW, Ballard RA, Gleason CA,
eds. Averys Diseases of the Newborn, 8th ed. Philadelphia; WB
Saunders, 1226-1256.
7. Maisels MJ, Gifford K. Normal serum bilirubin levels in new-
borns and effect of breast-feeding. Pediatrics 1986; 78 : 837-843.
8. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a
predischarge hour-specific serum bilirubin for subsequent
significant hyperbilirubinemia in healthy term and near-term
newborns. Pediatrics 1999; 103 : 6-14.
9. Gartner LM, Herschel M. Jaundice and breast-feeding. Pediatr
Clin North Am 2001; 48 : 389-399.
10. Gartner LM, Lee KS. Jaundice in the breast-fed infant. Clin
Perinatol 1999; 26 : 431-445.
11. Schneider AP. Breast milk jaundice in the newborn: A real
entity. JAMA 1986; 255 : 3270-3274.
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12. Clarkson JE, Cowan JO, Herbison GP. Jaundice in full term
healthy neonates: A population study. Aust Pediatr J 1984;
20 : 303-308.
13. Winfield CR, MacFaul R. Clinical study of prolonged jaundice
in breast and bottle-fed babies. Arch Dis Child 1978; 53: 506-
507.
14. Kramer LI. Advancement of dermal icterus in jaundiced
newborn. Am J Dis Child 1969; 118 : 454-458.
15. Singh M. Jaundice. In Singh M, ed. Care of the Newborn, 6th ed.
New Delhi; Sagar Publications, 2004; 248.
16. Stanley Ip, Mei Chung, John Kulig, Rebecca OBrien, Robert
Sege et al. Technical report, An evidence-based review of
important issues concerning neonatal hyperbilirubinemia.
Pediatrics 2004; 114 : e130-e150.
17. Maisels MJ, Baltz RD, Bhutani VK et al. Management of
hyperbilirubinemia in the newborn infant 35 or more weeks of
gestation. Pediatrics 2004; 114 : 297-316.
18. Maisels MJ. Jaundice. In MacDonald MG, Mullett MD, Seshia
MMK, eds. Averys Neonatology Pathophysiology and
Management of the Newborn, 6th ed. Philadelphia; Lippincott
Williams & Wilkins; 2005; 775.
19. Thomas BN, Petra L, Rita JJ, Donna MF, Yvonne WW.
Outcomes among Newborns with Total Serum Bilirubin
Levels of 25 mg per Deciliter or More. NEJM 2006; 354 : 1889-
1900.
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 144 88

Symposium on AIIMS Protocols in Neonatology V

Kangaroo Mother Care-an Alternative to Conventional

Care
Anu Thukral, Deepak Chawla, Ramesh Agarwal, Ashok K. Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar,
New Delhi, India

ABSTRACT

The term kangaroo mother care ( KMC ) is derived from practical similarities to marsupial care-giving, i.e., the premature infant
is kept warm in the maternal pouch and close to the breasts for unlimited feeding. It is a gentle and effective method that avoids
agitation routinely experienced in a busy ward with preterm infants. An important main stay of kangaroo mother care is
breastfeeding encouragement. Observational studies have shown reduction in mortality after institution of KMC. Preterm
babies exposed to skin to skin contact showed a better mental development and better results in motor tests. It also improves
thermal care. All stable LBW babies are candidate for KMC. Often this is desirable, until the babys gestation reaches term
or the weight is around 2500 g. The mother and family members are encouraged to take care of the baby in KMC and should
be counseled to come for follow-up visits regularly. [Indian J Pediatr 2008; 75 (5) : 497-503] E-mail: ashokdeorari_56
@hotmail.com

Key words : Kangaroo mother care; Skin to skin contact; Thermal care low birth weight; Skin contact and breast feeding

Kangaroo mother care (KMC) is care of preterm or low
birth weight infants carried skin-to-skin with the mother.
KMC was initially conceived as an alternative to the usual
minimal in-hospital care for stable low birth weight
infants. Low birthweight, defined as weight at birth of less
than 2500 g irrespective of gestational age, has an adverse
effect on child survival and development. World-wide,
twenty-five million LBW infants are born each year, the
great majority (96%) of them in developing countries.
Conventional neonatal care of LBW infants is expensive
and needs both trained personnel and permanent logistic
support. In developing countries, financial and human
resources for neonatal care are limited and hospital wards
for LBW infants are often overcrowded. Thus,
interventions for LBW infants that reduce neonatal
morbidity, mortality and costs would be desirable in
developing countries like India.
KMC was first suggested in 1978 by Dr Edgar Rey in
Bogot, Colombia. The term kangaroo care is derived
from practical similarities to marsupial care-giving, i.e.,
the premature infant is kept warm in the maternal pouch
Correspondence and Reprint requests : Dr. Ashok Deorari,
Professor, Department of Pediatrics, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi 110029, India
[Received April 28. 2008; Accepted April 28, 2008]
and close to the breasts for unlimited feeding. The
mothers are used as incubators and as the main source
of food and stimulation for LBW infants while they
mature enough to face extrauterine life in similar
conditions as those born at term. The method is applied
only after the LBW infant has stabilized. Introduction of
KMC results in early hospital discharge of low birth
weight infants.
In the last few decades, several health services have
adopted KMC, thus showing that it is possible to adapt
this practice to different contexts of access to neonatal care
technology. The first experiments conducted in
industrialized countries demonstrated that KMC was safe
in terms of physiological response of newborns and that
the method brought benefits regarding the breast feeding
practice and decreased the number of hospitalizations, in
addition to reduced infant crying at six months of life.1, 2
Experiments carried out in developing countries have
shown that KMC is safe in terms of mortality and may
reduce severe morbidity and avoid hospital
readmissions.3, 4 Therefore, KMC can potentially improve
the health and survival of LBW newborns, especially in
those places where resources are scarce.5
The major components of KMC are: (1) skin-to-skin
contact. Babies are kept, day and night, between the
mothers breasts firmly attached to the chest in an upright
position, (2) frequent and exclusive or nearly exclusive

Indian Journal of Pediatrics, Volume 75May, 2008 497

 145
A. Thukral et al
breast feeding and (3) early discharge from hospital
regardless of weight or gestational age. Respiratory,
thermal and feeding stabilization are crucial for the
success of this intervention. The definition of stabilization
is not precise, and has been defined as independent of
gestational age and weight, which are the main variables
associated with those vital functions.
COMPONENTS OF KMC
Kangaroo position
The kangaroo position consists of skin-to-skin contact
(SSC) between the mother and the infant in a strictly
vertical position, between the mothers breasts and under
her clothes. SSC should be started as early as possible
after birth and can be of two types depending upon the
duration: continuous or intermittent.1 The continuous
modality is usually employed as an alternative to
minimal care in an incubator for infants who have already
overcome major problems while adapting to extra-uterine
life, are able to suck and swallow properly and are
thriving in neutral thermal environment. To replace
incubators the kangaroo position should be maintained as
long as possible, ideally 24 hr/day. The provider must
sleep in a semi- reclining position to avoid the reflux in
more preterm infants. The Kangaroo position is
maintained until the infant no longer tolerates it- he
sweats and refuses the Kangaroo position. When
continuous care is not possible, the kangaroo position can
be used intermittently, providing the proven emotional
and breastfeeding promotion benefits. The kangaroo
position must be offered for as long as possible (1-2 hrs at
least), provided the infant tolerates it well. This 1-2 h span
is important as it provides the stimulation that the mother
needs to increase the milk volume and facilitate milk let-
down. This is initiated in the hospital and continued at
home.
Kangaroo nutrition
Kangaroo nutrition is the delivery of nutrition to
kangarooed infants as soon as oral feeding is possible.
It is based on exclusive breastfeeding by direct sucking,
whenever possible. Goal is to provide exclusive or nearly
exclusive breastfeeding with fortification if needed.
Breastfeeding is an integral component of KMC and it
might contribute to significant gains in neurological
development and IQ.
Kangaroo discharge and follow-up
Early home discharge in the kangaroo position from the
neonatal unit is one of the original components of the
KMC intervention. If not safely possible, the mother-
infant dyad can room-in together in a minimal care
facility (kangaroo wards) until safe discharge is possible.
Mothers at home require adequate support and follow-up
498
89
hence a follow-up program and access to emergency
services must be ensured.
Finally it is a gentle and effective method that avoids
agitation routinely experienced in a busy ward with
preterm infants.
BENEFITS OF KMC
Physiological benefits
Heart and respiratory rates, respiration, oxygenation,
oxygen consumption, blood glucose, sleep patterns and
behavior observed in preterm/LBW infants held skin-to-
skin tend to be similar to or better than those observed in
infants separated from their mothers.2, 3
CLINICAL BENEFITS
Effect on breastfeeding
An important main-stay of kangroo mother care is
breastfeeding encouragement. Although evidence shows
countless benefits of breastfeeding for preterm babies, the
prevalence of breastfeeding in this group is quite low. 6-
11
Studies carried out in areas where KMC is done show
that mothers who establish skin to skin contact with their
preterm babies have a significantly higher milk
production than their control group. Furthermore these
studies have also revealed that interruption of breast
feeding was more frequent among mothers who were not
submitted to this method. Whitelaw et al carried out a
randomized trial among babies less than 1500 gm and
found higher breastfeeding rates at 6 weeks in KMC
group (55% vs 28%).2
Ramanathan et al conducted a randomized control trial
to study the effect of Kangaroo Mother Care (KMC) on
breast feeding rates, weight gain and length of
hospitalization of very low birth neonates and to assess
the acceptability of Kangaroo Mother Care by nurses and
mothers.12 Babies whose birth weight was less than 1500
grams were included in the study once they were stable.
Neonates in the KMC group demonstrated better weight
gain after the first week of life (15.9 4.5 gm/day vs 10.6
4.5 gm/day in the KMC group and control group
respectively) and earlier hospital discharge (27.2 7 vs
34.6 7 days in KMC and control group respectively).
The number of mothers exclusively breastfeeding their
babies at 6 week follow-up was double in the KMC group
than in the control group (12/14 vs 6/14). Rao et al also
found higher rate of exclusive breastfeeding in KMC
group.13
In a meta-analysis by Neonatal Review Group of the
Cochrane Collaboration, randomized trials comparing
KMC and conventional neonatal care in LBW infants were
Indian Journal of Pediatrics, Volume 75May, 2008
 146
Kangaroo Mother Care-an Alternative to Conventional Care
analyzed.14 Three studies, involving 1362 infants, were
included. All the trials were conducted in developing
countries. KMC was found to decrease probability of not
exclusively breastfeeding at discharge (relative risk 0.41,
95% confidence interval 0.25 to 0.68).
Finally, studies of the effect of KMC on breast feeding
show that, where KMC is practiced, the duration of breast
feeding is prolonged, breast milk production is more
stable, the number of feeds per day is increased, breast
feeding competence is increased, and more premature
infants are discharged on exclusive breast feeding.
Mothers expressed a clear preference for KMC and health
workers found it safe and convenient. KMC was cheaper
in terms of salaries and other running costs.
Mortality and morbidity
Observational studies have shown reduction in mortality
after institution of KMC but interpretation of their results
is difficult because of remarkable difference in KMC
group from historical controls.15
A systematic review conducted by Cochrane Library14,
concluded that although KMC does not improve survival,
it reduces the incidence of respiratory tract infections and
decreases the rate of nosocomial infections..The authors
concluded that although KMC seemingly reduces infant
morbidity, evidence is still insufficient to recommend it as
a routine practice. They also pointed out that more
randomized; controlled and well designed trials should be
carried out.
Recently, a randomized control trial conducted in two
hospitals in South Africa16 revealed that babies who were
kept skin to skin contact had better outcome as regards
physiological stabilization compared to those babies who
were kept in incubators.
Growth
Mixed results are reported about long term growth
following KMC. A RCT from India has shown higher
increments in weight, length and head circumference in
kangaroo infants in neonatal period.12 In another RCT
KMC infants showed a slightly larger daily weight gain
while they were cared for in hospital, but in the overall
period of study their growth did not differ from that of
the control group. 13 In a meta-analysis by Neonatal
Review Group of the Cochrane Collaboration randomized
trials14 comparing KMC and conventional neonatal care in
LBW infants, KMC infants had gained more weight per
day by discharge than controls (weighted mean difference
3.6 g/day, 95% confidence interval 0.8 to 6.4) and had a
larger head circumference at 6 months corrected age than
controls (weighted mean difference 0.34 cm, 95%
confidence interval 0.11 to 0.57) although these differences
are of low clinical significance. Sloan et al in 1994 reported
there were no significant differences between the groups
in growth indices during the 6-month follow-up. No
Indian Journal of Pediatrics, Volume 75May, 2008
90
differences were seen in weight, length, or head
circumference at 41 weeks corrected gestational age or at
12 months corrected age or in weight at discharge.
Other effects
Prolonged skin-to-skin contact between the mother and
her preterm/LBW infant, as in KMC, provides effective
thermal control and may be associated with a reduced risk
of hypothermia.12,13, 17,18
In 1989, Affonso et al19 in a study involving 33 mothers
who had skin to skin contact with their babies and a
control group, observed a greater tendency towards
emotional stability in mothers exposed to KMC. They also
reported a more intense feeling of reliability and
competence in these mothers as compared with those
mothers whose babies received conventional care. In a
study involving 488 mothers of preterm babies, Tessier et
al 20 observed that those submitted to KMC felt more
competent and had an increased perception of babys
competences. Moreover they felt less stressed even when
the hospital stay was longer. These subjective feelings
may be seen as positive indirect signs of establishment of
parent and child bonding favored by KMC and could be
positive signs of greater participation of parents in baby
care and stimulation, allowing them a more
comprehensive and individualized care.
Brazelton21 in a careful study with babies asserted that
a preterm babys nervous system becomes more easily
organized while in calm environment without excessive
stimuli. By observing the physiological pattern during
intrauterine life it is generally noted that babys
experiences occur in a cyclic rhythm of activity and are
determined by the possibility to rest and sleep whenever
necessary, which according to Korrones22 occurred 80% of
the time. Mann et al23 regard sleep as a positive influence
on the development of the brain.
Preterm babies exposed to skin to skin contact showed
a better mental development and better results in motor
tests. The presence of parents facilitates skin to skin
contact which in its turn allows tactile proprioreceptive
stimulation and protects against an overload of aversive
stimuli, being an acceptable method for proper
stimulation of the babys neurobehavioral development.
Cost-effectiveness
Cost-effectiveness of KMC as compared to conventional
care has not been studies well and there is a need to
conduct such studies especially in low-resource settings.
Use of KMC in different settings
KMC may be used in three different scenarios:
Settings with a very low level of development and
severely restricted access to any level of neonatal care.
Premature infants who are born at home with no
499
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A. Thukral et al
assistance or with the assistance of a traditional birth
attendant and preterm infants who are born at first
level unit with no specialized care and no possibility
of being transferred to a healthcare unit with
specialized care. In such cases, KMC including skin-
to-skin contact, breastfeeding and the best possible
health-care follow-up represents the best means for
ensuring the survival of non-sick premature infants
who have no significant conditions other than being
premature. Safety, efficacy and applicability of KMC
in such a setting needs to be further investigated.
Access to appropriate resources but which are
insufficient for the number of premature births. Here
KMC represents an effective alternative which allows
better utilization of available resources.
Little or no restriction on access to high-technology
neonatal care. KMC is used mainly during
hospitalization to establish healthy bonding between
mother and infant and to increase the breastfeeding
rates. The intermittent kangaroo position in hospital
is the most widely used component in such a setting.
Requirements for KMC implementation
KMC is feasible everywhere, because it is not based on
equipment, and it presents advantages for the
organization of health services provided the following
requirements are met:
The health facility (the hospital or the neonatal ward)
should have an open doors policy for parents at all
times. A room near to or at the neonatal unit,
furnished with comfortable seats for the mothers, is
needed for conducting the kangaroo adaptation and
for teaching and training mothers. The presence of a
nurse available full time, trained in the kangaroo
technique, is indispensable.
Breastfeeding must be the official feeding policy of the
hospital for all newborn infants.
Staff should receive adequate training on KMC,
including the special breastfeeding and feeding needs
of LBWI. Extra training is usually needed on
stimulation of breastfeeding, expression and
conservation of breast milk, mode of administration of
expressed breast milk, and daily monitoring of
growth.
Whenever good quality follow-up (including initial
daily follow up visits) cannot be warranted, early
discharge in kangaroo position should be not
attempted. On the contrary, KMC should be provided
as an in-hospital activity, allowing mothers and infants
to room together for as long as needed.
Besides human and physical resources, implementing a
KMC program needs institutional, social and health care
workers support. During the II International Workshop
500
91
about KMC, problems faced while implementing KMC
programs were discussed and possible solutions were
suggested. The basic strategy for facilitating the
implementation and success of KMC programs can be
summarized in three words: communication,
sensitiveness and education.
Nurses, physicians and other staff involved in the care
of the mother and the baby should be trained. This
training may best be done by exposing them to units
already practicing KMC. Educational material such as
information sheets, posters, video films on KMC in local
language should be available to the mothers, families and
community. If possible, reclining chairs in the nursery
and postnatal wards, and beds with adjustable back rest
should be arranged. Mother can provide KMC sitting on
an ordinary chair or in a semi-reclining posture on a bed
with the help of pillows.
Criteria for eligibility of KMC
Baby
All stable LBW babies are eligible for KMC. However,
very sick babies needing special care should be cared
under radiant warmer initially. KMC should be started
after the baby is hemodynamically stable. Short KMC
sessions can be initiated during recovery with ongoing
medical treatment (IV fluids, oxygen therapy). KMC can
be provided while the baby is being fed via orogastric
tube or on oxygen therapy. Guidelines for practicing
KMC include:
Birth weight >1800 g: These babies are generally stable at
birth. Therefore, in most of them KMC can be initiated
soon after birth.
Birth weight 1200-1799 g: Many babies of this group have
significant problems in neonatal period. It might take a
few days before KMC can be initiated. If such a baby is
born in a place where neonatal care services are
inadequate, he should be transferred to a proper facility
immediately after birth, along with the mother/ family
member. He should be transferred to a referral hospital
after initial stabilization and appropriate management.
One of the best ways of transporting small babies is by
keeping them in continuous skin-to-skin contact with the
mother/family member during transport.
Birth weight <1200 g: Frequently, these babies develop
serious prematurity-related morbidity, often starting soon
after birth. They benefit the most from in-utero transfer to
the institutions with neonatal intensive care facilities. It
may take days to weeks before babys condition allows
initiation of KMC.
Mother
All mothers can provide KMC, irrespective of age, parity,
education, culture and religion.24 The following points
Indian Journal of Pediatrics, Volume 75May, 2008
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Kangaroo Mother Care-an Alternative to Conventional Care

must be taken into consideration when counseling on KMC procedure

KMC:
Kangaroo positioning: The baby should be placed
Willingness: The mother must be willing to provide between the mothers breasts in an upright position. The
KMC. Healthcare providers should counsel and head should be turned to one side and in a slightly
motivate her. Once the mother realizes the benefits of extended position. This slightly extended head position
KMC for her baby, she will learn and undertake KMC. keeps the airway open and allows eye to eye contact
between the mother and her baby. The hips should be
General health and nutrition: The mother should be
flexed and abducted in a frog position; the arms should
free from serious illness to be able to provide KMC.
also be flexed. Babys abdomen should be at the level of
She should receive adequate diet and supplements
the mothers epigastrium. Mothers breathing stimulates
recommended by her physician.
the baby, thus reducing the occurrence of apnea (Fig. 1).
Hygiene: The mother should maintain good hygiene: Support the babys bottom with a sling/binder.
daily bath/sponge, change of clothes, hand washing,
Monitoring: Babies receiving KMC should be monitored
short and clean finger nails.
Supportive family: Apart from supporting the mother,
family members should also be encouraged to provide
KMC when mother wishes to take rest. Mother would
need familys cooperation to deal with her
conventional responsibilities of household chores till
the baby requires KMC.
Supportive community: Community awareness about
the benefits should be created. This is particularly
important when there are social, economic or family
constraints.
Initiation of KMC
Counseling: When baby is ready for KMC, arrange a time
that is convenient to the mother and her baby. The first
few sessions are important and require extended
interaction. Demonstrate to her the KMC procedure in a
caring, gentle manner and with patience. Answer her
queries and allay her anxieties. Encourage her to bring her Fig. 1. Kangaroo positioning
mother/mother in law, husband or any other member of carefully especially during the initial stages. Nursing staff
the family. It helps in building positive attitude of the should make sure that babys neck position is neither too
family and ensuring family support to the mother which flexed nor too extended, airway is clear, breathing is
is particularly crucial for post-discharge home-based regular, color is pink and baby is maintaining
KMC. 25 It is helpful that the mother starting KMC temperature. Mother should be involved in observing the
interacts with someone already practicing KMC for her baby during KMC so that she herself can continue
baby. monitoring at home.
Mothers clothing: KMC can be provided using any front- Feeding: The mother should be explained how to
open, light dress as per the local culture. KMC works well breastfeed while the baby is in KMC position. Holding the
with blouse and sari, gown or shawl. Suitable apparel that baby near the breast stimulates milk production. She may
can retain the baby for extended period of time can be express milk while the baby is still in KMC position. The
adapted locally. baby could be fed with paladai, spoon or tube, depending
Babys clothing: Baby is dressed with cap, socks, nappy, on the condition of the baby.
and front-open sleeveless shirt. Privacy: KMC unavoidably requires some exposure on
the part of the mother. This can make her nervous and
Time of initiation
could be de-motivating. The staff must respect mothers
KMC can be started as soon as baby is stable and sensitivities in this regard and ensure culturally
receiving oral feeds. Babies with severe illness and those acceptable privacy standards in the nursery and the
requiring special treatment must wait until recovery wards where KMC is practiced.
before KMC can be started. Short KMC sessions can be
initiated during recovery with ongoing medical treatment Duration: Skin-to-skin contact should start gradually in
(iv fluids, low concentration of additional oxygen) the nursery, with a smooth transition from conventional

Indian Journal of Pediatrics, Volume 75May, 2008 501

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A. Thukral et al
care to continuous KMC. Sessions that last less than one
hour should be avoided because frequent handling may
be stressful for the baby. The length of skin-to-skin
contacts should be gradually increased up to 24 hours a
day, interrupted only for changing diapers. When the
baby does not require intensive care, she should be
transferred to the post-natal ward where KMC should be
continued.
Can the mother continue KMC during sleep and
resting?
The mother can sleep with baby in kangroo position in
reclined or semi recumbent position about 15 degrees
from horizontal. This can be done with an adjustable bed
or with pillows on an ordinary bed. A comfortable chair
with an adjustable back may be used for resting during
the day (Fig 2).
Fig. 2. Kangaroo mother care being provided in postnatal ward
Discharge criteria
The standard policy of the unit for discharge from the
hospital should be followed. Generally the following
criteria are accepted at most centers:26
Babys general health is good and no evidence of
infection
Feeding well, and receiving exclusively or
predominantly breast milk.
Gaining weight (at least 15-20 gm/kg/day for at least
three consecutive days)
Maintaining body temperature satisfactorily for at
least three consecutive days in room temperature.
The mother and family members are confident to take
care of the baby in KMC and should be asked to come
for follow-up visits regularly.
When to discontinue KMC?
When the mother and baby are comfortable, KMC is
502
93
continued for as long as possible, at the institution and
then at home. Often this is desirable until the babys
gestation reaches term or the weight is around 2500 g. She
starts wriggling to show that she is uncomfortable, pulls
her limbs out, cries and fusses every time the mother tries
to put her back skin to skin. This is the time to wean the
baby from KMC. Mothers can provide skin-to-skin
contact occasionally after giving the baby a bath and
during cold nights.
Post-discharge follow-up
Close follow up is a fundamental pre-requisite of KMC
practice. Baby is followed once or twice a week till 37-40
weeks of gestation or till the baby reaches 2.5-3 kg of
weight. Thereafter, a follow up once in 2-4 weeks may be
enough till 3 months of post-conception age. Later the
baby should be seen at an interval of 1-2 months during
first year of life. The baby should gain adequate weight
(15-20 gm/kg/day up to 40 weeks of post-conception age
and 10 gm/kg/ day subsequently). More frequent visits
should be made if the baby is not growing well or his
condition demands.
REFERENCES
1. Ludington-Hoe SM, Hadeed AJ, Anderson GC. Physiological
response to skin to skin contact in hospitalized premature
infants. J Perinatol 1991; 11: 19-24
2. Whitelaw A, Heisterkamp G, Sleath K, Acolet D, Richards M.
Skin to skin contact for very low birthweight infants and their
mothers. Arch Dis Child 1988; 63: 1377-1381.
3. Sloan NL, Camacho LW, Rojas EP, Stern C. Kangaroo mother
method: randomized controlled trial of an alternative method
of care for stabilized low-birthweight infants. Maternidad
Isidro Ayora Study Team. Lancet 1994; 344: 782-785.
4. Charpak N, Ruiz Pelaez JG, Charpak Y. Rey-Martinez
Kangaroo Mother Program: an alternative way of caring for
low birth weight infants? One year mortality in a two cohort
study. Pediatrics 1994; 94: 804-810.
5. Cattaneo A, Davanzo R, Worku B et al. Kangaroo mother care
for low birthweight infants: a randomized controlled trial in
different settings. Acta Paediatr 1998; 87: 976-985.
6. American Academy of Pediatrics. Workgroup on
breastfeeding and use of human milk. Pediatrics 1997; 100:
1035-1039.
7. Amin SB, Merle KS, Orlando MS, Dalzell LE, Guillet R. Brain
stem maturation in premature infants as a function of enteral
feeding type. Pediatrics 2000; 106: 318-320.
8. Carlson SE, Cooke RJ, Rhodes PG. Long term feeding of
formulas high in linolenic acid and marine oil to very low
birth weight infants: phospholipids fatty acids. Pediatr Res
1991; 30: 404-412.
9. Carlson SE, Werman SH, Cooke RJ, Rhodes PG, Peeples JM,
Tolley EA. Visual acuity development in healthy preterm
infants: effect of marine oil supplementation. Am J Clin Nutr
1993; 58: 35-42.
10. Lucas A, Morley R, Cole TJ, Lister G, Leeson Payne C. Milk
and subsequent intelligent quotient in infants born preterm.
Lancet 1992; 339: 261-264
11. Hurst NM, Valentine CJ, Renfro L, Burns P, Ferlic L. Skin-to-
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Kangaroo Mother Care-an Alternative to Conventional Care
skin holding in the neonatal intensive care unit influences
maternal milk volume. J Perinatol 1997; 17 : 213-217.
12. Ramanathan K, Paul VK, Deorari AK, Taneja U, George G.
Kangaroo Mother Care in very low birth weight infants. Indian
J Pediatr 2001; 68 : 1019-1023.
13. Rao PN, Udani R, Nanavati R. Kangaroo mother care for low
birth weight infants: a randomized controlled trial. Indian
Pediatr 2008; 45 : 17-23.
14. Conde-Agudelo A, Diaz Rossello JL, Belizan JM. Kangaroo
mother care to reduce morbidity and mortality in low
birthweight infants. Cochrane Database Syst Rev 2003:
CD002771.
15. Bergman NJ, Jurisoo LA. The kangaroo-method for treating
low birth weight babies in a developing country. Trop Doct
1994; 24 : 57-60.
16. Bergman NJ, Linley LL, Fawcus RR. Randomized controlled
trial of skin to skin contact from birth vs. conventional
incubator for physiological stabilization in 1200to 2199 gram
newborns. Acta Pediatr 2004; 93: 779-885.
17. Charpak N, Ruiz-Pelaez JG, Figueroa de CZ, Charpak Y.
Kangaroo mother versus traditional care for newborn infants
</=2000 grams: a randomized, controlled trial. Pediatrics 1997;
100 : 682-688.
18. Kadam S, Binoy S, Kanbur W, Mondkar JA, Fernandez A.
Feasibility of kangaroo mother care in Mumbai. Indian J
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Pediatr 2005; 72 : 35-38.
19. Affonso DD, Wahelber V, Persson B. Exploration of mothers
reactions to the kangroo method of prematurity care. Neonatal
Netw 1989; 7: 43-51.
20. Tessier R, Cristo M, Velez S et al. Kangroo mother care and the
bonding hypothesis. Pediatrics 1989; 102: 17-23.
21. Brazelton TB. Early intervention. In: Fritzgerald HE, Lester
BM, Yogman MV, ed. Theory and research in behavioral
pediatrics. New York; Plenum Press; 1982; 104-119.
22. Korones SB. Disturbance and infants rest. In Moore TD, ed.
Iatrogenic problems in intensive care. Report of 69 th . Ross
conference on Pediatric research. Columbus, OH: Ross
laboratories; 1976; 94-97.
23. Mann NP, Haddow R, Stokes L, Goodley S, Rutter N. effect of
night and day on preterm infants in newborn nursery:
randomized trial. BMJ 1986; 293: 1265-1267.
24. Udani RH, Nanavati RN. Training manual on Kangaroo mother
care. Published by the Department of neonatology. KEM
Hospital and Seth GS medical college Mumbai. September
2004.
25. Website of KMC India Network. Guidelines for parents and
health providers are available online at www.kmcindia.org
26. World Health Organization. Kangaroo mother care: a practical
guide. Department of Reproductive Health and Research,
WHO, Geneva.2003.
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Symposium on AIIMS Protocols in Neonatology III

Minimal Enteral Nutrition

Satish Mishra, Ramesh Agarwal, M. Jeevasankar, Ashok K. Deorari and Vinod K. Paul

WHO Collaborating Centre for Training & Research in Newborn Care, Division of Neonatology, Department of
Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

ABSTRACT
Although parenteral nutrition has been used widely in the management of sick very low birth weight infants, a smooth transition
to the enteral route is most desirable. Trophic feeding is the practice of feeding small volume of enteral feeds in order to
stimulate the development of the immature gastrointestinal tract of the preterm infant. This practice has also been termed as
minimal enteral nutrition (MEN). MEN improves gastrointestinal enzyme activity, hormone release, blood flow, motility and
microbial flora. Clinical benefits include improved milk tolerance, greater postnatal growth, reduced systemic sepsis and shorter
hospital stay. There is currently no evidence of any adverse effects following MEN. MEN can be commenced in neonates on
ventilation and total parenteral nutrition. A protocol of giving MEN has been presented here. [ Indian J Pediatr 2008;
75(3) : 267-269] E-mail: ashokdeorari_56@hotmail.com

Key words : Very low birth weight infant; Minimal enternal nutrition; Expressed breast milk

Because of concern that oral feedings might increase the
risk of necrotizing enterocolitis (NEC), some high-risk
infants have received prolonged period of total parenteral
nutrition (TPN) without any enteral feedings. However,
lack of enteral nutrients may diminish gastrointestinal
functional and structural integrity by diminishing
hormonal activity, growth of intestinal mucosa, lactase
activity, nutrient absorption, or motor maturation. These
problems may then compromise later feeding tolerance
and growth, and thus prolong the hospital stay. The
practice of providing minimal enteral nutrition (MEN) or
trophic feedings (small volume feedings that provide
minimal calories) for some period after birth was
developed as a strategy to enhance the functional
maturation of the gastrointestinal tract and to facilitate a
smooth and rapid transition from parenteral to enteral
nutrition .
Problems of delayed feeding
In several animal species, absence of enteral nutrients is
associated with diminished intestinal growth, atrophy of
intestinal mucosa, delayed maturation of intestinal
enzymes, and increase in permeability and bacterial
translocation. A lack of enteral nutrients also affects
intestinal motility, perfusion, and hormonal responses.1 It
is possible that a prolonged delay in starting feeds in
Correspondence and Reprint requests : Dr. Ashok K Deorari,
Professor, Department of Pediatrics, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi 110029, India.
[Received February 7, 2008; Accepted February 7, 2008]
preterm neonates may be partly responsible for the
common problems of feed intolerance encountered in
these newborns.
Minimal enteral nutrition (MEN)
This is a practice wherein some minute volumes of feeds
are given to the baby in order to stimulate the
development of the immature gastrointestinal tract of the
preterm infant. Studies have shown that neonates who
were fed earlier with minimal feeds had lower episodes of
feeding intolerance and gained weight faster as compared
to neonates who were fed late.2-4 These feeds are of small
volume ranging from 10 to 15mL/Kg/day and not
intended for providing adequate calories. Although MEN
does not provide sufficient calories for growth, it is
beneficial as it exerts a trophic effect on the gut mucosa.
Benefits of MEN
Animal studies have shown a 2-3 fold increase in
intestinal mucosa mass with early feeding. The trophic
effect on intestinal mucosa may be mediated via various
growth factors in human milk. These include insulin,
epidermal growth factor and other peptides known to
exert direct trophic effects. Premature infants receiving
MEN had cumulative greater milk intake, which was
associated with lower serum alkaline phosphatase
activity. 5 Intestinal motility pattern matures more rapidly
in premature infants receiving early enteral feeding. 4
Investigators have demonstrated that trophic feeds were
associated with greater absorption of calcium and
phosphorus, greater lactase activity, and reduces
intestinal permeability.

Indian Journal of Pediatrics, Volume 75March, 2008 267

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S. Mishra et al
Besides the effect on intestinal mucosa, other beneficial
responses to MEN include: (a) motor effects: which
include better peristaltic activity and coordinated motor
activity in response to feeding. (b) vascular effects: which
include post-prandial decrease in splanchnic vascular
resistance. This decrease would be associated with an
increase in intestinal blood flow and oxygen uptake in
response to feeding. (c) endocrine: effects which include
the significant increases in plasma concentrations of
enteroglucagon, gastrin, and gastric-inhibiting
polypeptide in preterm infants after milk feedings of as
little as 12 mL/kg per day. Similar surges in the trophic
hormones were not seen in intravenously nourished
infants. 6
Clinical benefits of MEN
Cochrane meta-analysis on studies evaluating the clinical
effects of MEN done by Tyson et al,7 has showed that,
among infants given trophic feedings, there was an
overall reduction in mean days to full feeding (weighted
mean difference [WMD] = -2.6 days; number of days that
feeding was withheld (WMD = -3.1 days; and total
hospital stay (WMD = -11.4 days) compared to infants
given no enteral nutrient intake. There was no significant
increase in the risk of necrotizing enterocolitis (relative
risk = 1.16 [0.75, 1.79]). McClure et al, 8 have shown a
reduction in episodes of culture confirmed sepsis and
faster weight gain in babies receiving minimal enteral
nutrition. However, conclusive evidence in favor of MEN
is not yet available due to the small size and number of
studies on this issue. Nonetheless, due to obvious
beneficial effects (Table 1), MEN has become a widely
used practice in neonatal intensive care units.
Adverse effects of MEN
There is currently no evidence of any adverse effects
TABLE 1. Advantages of Gastrointestinal Priming with MEN1
1. Shortens time to regain birth weight
2. Improves feeding tolerance
3. Enhances enzyme maturation
4. Improves gastrointestinal motility
5. Improves mineral absorption, mineralization
6. Lowers incidence of cholestasis
TABLE 2. Protocol on Minimal Enteral Nutrition (MEN)*
For whom
All preterm infants especially those less than 32 weeks gestation, who are hemodynamically stable but cannot be given enteral feeds
What to feed
Preferably expressed breast milk (EBM)
How much to feed
EBM 8-12 mL/kg/day divided into 4-8 feeds given by gavage feeding
For <1000g 1-2ml every 4-6 hour; for 1000 g 2-3 ml every 2-4 hour;
*Can be started while baby is on ventilator and /or receiving total parenteral nutrition
*In severe birth asphyxia, MEN should be started after 48-72 hours
*VLBW infants born with antenatal diagnosis of altered umbilical arterial blood flow (reversed or absent end diastolic flow), MEN can
possibly be delayed for 2 to 3 days.
268
96
following MEN.9
Indications for MEN
All preterm infants especially 32 weeks of gestation, in
whom enteral feeding has not yet been started due to
underlying illness, should be commenced on MEN.
Contraindications
MEN should be avoided in infants with severe
hemodynamic instability, suspected or confirmed NEC,
evidence of intestinal obstruction perforation or
paralytic ileus. Mechanical ventilation and or use of
umbilical catheters are not contraindication to using
MEN
Protocol for MEN
MEN should be commenced after ensuring hemodynamic
stability in preterm neonates. This is usually possible by
day 2-3 in sick preterm neonates. However MEN may be
started on the first day itself in hemodynamically stable
neonates if no contraindications to feeding exist.
Expressed human breast milk is the preferred milk for
MEN. Commercial formulas are best avoided for MEN.10
Recommended volume is 10-15 mL/Kg/day. This should
be divided into equal aliquots and administered by
gavage feeding in a 3-6 hourly schedule. In preterm very
low birth weight infants born with antenatal diagnosis of
altered in umbilical arterial blood flow (reversed or
absent end diastolic flow), MEN can possibly be delayed
for 2 to 3 days. Advancement of feeds should also be slow
and carefully monitored in these infants.
Monitoring
The infant should be monitored for any evidence of feed
intolerance including abdominal girth, gastric residuals or
clinical signs of NEC. If the abdominal girth has increased
by 2 cm, gastric residual volume (GRV) should be
checked. Feeding should be stopped in the presence of
significant aspirate (>25% of feed or >3mL whichever is
more) and/or bilious or blood stained aspirates.
Progression to full feeds As baby gains clinical
stability, feeds are advanced at the rate of 20-30 mL/Kg/
day. Baby is monitored as mentioned above and volume
of feeds increased gradually to full enteral feeds.
Indian Journal of Pediatrics, Volume 75March, 2008
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Minimal Enteral Nutrition

In view of profound clinical benefits routine practice of 4. Berseth CL. Effect of early feeding on maturation of the
minimal enteral nutrition should be encouraged in preterm infants small intestine. J Pediatr 1992; 120 : 947-953.
5. Klagsbrun M. Human milk stimulates DNA synthesis and
developing countries using expressed breast milk for
cellular proliferation in cultured fibroblasts. Proc Natl Acad Sci
VLBW infants. USA 1978; 75 : 5057-5061.
6. Berseth CL. Minimal enteral feedings. Clin Perinatol 1995; 22:
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7. Tyson JE, Kennedy KA. Trophic feeds for parenterally fed
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1. Schanler RJ. Enteral nutrition for high risk neonates. In
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Ballard RA, ed. Averys Diseases of the Newborn, Philadelphia;
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WB Saunders, 2005: 1044.
Neonatal 2000; 82 : F29-F33.
2. Dunn L, Hulman S, Weiner J, Kliegman R. Beneficial effects of
9. McClure RJ. Trophic feeding of the preterm infant. Acta Pediatr
early hypocaloric enteral feeding on neonatal gastrointestinal
2001; 90 : 19-23.
function. Preliminary report of a randomized trial. J Pediatr
10. Troche B, Harvey-Wilkes K, Engle WD, Nielsen HC, Frantz
1988; 112 : 622-629.
ID, Mitchell ML, Hermos RJ. Early minimal feedings promote
3. Slagle Ta, Gross SJ. Effect of early low volume enteral
growth in critically ill premature infants. Biol Neonate 1995; 67:
substrate on subsequent feeding tolerance in very low birth
172-181.
weight infants. J Pediatr 1988; 113 : 526-531.

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Symposium on AIIMS Protocols in Neonatology III

Patent Ductus Arteriosus in Preterm Neonates

Ramesh Agarwal, Ashok K. Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar,
New Delhi, India

ABSTRACT
Failure of the ductus arteriosus to close within 48-96 hours of postnatal age results in a left to right shunt across the ductus
and overloading of the pulmonary circulation. This is more likely to happen in premature neonates with respiratory distress
syndrome. Deterioration in the respiratory status on day 3-4 in a ventilated neonate and unexplained metabolic acidosis may
be the earliest indicators of a patent ductus arteriosus (PDA). Indomethacin is the main stay of medical management of PDA
in preterm neonates. Guidelines for administration of indomethacin have been described in the protocol. Restricted fluid
therapy may be beneficial in the prevention of PDA in preterm neonates. Presence of PDA in a term neonate should be
investigated to rule out an underlying congenital heart disease. [Indian J Pediatr 2008; 75 (3) : 277-280] E-mail:
ashokdeorari_56@hotmail.com

Key words : Preterm; Patent ductus arteriosus; Indomethacin; Ibuprofen

During intrauterine life, 10% of the cardiac output passes Ductus arteriosus in preterm neonates
through the lungs. The remaining 90% is shunted via the
The normal mechanisms of ductal closure fail to work in
ductus arteriosus (DA) to the aorta and systemic
preterm neonates. The various factors contributing to an
circulation. After birth, most of the right ventricular
increased incidence of PDA in preterms include: (a)
output should pass through the lungs to facilitate proper
Increased sensitivity of the ductus to prostaglandins as
gas exchange. In order to make this possible, the ductus
compared to term neonates (b) Sensitivity to
undergoes constriction and functional closure soon after
prostaglandins is sustained for a longer period (c) Higher
birth in term neonates. Eighty percent (80%) of the DA in
incidence of hypoxia and acidosis (d) Defective smooth
term infants close by 48 hours and nearly 100% by 96
muscle migration resulting in compromised anatomical
hours. Failure of this normal closure results in problems
closure.
especially in preterm neonates.
Hemodynamic consequences of PDA
PHYSIOLOGY Shunting of blood from the systemic circulation to the
pulmonary circulation results in congestive cardiac
failure, which manifests clinically with wide pulse
Oxygen and endothelin are very strong vasoconstrictors
pressure and bounding pulses. Overloading of the
and prostaglandins E2 and I2 are strong vasodilators of the
pulmonary vasculature leads to pulmonary edema/
DA. Lower oxygen concentrations in utero and high
hemorrhage which predisposes the neonate to chronic
circulating PgE2 and PgI2 levels help in keeping the ductus
lung disease. Blood flow to the kidney and
patent. Sudden elevation in circulating oxygen tension
gastrointestinal tract is compromised predisposing to
and fall in prostaglandin levels soon after delivery results
acute renal failure (ARF) and necrotizing enterocolitis
in strong vasoconstriction and functional closure of the
(NEC). Hypo-perfusion followed by reperfusion increases
DA soon after delivery. It is believed that this action of
the risk of intraventricular hemorrhage (IVH).
oxygen is mediated via the formation of the endothelin
molecule. This functional closure is followed by Risk factors for PDA in preterm neonates
anatomical closure in the next 1-3 months.
The incidence of PDA is inversely related to gestational
age and birth weight. A hemodynamically significant
shunt due to PDA has been reported in 40% of infants less
Correspondence and Reprint requests : Dr Ashok K. Deorari, than 1000 grams and 20% of infants between 1000-1500
Professor, Department of Pediatrics, All India Institute of Medical grams.1-3 Respiratory distress syndrome (RDS) in preterm
Sciences, Ansari Nagar, New Delhi 110029, India. neonates needing ventilation and surfactant is an
[Received February 7, 2008; Accepted February 7, 2008]

Indian Journal of Pediatrics, Volume 75March, 2008 277

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R. Agarwal et al
additional risk factor for PDA. Prophylactic use of
synthetic surfactant has been associated with an increased
risk of PDA. Lack of antenatal steroids, presence of sepsis,
and liberal fluid therapy are other risk factors for
developing PDA.
CLINICAL FEATURES
Hyperdynamic circulation : A wide pulse pressure (>25 mm
Hg), prominent precordial pulsations and bounding
pulses and an ejection systolic murmur (occasionally pan
systolic and continuous murmur) heard best at the 2nd left
parasternal area 4 are usually present on clinical
examination.
Indicators of ductus opening on a ventilated baby: Metabolic
acidosis not attributable to hypoperfusion and sepsis,
deteriorating respiratory status on day 3-4 after a period
of relative stability, increasing ventilatory requirements
on day 3-4, unexplained CO2 retention, fluctuating FiO2
requirements and recurrent apneas in a ventilated baby
should raise clinical suspicions of a symptomatic PDA.
Studies have revealed that echocardiographic criteria
of a significant left to right shunt usually precede clinical
symptoms by an interval of 2-3 days. However, clinical
features have a better correlation with long-term
morbidity and available evidence does not recommend
routine screening with echocardiography for at-risk
neonates.3
Differential Diagnosis
(i) AV fistula, (ii) Ruptured sinus of valsalva, (iii) Aorto-
pulmonary window.
INVESTIGATIONS
Chest X-ray: Radiographic findings are non-specific for
diagnosis of PDA. They include cardiomegaly, upturned
left bronchus due to left atrial enlargement and
pulmonary plethora.
Echocardiography : Echocardiography is not
recommended routinely for all preterm neonates. A
clinical diagnosis of PDA should preferably be confirmed
by echo prior to starting medical therapy.
Echocardiographic criteria include (a) Left atrial dilatation
(Left atrial: Aortic root>1.6) (b) Diastolic turbulence
(backflow) on doppler in the pulmonary artery and (c)
Direct imaging to measure the diameter of PDA.
A hemodynamically significant PDA is diagnosed in
the presence of a ductus diameter >1.5mm and absent/
retrograde diastolic flow in the post-ductal aorta. Doppler
echo is more specific and sensitive for the diagnosis of
PDA while an M mode echo is useful for assessing the
278
99
severity of the shunt across the PDA.
STRATEGIES OF MANAGEMENT5
Prophylactic treatment: In this strategy, treatment is
started before the appearance of PDA, usually within the
first 24 hours of birth. Indomethacin has been tried as
prophylactic treatment in very preterm neonates,
especially <1000 grams. Although it was found to
decrease symptomatic PDA and IVH, it was not
associated with any change in long-term morbidity and
neuro-developmental outcome. More over, indomethacin
has also been found to decrease cerebral and renal blood
flow and hence is not recommended as a prophylactic
agent in the prevention of PDA6. Trials with prophylactic
ibuprofen are still going on7.
Early Symptomatic: In this strategy, treatment is started
as soon as the PDA is detected even if it is not
hemodynamically significant.
Weight <1000 grams: Among neonates detected to
have a PDA, 80% of neonates would progress to develop
a hemodynamically significant shunt. Hence , it is
recommended to treat PDA in this group early even
though it may not be hemodynamically significant.
However, in view of the recent evidence, the risk and
benefits must be weighed before treating asymptomatic
babies.8
Weight >1000 grams: Early treatment is not
recommended in this group as progression to
symptomatic PDA is less common and spontaneous
closure are known to occur in this group 8 .
Late Symptomatic : Only hemodynamically significant
PDA is treated in this strategy and it is the recommended
approach for neonates >1000 grams.
MANAGEMENT
(i) General measures
Fluid restriction: 60% of maintenance fluids
TABLE Dosage of Indomethacin and Ibuprofen for Closure of
Patent Ductus Arteriosus
Indomethacin
Initial Dose
0.2 mg/kg stat followed by age adjusted doses:
Subsequent dose
< 2 day- 0.1 mg/kg/dose 12 hourly for 2 doses
2-7 day- 0.2 mg/kg/dose 12 hourly for 2 doses
> 7 day- 0.25 mg/kg/dose 12 hourly for 2 doses
Ibuprofen
10 mg/kg stat followed by
5 mg/kg/dose 24 hourly for 2 doses
Indian Journal of Pediatrics, Volume 75March, 2008
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Patent Ductus Arteriosus in Preterm Neonates

Avoid hypoxia and acidosis enlarging or evolving intraventricular hemorrhage (IVH);

platelet count < 60,000/mm3
High peek end expiratory pressure (PEEP) and lower
inspiratory time (Ti), if otherwise appropriate9. Gastrointestinal: necrotizing enterocolitis; blood in stool
Frusemide is generally not required. Frusemide Efficacy
increases prostaglandin levels, which may interfere
The closure rate with indomethacin is 80%. The efficacy is
with the therapeutic effect of indomethacin. However
unaffected by gestation or birth weight. The full course
enough evidence for this concern is not yet available10.
should be completed even if closure is achieved before the
In intractable CHF, we occasionally use frusemide in a
third dose. Longer treatment with lower doses (0.1 mg/
dose of 1 mg/kg/dose 12 hourly. Careful evaluation of
kg/dose for 6 doses) has similar toxicity and efficacy and
hydration status is essential before and during
are not recommended.12
treatment with frusemide.
Ibuprofen is also an inhibitor of prostaglandin synthesis
Digoxin has no role in management of PDA.
and is effective in closing the ductus. It has an equal
(ii) Medical Management efficacy as compared to indomethacin with fewer side
effects.13 Its use is associated with a lower incidence of
(a) Indomethacin
oliguria and renal compromise. It has been found to have
Mechanism of action: The postulated mechanism of action a lesser effect on mesenteric and cerebral blood flow as
is an inhibition of cyclo-oxygenase (COX) enzyme in the compared to indomethacin. The dose is 10 mg/kg stat
prostaglandin pathway. Indomethacin has a greater followed by 5 mg/kg/dose x 2 doses at 24 hour intervals
affinity for COX 1 (renal) as against COX 2 (extra-renal). given orally.
Due to this greater affinity for renal COX1, the incidence
of renal complications is higher with indomethacin as
compared to other inhibitors of prostaglandin synthesis.
Indications for indomethacin use:
Early symptomatic treatment of PDA in <1000 grams
Late symptomatic treatment of PDA in > 1000 grams *
Re-treatment after failure of the first course of
Indomethacin.
Recurrence of PDA after the first course of
indomethacin.
Oral medication: Due to non-availability of the IV
formulation, we have been using oral indomethacin for
closure of PDA. Oral indomethacin is available as 25 mg
tablets and it can be broken into lower doses. We usually
mix the dose with 2-5 ml expressed breast milk and
administer it through the oro-gastric tube.
Side effects and monitoring: Adverse effects include renal
compromise due to its effect on COX 1, bleeding tendency
due to its effect on platelet function and increased risk of
necrotizing enterocolitis. Decreased cerebral blood flow
associated with the use of indomethacin may be
associated with poor neuro-developmental outcome.
Various parameters that should be monitored include (a)
Urine output: If urine output falls below 1 ml/kg/hr low
dose dopamine at 1-2 mg/kg/min for its renal effect may
be used 11 (b) Renal function (alternate days) and (c)
Platelet counts (daily)
Contraindications
Renal: Urine output< 0.6 ml/kg/h, blood urea>30 mg/dl,
creatinine>1.8 mg/dl
*Risk benefit must be weighed for asymptomatic growth
Bleeding: Bleeding from IV sites; gastrointestinal bleeding, retended baby16

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R. Agarwal et al
(b) Surgical ligation : The indications for surgical therapy
include a contraindication to medical therapy and failure
of a second course of indomethacin. Surgical ligation may
be carried out by Thoracotomy or Video assisted
thoracoscopy.14
(c) Restricted fluid intake for prevention of PDA
15
Bell et al have conducted a meta-analysis on studies
evaluating fluid therapy and have shown that restricted
fluid intake in the initial 4-5 days of life is associated with
a lower incidence of PDA. In our unit, we usually start
with 60 ml/kg in babies weighing between 1000-1500
grams and 80 ml/kg for babies between 750-1000 grams.
We try to maintain serum sodium of 135-145 meq/L,
urine output of 1-3 ml/kg/hr and a urine specific gravity
of 1.005 to 1.012. We use thin transparent plastic barriers
(clingwrap) to create a microenvironment around the
baby in order to decrease insensible water losses. We
would allow a weight loss of at least 2-3% per day and
generally do not exceed a fluid intake of 150-160 ml/kg/
day by day 5-7 day of life. Using this scheme of fluid
therapy, we have achieved a low incidence of PDA in our
unit.
GUIDELINES FOR TREATMENT
Preterm babies are at risk of developing
hemodynamically significant PDA.
Prematurity, lack of antenatal steroids, RDS and
sepsis increase the risk of PDA.
At-risk preterm neonates should be monitored for
clinical features suggestive of PDA.
Echocardiography should be used to confirm a
clinical suspicion of PDA. In the absence of an echo,
treatment may be started with a clinical diagnosis.
Babies <1000 grams with a diagnosis of PDA
(irrespective of hemodynamic effect) should be
treated. Risk benefit must be weighed specially in
growth retarded babies with absent or reverse
diastolic blood flow.16
Babies >1000 grams with a diagnosis of PDA should
be treated only if a hemodynamically significant left
to right shunt is present.
Prophylactic treatment with indomethacin is not
recommended.
Platelet counts and renal parameters should be
checked prior to starting therapy with indomethacin
and repeated after 24 hours.
A second course of indomethacin should be tried
after failure of the first course or recurrence after the
first course.
Preliminary studies seem to suggest that ibuprofen is
a safe alternative to indomethacin in the treatment of
PDA.
280
101
Surgical ligation should be considered if PDA recurs
after the second course or if contraindications to
indomethacin/ ibuprofen exist.
Both ibuprofen and indomethacin may be used
orally.
These recommendations do not apply to PDA in term
neonates. Term neonates with PDA should not be treated
with indomethacin/ ibuprofen and should have a
detailed echo to rule out an underlying congenital heart
defect. They would require surgery for closure of an
isolated patent ductus arteriosus.
REFERENCES
1. Wechsler SB, Wernovsky G. Cardiac disorders. In Cloherty JP,
Stark AR, eds. Manual on neonatal care, 6th ed. 2008; 388-435.
2. Archer N. Cardiac diseases. In Rennie JM, Roberton NRC, eds.
Textbook of neonatal care, 3rd ed. Churchill Livingstone, 1999;
687-689.
3. Clyman RI. Patent ductus arteriosus in preterm neonates. In
Taeush HW, Ballard RA, eds. Averys diseases of the newborn,
8th ed. WB Saunders; 2005; 816-826.
4. Zahaka KG, Patel CR. Congenital cardiac defects. In Fanaroff
AA, Martin RJ, eds. Neonatal perinatal medicine Disorders of the
fetus and infants, 6 th ed. 1997; 1155-1157.
5. Clyman RI. Treatment of premature neonates with patent
ductus arteriosus: analysis of four treatment strategies. J
Pediatr 1996; 128 : 601-607.
6. Foulie WP. Prophylactic Indomethacin - systematic review
and meta-analysis. Arch Dis Child 1996; 74 : F81-F87.
7. De Carolis MP, Romagnoli C, Polimeni V, Piersigilli F, Zecca
E, Pappacci P et al. Prophylactic ibuprofen therapy of patent
ductus arteriosus in preterm infants. Eur J Pediatr 2000; 159 :
364-368.
8. Bose CL, Laughan MM. Patent ductus arteriosus: Lack of
evidence for common treatments. Arch Dis Child Fetal Neonatal
2007; 92 : F498-F502.
9. Vanhaesebrouck S, Zonnenberg I, Vandervoot P et al.
Conservative treatment for patent ductus arteriosus in the
preterm. Arch Dis Child Fetal Neonatal Ed 2007; 92 : F244-F247.
10. Brion LP, Campbell DE. Furosemide in indomethacin treated
infants - systematic review and meta-analysis. Pediatr Nephrol
1999; 13 : 212-218.
11. Fajardo CA, Whyte RK, Stele BT. Effect of dopamine on
failure of indomethacin to close patent ductus arteriosus. J
Pediatr 1992; 121 : 771-775.
12. Tammela O, Ojala R, Livainen T, Lautamatti V, Pokela ML,
Janas M et al. Short versus prolonged indomethacin therapy
for patent ductus arteriosus in preterm infants. J Pediatr 1999;
134: 552-557.
13. Van Overmeire B, Smets K, Lecoutere D, Van de Broek H,
Weyler J, Degroote K et al. A comparison of ibuprofen and
indomethacin for closure of patent ductus arteriosus. N Engl
J Med 2000; 343 : 674-681.
14. Burke RP, Jacobs JP, Cheng W, Trento A, Fontana GP. Video-
assisted thoracoscopic surgery for patent ductus arteriosus in
low birth weight neonates and infants. Pediatrics 1999; 104:
227-230.
15. Bell EF, Acarregui MJ. Restricted versus liberal water intake
for preventing morbidity and mortality in preterm infants.
Cochrane Database Syst Rev 2000; 2 : CD000503.
16. Mc Namara, Sehgal A. Towards rational management of the
patent ductus arteriosus: the need for disease staging. Arch Dis
Child Fetal Neonatal 2007; 92: F425-F427.
Indian Journal of Pediatrics, Volume 75March, 2008
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Symposium on AIIMS Protocols in Neonatology IV

Perinatal HIV
Sunil Saharan, Rakesh Lodha, Ramesh Agarwal, Ashok K. Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New
Delhi, India

ABSTRACT
HIV pandemic is one of the most serious health crises the world faces today. Approximately 5-10% of all cases of HIV are
children. Majority of children acquire infection through mother-to-child transmission either during pregnancy, delivery, or by
breast-feeding. MTCT can be reduced to <2% by antiretroviral prophylaxis to women during pregnancy and labour and to the
infant in the first weeks of life, obstetrical interventions including elective cesarean delivery and complete avoidance of
breastfeeding. Guidelines for postnatal diagnosis of HIV infection, feeding, immunization and administration of cotrimoxazole
prophylaxis have been described in the protocol. [Indian J Pediatr 2008; 75 (4) : 359-362] E-mail: aranag@rediffmail.com

Key words : HIV; Pregnancy; Perinatal; Mother-child transmission; Neonate

The human immunodeficiency virus (HIV) pandemic is

Abbreviations
one of the most serious health crises the world faces
ART - Antiretroviral therapy
today. AIDS has killed more than 25 million people since AZT - Zidovudine
1981 and an estimated 33.2 million people are now living Sd NVP - Single dose nevirapine
with HIV, about 2.5 million of whom are children.1 In 2007
alone, an estimated 420,000 children were newly infected
with HIV.1 In India it is estimated 2.47 million (2 - 3.1 Maternal factors: Advanced disease (low CD4 count,
million) people were living with HIV infection in year symptoms of AIDS), primary infection of mother
2006. Adult prevalence of HIV infection in our country is during pregnancy, first of twins, rupture of
0.36% (0.27-0.47%). The prevalence rate for females is 0.29 membranes more than four hours, maternal bleeding,
percent, while for males it is 0.43 percent. Prevalence of mother not on antiretroviral therapy, vaginal delivery,
HIV in pregnant women population was observed to be other sexually transmitted diseases, isolated HIV-1
0.60%.2 infection

Mode of transmission Fetoplacental factors: chorioamnionitis, placenta previa,

Most children living with HIV acquire the infection
through mother-to-child transmission (MTCT). HIV
infection can be transmitted from an infected mother to
her fetus during pregnancy, during delivery, or by breast-
feeding. HIV can be transmitted to the fetus as early as the
first and second trimester of pregnancy. However,
maternal transmission to the fetus occurs most commonly
in the perinatal period.
Prevention of perinatal HIV
Risk factors for perinatal HIV transmission3
Viral factors: High viral load, non syncytium inducing
phenotype, HIV 1
Correspondence and Reprint requests : Dr. Ramesh Agarwal,
Assistant Professor, Department of Pediatrics, All India Institute of
Medical Sciences, Ansari Nagar, New Delhi, India
[Received March 17, 2008; Accepted March 17, 2008]
prematurity (increased peripartum transmission)
Infant factors: HLA concordance with mother
Postnatal factors: breast feeding, higher breast milk
virus load, mastitis or maternal nipple lesions,
maternal seroconversion during breastfeeding, infant
having thrush at less than six month age (in
breastfeeding infant)
In the absence of any intervention, the risk of perinatal
transmission is 1530% in non-breastfeeding
population.
Breastfeeding by an infected mother increases the risk
by 520% to a total of 2045%.4
The risk of MTCT can be reduced to less than 2% by
interventions that include antiretroviral (ARV)
prophylaxis given to women during pregnancy and

Indian Journal of Pediatrics, Volume 75April, 2008 359

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S. Saharan et al
labour and to the infant in the first weeks of life,5
obstetrical interventions including elective cesarean
delivery (prior to the onset of labour and rupture of
membranes), 6 and complete avoidance of
breastfeeding.7
ARV regimens for treating pregnant women8
Refer to Fig (1A)
Recommended regimen for pregnant women with
indication for antiretroviral therapy (ART) is
combination of zidovudine (AZT), lamivudine (3TC)
and nevirapine (NVP) in antepartum, intrapartum
and postpartum period.
Recommended regimen for pregnant women who are
not eligible for ART, but for preventing MTCT is:
Antepartum: AZT starting at 28 weeks of
pregnancy
Intrapartum: a combination of single dose (Sd)
NVP, AZT and 3TC
Postpartum: a combination of AZT and 3TC for 7
days.
Recommended regimen for pregnant women who are
in labour and have not received ART is:
Intrapartum: a combination of Sd-NVP, AZT and
3TC
Postpartum: a combination of AZT and 3TC 7
days
Omission of the Sd-NVP for the mother may be
considered for women who receive at least four weeks
of AZT before delivery.
When Sd-NVP is used to prevent MTCT, either alone
or in combination with AZT, the rationale of giving
AZT and 3TC intrapartum and for seven days
postpartum is to prevent resistance to NVP.
ARV regimens for infants born to HIV positive
mothers8
Refer to Fig. 1(B)
The recommended regimen for infants is Sd-NVP +
AZT for one week.
When delivery occurs within two hours of a woman
taking Sd-NVP, the infant should receive Sd-NVP
immediately after delivery and AZT for four weeks.
If the mother receives less than four weeks of
antenatal ART, then four weeks rather than one week
of AZT is recommended for the infant.
Zidovudine 4 mg/kg/dose, Nevirapine 2 mg/kg
Intrapartum interventions
Avoid artificial rupture of membrane ARM unless
360
103
medically indicated.
Delivery by elective cesarean section at 38 weeks
before onset of labour and rupture of membranes.
Avoid procedures increasing risk of exposure of child
to maternal blood and secretions like use of scalp
electrodes.
Breast feeding
Breast-feeding is an important modality of
transmission of HIV infection in developing countries.
The risk of HIV infection via breast-feeding is highest
in the early months of breast-feeding.9
Factors that increase the likelihood of transmission
include detectable levels of HIV in breast milk, the
presence of mastitis and low maternal CD4+ T cell
count.
Exclusive breast-feeding has been reported to carry a
lower risk of HIV transmission than mixed feeding.7
According to current UN recommendations (WHO,
2001) when replacement feeding is acceptable,
feasible, affordable, sustainable and safe (AFASS),
avoidance of all breastfeeding by HIV-infected moth-
ers is recommended. Otherwise exclusive
breastfeeding is recommended during the first
months of life.
WHO recommends that the transition between
exclusive breastfeeding and early cessation of
breastfeeding should be kept as short as possible, -
early and abrupt cessation - bearing in mind that
mixed feeding during this period carries a 70% greater
risk of MTCT.10
Replacement feeding should be given by katori spoon.
Postnatal Diagnosis of HIV Infection11
Refer to Fig. 2
In children younger than 18 months, diagnosis of HIV
infection is based on: a positive virological test at 6
weeks for HIV or its components (HIV-RNA or HIV-
DNA or HIV p24 antigen) confirmed by a second
virological test obtained from a separate
determination taken more than four weeks after the
first one.12
If an infant or child is breastfeeding, he or she remains
at risk of acquiring HIV infection throughout the
breastfeeding period. Virological assays for HIV
infection should be conducted at least six weeks or
more after the complete cessation of breastfeeding to
rule out HIV infection.
Antibody testing is not recommended for definitive or
confirmatory diagnosis of HIV infection in children
until 18 months of age.13
Indian Journal of Pediatrics, Volume 75April, 2008
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Perinatal HIV

Note:
If the mother receives less than four weeks of AZT before delivary, the AZT dose for the infant should be extended to four weeks
When delivery occurs within two hours of a woman taking Sd-NVP, the infant should receive Sd-NVP immediately after delivery
and AZT for four weeks

Fig. 1. Protocol on approach to (A) HIV infected mother (B) Baby born to HIV infected mother8

Fig. 2. Diagnostic approach for HIV exposed infants11

Indian Journal of Pediatrics, Volume 75April, 2008 361

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S. Saharan et al
Co-trimoxazole prophylaxis
Co-trimoxazole prophylaxis is recommended for all
HIV-exposed infants under age 18 months starting at
46 weeks of age or when first seen and continued
until HIV infection can be excluded.14
Co-trimoxazole prophylaxis is also recommended for
a breastfeeding child of any age, continued until HIV
infection can be excluded following cessation of
breastfeeding, with testing performed six weeks or
more after breastfeeding was stopped.
In children < 6 month dose is 2.5 ml once a day
(trimethoprim 40 mg and sulphamethoxazole 200
mg/5 ml)
Immunization15
HIV exposed or infected but asymptomatic children
should receive all standard vaccines as per national
schedule.
HIV infected children with immune suppression or
symptoms should receive all standard vaccines except
varicella, BCG and OPV vaccines.
Consider HiB and pneumococcal vaccines in all HIV
exposed children (irrespective of symptoms or CD4
count)
REFERENCES
1. UNAIDS/WHO. AIDS Epidemic Update. December, 2007.
2. National AIDS Control Organization. HIV Sentinel
Surveillance and HIV estimation 2006. Available at: http://
www.nacoonline.org/upload/NACO%PDF/Note%20on%20
HIV%20Sentinel%Surveillance%20and20%HIV%20
Estimation_01%Feb%2008.pdf(accessed on 1/4/2008).
3. Havens P, Waters D. Management of the infant born to a
362
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mother with HIV infection. Pediatr Clin North Am 20004; 51:
909-937.
4. De Cock KM, Fowler MG, Mercier E et al. Prevention of
mother-to-child HIV transmission in resource-poor countries:
translating research into policy and practice. JAMA 2000; 283:
1175-1182.
5. Lallemant M, Jourdain G, Le Coeur S et al. Single-dose
Perinatal nevirapine plus standard zidovudine to prevent
mother-to-child transmission of HIV-1 in Thailand. N Engl J
Med 2004; 351 : 217-228.
6. Thome C, Patel D, Fiore S, Peckham C, Newell ML. Mother-
to-child transmission of HIV infection in the era of highly
active antiretroviral therapy. Clin lnfec Dis 2005; 40:458-465.
7. Magoni M, Bassani L, Okong P et al. Mode of infant feeding
and HIV infection in children in a program for prevention of
mother-to-child transmission in Uganda. AIDS 2005; 19 : 433-
437.
8. WHO. Antiretroviral drugs for treating pre~nant women and
preventing HIV infection in infants: towards universal access. 2006.
9. Dunn DT, Tess BH, Rodrigues LC, Ades AE. Mother-to-child
transmission of HIV: implications of variation in maternal
infectivity. AIDS 1998; 12 : 2211-2216.
10. WHO. New data on the prevention of Mother-to-Child
Transmission of HIV and their policy implications. Conclusions
and recommendations, Geneva, 2001.
11. WHO. Intiretroviral therapy of HIV infection in infants and
children: towards universal access. 2006.
12. Sherman GG, Cooper PA, Coovadia AH et al. Polymerase
chain reaction for diagnosis of human immunodeficiency
virus infection in infancy in low resource settings. Pediatr
Infect Dis J 2005; 24 : 993-997.
13. Chantry CJ, Cooper ER, Pelton SI, Zorilla C, Hillyer GV, Diaz
C. Seroreversion in human immunodeficiency virus-exposed
but un infected infants. Pediatr Infect Dis J 1995; 14 : 382-387.
14. WHO. Guidelines on co-trimoxazole prophylaxis for HIV-related
infections among children, adolescents and adults in resource-
limited settings recommendations for a public health approach.
2006.
15. Anonymous. Immunization in special circumstances. In Shah
RC, Shah NK, Kukreja S (Eds). IAP Guide Book on
Immunization, Mumbai; IAP Committee on Immunization,
2005-2006; 52-54.
Indian Journal of Pediatrics, Volume 75April, 2008
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175
176
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 178
Indian J Pediatr (2010) 77:11171121
DOI 10.1007/s12098-010-0177-z
SYMPOSIUM ON AIIMS PROTOCOLS IN NEONATOLOGY-I
Management of Polycythemia in Neonates
M. Jeeva Sankar & Ramesh Agarwal & Ashok Deorari &
Vinod K. Paul
Received: 27 July 2010 / Accepted: 2 August 2010 / Published online: 21 August 2010
# Dr. K C Chaudhuri Foundation 2010
Abstract Polycythemia is defined as a venous hemato-
crit above 65%. The hematocrit in a newborn peaks at
2 h of age and decreases gradually after that. The
relationship between hematocrit and viscosity is almost
linear till 65% and exponential thereafter. Increased
viscosity of blood is associated with symptoms of
hypo-perfusion. Clinical features related to hyperviscos-
ity may affect all organ systems. Neonates born small for
gestational age (SGA), infants of diabetic mothers
(IDM), and multiple births are at risk for polycythemia.
They should therefore undergo screening at 2, 12, and
24 h of age. Polycythemia may be symptomatic or
asymptomatic and guidelines for the management of both
types based on the current evidence are provided in the
protocol.
Keywords Polycythemia . Blood viscosity . Newborn .
Therapy
Polycythemia or an increased hematocrit is associated
with hyperviscosity of blood. As the viscosity increases,
there is an impairment of tissue oxygenation and perfusion
and a tendency to form microthrombi. Significant damage
may occur if these events occur in the cerebral cortex,
kidneys and adrenal glands. Hence, this condition requires
urgent diagnosis and prompt management.
M. J. Sankar : R. Agarwal : A. Deorari : V. K. Paul
Division of Neonatology, Department of Pediatrics,
All India Institute of Medical Sciences,
Ansari Nagar, New Delhi, India
A. Deorari (*)
Department of Pediatrics, All India Institute of Medical Sciences,
Ansari Nagar, New Delhi 110029, India
e-mail: ashokdeorari_56@hotmail.com
106
The viscosity of blood is directly proportional to the
hematocrit and plasma viscosity and inversely proportional
to the deformability of red blood cells. Symptoms of
hypoperfusion correlate better with viscosity as compared
to hematocrit. Viscosity is, however, difficult to measure at
the bedside. Hyperviscocity is therefore suspected in the
presence of an abnormally high hematocrit with or without
suggestive symptoms. Relationship between viscosity and
hematocrit is almost linear up to a hematocrit of 65%
and exponential thereafter [1, 2]. The polycythemia-
hyperviscocity syndrome is thus usually confined to infants
with hematocrits of more than 65%; it is very rare with
hematocrits of <60%.
Definition
A diagnosis of polycythemia is made in the presence of a
venous hematocrit more than 65% or a venous hemoglobin
concentration in excess of 22.0 g/dl. Hyperviscosity is
defined as a viscosity greater than 14.6 cP at a shear rate of
11.5 per second [3].
Incidence
The incidence of polycythemia is 1.5%4% of all live births
[4, 5]. The incidence is higher among both small for
gestational age (SGA) and large for gestational age (LGA)
infants. The incidence of polycythemia is 15% among term
SGA infants as compared to 2% in term appropriate for
gestational age (AGA) infants [6]. Neonates born at high
altitudes also have a higher incidence of polycythemia [1].
Polycythemia is unlikely to occur in neonates born at less
than 34 week gestation.
 179 107
1118 Indian J Pediatr (2010) 77:11171121

Table 1 Clinical features

ascribed to polycythemia and
hyperviscosity
Central nervous system
Early: Hypotonia and sleepiness, irritability, jitteriness , seizures and infarcts
Late: Motor deficits, lower achievement and IQ scores
Metabolism
Hypoglycemia
Jaundice
Hypocalcemia
Heart and lungs
Tachycardia, tachypnea, respiratory distress
Cyanosis, plethora
Chest radiography: cardiomegaly, pulmonary plethora
Echocardiography: increased pulmonary resistance, decreased cardiac output
Gastrointestinal tract
Poor suck, vomiting
Feed intoleranceabdominal distenstion
Necrotizing enterocolitis
Kidneys
Oliguria (depending on blood volume)
Transient hypertension
Renal vein thrombosis
Hematology
Mild thrombocytopenia
Thrombosis (rare)
Miscellaneous
Peripheral gangrene
Priapism
Testicular infarction

Physiological Changes in Postnatal Life high-risk neonates at 2 h of age. A normal value at 2 h of

Significant changes take place in the hematocrit from birth
through the first 24 h of life. The hematocrit peaks at 2 h of
age and values up to 71% may be normal at this age [7, 8]
It gradually declines to 68% by 6 h and usually stabilizes
by 12 to 24 h. The initial rise in hematocrit is related to a
transudation of fluid out of the intravascular space.
age (hematocrit <65%) does not merit any further
screening unless the infant is symptomatic. Hematocrit
values >65% at 2 h of age merit repeat screening at 12 and
24 h. Any infant with clinical features suggestive of
polycythemia should be investigated for the same.
Capillary vs. Venous Hematocrit

Capillary hematocrit measurements are unreliable and

Clinical Features
Polycythemia can result in a wide range of symptoms involving
several organ systems (Table 1). About 50% of neonates with
polycythemia develop one or more symptoms. However, most
of these symptoms are non-specific and may be related to the
underlying conditions rather than due to polycythemia per se.
highly subject to variations in blood flow. Capillary
hematocrits are significantly higher than venous hematoc-
rits. This difference is even more apparent in infants
Table 2 Screening for Polycythemia
Screening is recommended for the following:

(a) Small for gestational age (SGA) infants

(b) Infants of diabetic mothers (IDM)
Screening for Polycythemia
(c) Large for gestational age (LGA) infants
(d) Monochorionic twins especially the larger twin
Screening should be done for polycythemia in certain
(e) Morphological features of growth retardation.
high-risk groups (Table 2). We recommend screening in
 180 108
Indian J Pediatr (2010) 77:11171121 1119

receiving large placental transfusion [9]. Capillary samples

Capillary hematocrit >65%
may be used for screening, but all high values should be
confirmed by a venous sample for the diagnosis of
polycythemia. Confirm with venous hematocrit

Methods of Hematocrit Analysis

The two available methods are: Exclude dehydration

Automated hematology analyzer: This calculates the Check weight loss
hematocrit from a direct measurement of mean cell
volume and the hemoglobin.
Micro-centrifuge: Blood is collected in heparinized
micro-capillaries (110 mm length and 12 mm
internal diameter) and centrifuged at 10,00015,000 Symptomatic Asymptomatic
revolutions per min (rpm) for 35 min. Plasma
separates and the packed cell volume is measured
to give the hematocrit. An automated analyzer gives
lower values as compared to hematocrits measured
by the centrifugation method [10]. Most of the PET PCV 65-70 PCV 70-75 PCV >75%
reported data on polycythemia is on centrifuged
hematocrits.

Management
Before a diagnosis of polycythemia is considered, it is
mandatory to exclude dehydration. If the birth weight is
known, re-weighing the baby and looking for excessive
weight loss would help in the diagnosis of dehydration.
If this is present, it should be corrected by increasing
fluid intake. The hematocrit should be measured again
after correction of dehydration. Once a diagnosis of
polycythemia is made, associated metabolic problems
including hypoglycemia should be excluded.
Management of polycythemia is dependent upon two
factors (Fig. 1):
1. Presence of symptoms suggestive of polycythemia
and/or
2. Absolute value of hematocrit
Monitoring Consider
hydration PET
Actively look for
symptoms
PET: partial exchange transfusion
Fig. 1 Algorithm for management of polycythemia
(a) Symptomatic Polycythemia
The definitive treatment for polycythemia is to perform a
partial exchange transfusion (PET). PET involves removing
some of the blood volume and replacing it with fluids so as
to decrease the hematocrit to a target packed cell volume of
55%. Following partial exchange transfusion, symptoms
like jitteriness may persist for 12 days despite the
hematocrit being lowered to physiological ranges.

Volume to be Blood volume* x (Observed hematocrit Desired hematocrit)

exchanged =
Observed hematocrit

*Blood volume is estimated to be 80-90 ml/kg in term babies and 90-100 ml/kg
in preterm babies
 181
1120
The volume of blood to be exchanged is given by the
formula shown in the box.
As a rough guide, the volume of blood to be exchanged
is usually 20 ml/kg.
PET: Peripheral vs. Umbilical Route
Partial exchange transfusion may be carried out via the
peripheral route or the central route. In the former, blood is
withdrawn from the peripheral arterial line and replaced
simultaneously with saline via the venous line. In the central
route, the umbilical venous catheter is used for withdrawing
blood while the same amount of saline is replaced through a
peripheral vein. Alternatively, the umbilical venous catheter
may be used both for withdrawal of blood and replacement
with saline. Two systematic reviews (including a Cochrane
review) have shown that the partial exchange transfusion
through umbilical route may be associated with increased
risk of necrotizing enterocolitis [11, 12].
PET: Fluids to Be Used
Crystalloids such as normal saline (NS) or ringers lactate
(RL) are preferred over colloids because they are less
expensive and easily available, produce a similar reduction
in hematocrit as colloids [13, 14], and do not have the risk
of transfusion associated infections. Moreover, adult plasma
has been shown to increase the blood viscosity when mixed
with fetal erythrocytes. We use only normal saline for
partial exchange transfusion.
(b) Asymptomatic polycythemia
The line of management in infants with asymptomatic
polycythemia depends upon their hematocrit values.
i. Hematocrit >75%: These infants are usually managed
with partial exchange transfusion.
ii. Hematocrit between 70% and 75%: Conservative
management with hydration may be tried in infants
with hematocrit of 70% to 75%. An extra fluid aliquot
of 20 ml/kg may be added to the daily fluid require-
ments. The additional fluid may be ensured by either
enteral (supervised feeding) or parenteral route (IV
fluids). The rationale for this therapy is hemodilution
and the resultant decrease in viscosity. However, liberal
fluid therapy may be associated with problems espe-
cially in preterm neonates.
iii. Hematocrit between 65% and 70%: They only need
monitoring for any symptoms of polycythemia and re-
estimation of hematocrit. Further management depends
upon the repeat hematocrit values.
109
Indian J Pediatr (2010) 77:11171121
Evidence for Management of Polycythemia
Partial exchange transfusion reverses the physiological
abnormalities associated with the polycythemia-
hyperviscocity syndrome. It improves capillary perfusion,
cerebral blood flow and cardiac function. However, there
is very little data to suggest that PET improves long term
outcome in patients with polycythemia. The Cochrane
reviewpublished this year (2010)concludes that
there are no proven clinically significant short or long-
term benefits of PET in polycythemic newborn infants
who are clinically well or who have minor symptoms
related to hyperviscosity; PET may lead to an increase in
the risk of NEC [12]. However, as the review authors
pointed out, the data regarding developmental outcomes
are extremely imprecise due to the large number of
surviving infants who were not assessed and, therefore,
the true risks and benefits of PET are unclear. It is possible
that the underlying etiology of polycythemia is a more
important determinant of ultimate outcome. Given the
uncertainty regarding the long term outcomes, it is
preferable to do partial exchange transfusion in symptom-
atic infants with hematocrit of >65% and in asymptomatic
neonates with hematocrit of >75%.
References
1. Mackintosh TF, Walkar CH. Blood viscosity in the newborn. Arch
Dis Child. 1973;48:54753.
2. Phibbs RH. Neonatal Polycythemia. In: Rudolph AB, editor.
Pediatrics. 6th ed. New York: Appleton Century Crofts; 1997. p.
179.
3. Ramamurthy RS, Brans WY. Neonatal Polycythemia I. Criteria
for diagnosis and treatment. Pediatrics. 1981;68:16874.
4. Wirth FH, Goldberg KE, Lubchenco LO. Neonatal hyperviscocity
I. Incidence. Pediatrics. 1979;63:8336.
5. Stevens K, Wirth FH. Incidence of neonatal hyperviscosity at sea
level. Pediatrics. 1980;97:118.
6. Bada HS, Korones SB, Pourcyrous M, et al. Asymptomatic
syndrome of polycythemic hyperviscocity: effect of partial
exchange transfusion. J Pediatr. 1992;120:57985.
7. Shohat M, Merlob P, Reisner SH. Neonatal Polycythemia. I. Early
diagnosis and incidence relating to time of sampling. Pediatrics.
1984;73:710.
8. Shohat M, Reisner SH, Mimouni F, Merlob P. Neonatal
polycythemia II. Definition related to time of sampling. Pediatrics.
1984;73:113.
9. Oh W. Neonatal polycythemia and hyperviscosity. Pediatr Clin
North Am. 1986;33:52332.
10. Goldberg K, Wirth FH, Hathaway WE, et al. Neonatal hyper-
viscocity II. Effect of partial exchange transfusion. Pediatrics.
1982;69:41925.
11. Dempsey EM, Barrington K. Short and long term outcomes
following partial exchange transfusion in the polycythaemic
newborn: a systematic review. Arch Dis Child Fetal Neonatal
Ed. 2006;91:F26.
 182
Indian J Pediatr (2010) 77:11171121
12. Ozek E, Soll R, Schimmel MS. Partial exchange transfusion to
prevent neurodevelopmental disability in infants with
polycythemia. Cochrane Database Syst Rev 1. 2010:
CD005089.
13. Deorari AK, Paul VK, Shreshta L, Singh M. Symptomatic
neonatal polycythemia: comparison of partial exchange
110
1121
transfusion with saline versus plasma. Indian Pediatr.
1995;32:116771.
14. de Waal KA, Baerts W, Offringa M. Systematic review of the
optimal fluid for dilutional exchange transfusion in neonatal
polycythaemia. Arch Dis Child Fetal Neonatal Ed. 2006;91:
F710.
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185
186
 187 111

Symposium on AIIMS Protocols in Neonatology II

Post-resuscitation Management of Asphyxiated Neonates

Ramesh Agarwal, Ashish Jain, Ashok K. Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New
Delhi, India

ABSTRACT
Inspite of major advances in monitoring technology and knowledge of fetal and perinatal medicine, perinatal asphyxia is one
of the significant causes of mortality and long term morbidity. Data from National Neonatal Perinatal Database suggests that
perinatal asphyxia contributes to almost 20% of neonatal deaths in India. Failure to initiate or sustain respiration after birth
has been defined as criteria for the diagnosis of asphyxia by WHO. Perinatal asphyxia results in hypoxic injury to various
organs including kidneys, lungs and liver but the most serious effects are seen on the central nervous system. Levenes
classification is a useful clinical tool for grading the severity of hypoxic ischemic encephalopathy. Good supportive care is
essential in the first 48 hours after asphyxia to prevent ongoing brain injury in the penumbra region. Strict monitoring and
prompt correction is needed for common problems including temperature maintenance, blood sugars, blood pressure and
oxygenation. Phenobarbitone is the drug of choice for the treatment of convulsions. [Indian J Pediatr 2008; 75 (2) : 175-180]
E-mail: vinodkpaul@hotmail.com

Key words : Asphyxia; HIE

According to latest estimates by World Health
Organization (WHO), approximately 4 million babies die
each year before they reach the age of one month.1 Ninety-
eight percent of these neonatal deaths take place in the
developing countries. Perinatal asphyxia and birth
injuries together contribute to almost 29% of these deaths.1
Most of the births in developing countries occur at home,
usually attended by untrained birth attendants. Failure to
initiate and sustain breathing immediately after delivery
has been associated with hypoxic-ischemic injury to the
central nervous system (CNS) and the clinical
manifestations of this injury have been termed as hypoxic
ischemic encephalopathy (HIE). Some experts prefer to
use term neonatal encephalopathy , as it is not always
possible to document the hypoxic ischemic insult and
there may be potential several other etiologies operating.
HIE is of concern in an asphyxiated neonate because it can
lead to serious long-term neuro-motor sequelae among
survivors.
DEFINITION
A gold standard definition of birth asphyxia does not
exist. It is probably better to use the term perinatal
asphyxia since asphyxia may occur in utero, at birth or in
the postnatal period. WHO 2 has defined perinatal
asphyxia as a failure to initiate and sustain breathing at
birth The National Neonatal Perinatal Database (NNPD),
2000 used a similar definition for perinatal asphyxia.3 It
defined moderate asphyxia as slow gasping breathing or
an Apgar score of 4-6 at 1 minute of age. Severe asphyxia
was defined as no breathing or an Apgar score of 0-3 at 1
minute of age.
As per the American Academy of Pediatrics (AAP) and
American College of Obstetrics and Gynecology (ACOG),
all of the following must be present for designation of
asphyxia viz. (a) profound metabolic or mixed academia
(pH< 7.00) in cord. (b) persistence of Apgar scores 0-3 for
longer than 5 minutes. (c) neonatal neurologic sequelae
(e.g., seizures, coma, hypotonia). (d) multiple organ
involvement (e.g., of the kidney, lungs, liver, heart,
intestine)
Definitions based on Apgar scores may be useful as it
can be used for formulating guidelines for post-asphyxial
treatment of neonates. Apgar scores are also useful for
predicting long term outcome in infants with perinatal
asphyxia.4,5

Correspondence and Reprint requests : Dr Vinod K. Paul, INDIAN DATA

Professor, Department of Pediatrics, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi 110029, India According to NNPD 20003 data collected from 17 tertiary
[Received January 11, 2008; Accepted January 11, 2008] neonatal intensive care units in India, Apgar scores <7 at

Indian Journal of Pediatrics, Volume 75February, 2008 175


R. Agarwal et al
1 minute (includes moderate and severe asphyxia) were
documented in 9% of all intramural deliveries.2 2.5%
babies continued to have Apgar scores <7 at 5 minutes of
age. Bag and mask ventilation was used in 4.5% infants
and less than 1% infants needed cardiac compressions
and/or medications for resuscitation at birth. Perinatal
asphyxia was responsible for 20% of all neonatal deaths.
Manifestations of HIE were seen in approximately 1.5% of
all babies. Perinatal asphyxia was the commonest cause of
still-births accounting for one-third of all such cases.
SYSTEMIC CONSEQUENCES OF ASPHYXIA
Perinatal asphyxia leads to muti-organ dysfunction.
Virtually any organ can be effected. And care in the
nursery should be oriented to determining the presence or
the absence of dysfunction of the critical organ systems..
Many of these complications are potentially fatal. In term
infants with asphyxia, renal, CNS, cardiac and lung
dysfunction occur in 50%, 28%, 25% and 25% cases,
respectively.6 The extent of organ system dysfunction
determines the early outcome of an asphyxiated neonate
(Table 1).
TABLE 1. Organ System Dysfunction in Perinatal Asphyxia
CNS Hypoxic ischemic encephalopathy, intracranial
hemorrhage seizures, long-term neurological
sequelae
Cardiac Myocardial dysfunction, valvular dysfunction,
rhythm abnormalities, congestive cardiac failure
Renal Hematuria, acute tubular necrosis, renal vein
thrombosis
Metabolic Acidosis, hypoglycemia, hypocalcemia,
hyponatremia
Pulmonary Delayed adaptation, respiratory failure, meconium
aspiration
Surfactant depletion, primary pulmonary
hypertension
GI tract Necrotizing enterocolitis, hepatic dysfunction
Hematological Thrombocytopenia, coagulation abnormalities
Metabolic involvement may include hypocalcemia,
hyponatremia (as a result of SIADH or direct renal
injury), and alterations in glucose metabolism. There may
be hematological alterations (thrombocytopenia and DIC)
Hypoxic ischemic encephalopathy (HIE) refers to the
CNS dysfunction associated with perinatal asphyxia. HIE
is of foremost concern in an asphyxiated neonate because
of its potential to cause serious long-term neuromotor
sequelae among survivors. A detailed classification of HIE
TABLE 2. Classification of HIE (Levene)8
Feature Mild
Consciousness Irritable
Tone Hypotonia
Seizures No
Sucking/respiration Poor suck
176
188 112
in term neonates was proposed by Sarnat and Sarnat7. A
simple and practical classification of HIE by severity of
manifestations provided by Levene is recommended for
routine use (Table 2).8
EVOLUTION OF HIE CHANGES
Hypoxic-ischemic brain damage is a gradually evolving
process, which begins during the insult and extends
beyond the resuscitation period. Although the initial
brain injury (phase of energy failure) is related to hypoxia
and ischemia, subsequent reperfusion and generation of
free radicals contributes to ongoing injury.9 The initial
hypoxic-ischemic injury results in an area of infarction.
The immediate area surrounding this area is termed as
penumbra.9 The penumbra continues to show adverse
changes in the form of neuronal necrosis or apoptosis
(programmed cell death) even after the hypoxic insult is
over.9 It is possible that these post-hypoxic changes in the
penumbra area may be amenable to therapeutic
interventions. The duration of this delayed phase of
neuronal injury is not known precisely, but appears to
increase over first 24 to 48 hours and than starts to resolve.
Thus good supportive therapy is essential for the first 48
hours of post-asphyxial period to reduce neuronal injury
in the penumbra area. The extent of penumbra and the
duration for which these adverse changes continue is
variable. Additional factors that may influence the
outcome include the nutritional satus of the brain, severe
intrauterine restriction, preexisting brain pathology, and
the frequent siezuure disorder that anifest in the early
postnatal age ( within hours of birth)This phase may also
provide a therapeutic window for newer modes of
therapy in asphyxiated neonates.
MANAGEMENT OF A NEONATE WITH
PERINATAL ASPHYXIA
Initial management (Fig. 1)
Management of each and every baby needs to be
individualized. Given below are broad guidelines.
Transfer the baby to special care newborn unit: A baby
who fails to initiate and sustain respiration at birth is at
risk of hypoxic brain injury and needs regular monitoring.
All these bsbies should have a cord gas analysis
performed. Infants with moderate asphyxia (Apgar score
Moderate Severe
Lethargy Comatose
Marked hypotonia Severe hypotonia
Yes Prolonged
Unable to suck Unable to sustain spontaneous respiration
Indian Journal of Pediatrics, Volume 75February, 2008
 189
Post-resuscitation Management of Asphyxiated Neonates
Transfer to newborn unit
(Obtain a cord gas)
Keep baby under radiant
warmer, maintain normal
temperature (avoiod hyperthermia)
Check vital signs
at regular intervals as needed
Check blood gases, blood sugar,
hematocrit and serum calcium
if needed/ siezures
Insert intravenous line for
dextrose and lab work
other lines like for Invasive BP (UAC) , and UVC for CVP
monitoring is preferred in sick baby
Consider use of volume
Expander
Keep the ionotropes standby if no response
Vitamin K, stomach wash
urine output monitoring
Calcium (40mg/kg) is started in babies with severe birth asphyxia
prophylactically
Fig. 1. Summary of initial management of asphyxiated neonates
4-6 at 1 minute of age) may be transferred to the mother.
However, these infants should also be monitored
frequently in the first 48-72 hours for features suggestive
of HIE. Infants with severe asphyxia (Apgar score 0-3 at 1
minute or need for prolonged bag and mask ventilation
>5 minutes) should be transferred to a special care
newborn unit for observation and treatment.
Maintain temperature : Place the baby under the radiant
warmer after drying the baby. Maintain normal
temperature of the baby. Adverse outcomes have been
associated with pyrexia in these newborns, hence it is to
be avoided. It is during these early minutes after birth that
the chances of hypothermia are highest. Hypothermia
imposes additional stress to the baby by increasing
metabolic needs in the face of hypoxia-ischemia. This may
Indian Journal of Pediatrics, Volume 75February, 2008
113
lead to acidosis, myocardial depression, hypotension,
bleeding tendency and pulmonary hemorrhage etc.
The therapeutic modality of hypothermia to prevent
disability is a new evolving therepy.10 The combination of
the three main trials suggest that mild hypothermia is
associated with significant reduction in deaths and severe
disability following asphyxia.11 Therapeutic hypothermia
for encephalopathic asphyxiated newborn infants should
be only administered in well designed randomized
controlled trials as of now.12, 13, 14 as many of the aspects of
hypothermia need to be optimized and refined, and the
magnitude of the risk vs the benefit when applied to the
population of the infants with HIE has yet to be
established.
Check vital signs: Immediate clinical assessment should
be made by recording respiration, heart rate, blood
pressure, capillary refill time, temperature and oxygen
saturation. Urine output monitoring should be done.
Start intravenous fluids (in severely affected babies): All
babies with Apgar scores <4 at 1 minute or <7 at 5minutes
of age should be started on intravenous fluids. Current
recommendations to restrict fluid input are based mainly
on data from the treatment of adults and older children,
or from animal models of cerebral hypoxia. The rationale
is that fluid restriction may limit cerebral oedema, which
may be important in the pathogenesis of brain damage
after perinatal asphyxia. However, there is concern that
excessive fluid restriction may cause dehydration and
hypotension, resulting in decreased cerebral perfusion
and further brain damage.15
Check blood sugar, hematocrit and blood gases: Check
blood sugar (to detect hypoglycemia or hyperglycemia),
hematocrit (to detect anemia and polycythemia) and
blood gases (to detect metabolic acidosis, hypoxia,
hyperoxia and respiratory failure). Hyperoxia, hypocarbia
and hyperglycemia are equally detrimental to an injured
brain and emphasis should be given to maintaining all
parameters in the normal range for the first 48-72 hours.
Maintain the blood gases and acid-base status in the
physiological ranges including partial pressure of arterial
oxygen (PaO2), 80-100 mm Hg; partial pressure of arterial
carbon dioxide (PaCO2), 35-40 mm Hg; and pH, 7.35-7.45.
Consider volume expander: If the capillary refill time is
more than 3 seconds or if there is metabolic acidosis,
volume expansion with normal saline (or Ringers lactate)
10 ml/kg over 5-10 min should be instituted. This may be
repeated, if required. One should remember that decrease
in vascular tone results in relative hypovolemia (preload)
in babies with asphyxia. Maintain the mean BP above 35
mm Hg (for term infants). Dopamine or dobutamine can
be used to maintain adequate cardiac output. Attention to
perfusion is the single most important component of therapy of
asphyxiated neonates at this stage.
177
 190
R. Agarwal et al
Miscellaneous: Vitamin K (I mg IM) should be
administered to all infants with perinatal asphyxia. A
stomach wash may be performed if there was meconium
staining.
SUBSEQUENT MANAGEMENT
Continue monitoring: Monitoring of vital parameters
referred to above must be continued. Accurate record of
urine output is a must. Blood gases should be checked as
often as required. In addition, periodic evaluation of
blood chemistry should be done: blood sugar (2, 6, 12, 24,
48 and 72 hours of age), hematocrit (once a day for the
first few days) and serum sodium, potassium and
calcium (once a day). The renal function studies (serum
creatinine, creatinine clearance, and BUN ) may be
estimated if required. Cardiac and liver enzymes values
are an adjunct to assess the degree of hypoxic-ischemic
injury to these other organs. These studies also provide
some insight into injuries to other organs, such as the
bowel.
A special effort needs to be made for monitoring the
neurological status of the baby. Assessment of sensorium,
tone, seizures, autonomic disturbance and reflexes should
be made every 4-6 hours. Hypotonia in HIE is typically
differential in term babies, especially in the early stages of
HIE. It affects upper limbs more than lower limbs and
involves proximal musculature more than the distal
musculature. Thus, scarf sign becomes readily abnormal.
Flexors of neck become weak and poor traction response
is seen. Seizures may be subtle in character and therefore,
a close observation is required to document them. Based
on the findings, HIE is classified as mild, moderate and
severe using Levenes classification (Table 2).
Special investigations: EEG does not help in the routine
management of most cases of HIE. Its use lies in
prognostication to some extent. Burst suppression
pattern, low voltage or iso-electric EEG indicates poor
outcome.
Amplitude-integrated electroencephalography (aEEG):
Several studies have shown that a single-channel aEEG
performed within a few hours of birth can help evaluate
the severity of brain injury in the infant with HIE. While
a normal aEEG may not necessarily mean that the brain is
normal, a severe or moderately severe aEEG abnormality
may indicate brain injury and poor outcome. The
abnormalities include wide fluctuations in the amplitude
with the baseline voltages dropping to near zero and the
peak amplitudes under 5 mV. Seizure spikes may be
seen.15 Although many centers are using aEEG, note that
considerable training is required for conducting and
properly interpreting the aEEG tracings.
Cranial ultrasound (US): Cranial ultrasound is not good
for detecting changes of HIE in the term babies.
178
114
Hypoechoic areas are seen only in very severe cases
(having large areas of infraction). In preterm babies,
however, cranial ultrasound is able to detect
periventricular leukomalacia and intraventricular-
periventricular hemorrhage.
Computed tomography (CT): CT scan in the acute stage of
HIE in term babies many show generalized low
attenuation of brain parenchyma.
Magnetic resonance maging: MRI provides prognostic
information, The findings of abnormalities of thalami and
ganglia in term, White and grey matter abnormalities at
term equivalent in preterms are strong predictors of
subsequent risk of poor neurodevelopmental outcome.16
It is important to understand that MRI is preferred over
CT as it has a greater interobserver agreement and no
radiation exposure.
In general, EEG, CT and US does not help a great deal
in the acute management of the baby. Their utility is
essentially for prognostication.
ECHO: In infants needing ionotropic support, an ECHO
at times may give an insight into the contractinbility and
the asphyxial injury to the heart (MR,)and guide
appropriate management strategy.
Treatment (Fig. 2)
(a) Maintain oxygenation and ventilation: Babies with
respiratory failure require oxygen and assisted
ventilation. Some babies would already be on oxygen and
bag and mask (or endotracheal tube) ventilation when
transferred from the labor room. Oxygenation in those
Maintain
oxygenation
and ventilation
Maintain
Maintain
normal
adequate
perfusion
glucose
Subsequent management of
asphyxiated neonates
Maintain normal
Treat seizures Maintain normal serum calcium
hematocrit
Fig. 2. Summary of subsequent management of asphyxiated neonates
Indian Journal of Pediatrics, Volume 75February, 2008
 191
Post-resuscitation Management of Asphyxiated Neonates
babies who have adequate spontaneous breathing can be
achieved in the oxygen hood. But if there is apnea, or
spontaneous respiration is inadequate or there is
continuing hypoxia or hypercarbia, assisted ventilation is
indicated. pH should be maintained above 7.30. The
target PaO2 is 80-100 torr in term babies and 60-80 torr in
preterm infants. Pulse oximeter saturation values are
maintained in the 90-95% range in term babies and 90-93%
in the preterm infants. The target PaCO2 value is 40-45
torr.
(b) Maintain adequate perfusion: Ensuring normal
perfusion is of critical importance in management. The
markers of normal perfusion are normal blood pressure,
capillary refill time of less than 3 seconds, normal urine
output, and absence of metabolic acidosis. The BP should
be maintained in the upper normal range. In sick babies,
arterial line is placed for guiding management of blood
pressure. This is achieved by judicious use of volume
expanders and vasopressors:
(c) Volume expansion: Use saline, Ringers lactate and
blood to maintain intravascular volume. In sick neonates,
confirm central venous pressure (CVP) by placing an
umbilical venous line.
(d) Vasopressors: Dopamine and dobutamine are the
drugs of choice. Begin with dopamine 3-5 microgram/
kg/min. Increase the dose in a stepwise fashion. At about
10 microgram/kg/min dose, if the perfusion is still poor,
dobutamine should be added in a dose of 5 microgram/
kg/min. The usual maximum dose of each drug is 20
microgram/kg/min.
(e) Maintain normal blood glucose: Both hypoglycemia
and hyperglycemia are indesirable. Glucose is the
substrate for brain and its requirements go up in HIE.
Hence, it must be made available. But hyperglycemia can
precipitate hyperosmolality and aggravate lactic acidosis.
Hence, the dictum is to maintain blood sugar above 60
mg/dl, but not exceeding 100 mg/dl.
(f) Maintain normal calcium level: Calcium should be
provided in a maintenance dose of 4 ml/kg/day (of 10%
calcium gluconate) for 1-2 days. This may be given as a
continuous infusion or as 1:1 diluted boluses, slowly
under cardiac monitoring. The aim is to maintain serum
calcium concentration in the normal range.
(g) Maintain normal hematocrit: Anemia should be
corrected and hemotocrit should be maintained >40% in
ventilated neonates. It is also equally important to treat
polycythemia. Polycythemia causes hyperviscosity with
adverse cardiopulmonary consequences. It is therefore
recommended that if the venous hematocrit in a baby is
above 65%, it should be brought down to 55% by partial
exchange transfusion using normal saline.
(h) Treat seizures: The anticonvulsant of choice for
controlling seizures is phenobarbitone. The initial dose is
Indian Journal of Pediatrics, Volume 75February, 2008
115
20 mg/kg, intravenously slowly over 20 minutes. If there
is no response, two additional doses of 10 mg/kg can be
given every 15 minutes. The maximum loading lose is
thus 40 mg/kg. The rate of infusion of phenobarbitone
should not exceed 1 mg/kg/min and preferably an
infusion pump should be used to deliver the drug. If
convulsions are still uncontrolled, phenytoin sodium
should be added in a dose of 20 mg/kg intravenously
slowly over 20 minutes. Maintenance therapy of both
phenobarbitone and phenytoin is started 12 hours later in
a dose of 5 mg/kg/day in a single dose. Generally, one or
both of these anticonvulsants are effective. Occasional,
short-lasting, mild seizures not interfering with
cardiopulmonary status may be left alone. For intractable
seizures Clonazepam, Midazolam, Paraldehyde, and
Valproate may be tried. Diazepam is generally avoided in
neonates. Always look and treat for other specific etiology
of seizures (hypoglycemia, hypocalcemia,
hypomagnesemia, polycythemia), which may co-exist.
NEWER MODES OF THERAPY
Corticosteroids have no role on the treatment of HIE.
Likewise, the current evidence does not support the use of
mannitol in the management of HIE.
Some interest has been generated in the protective role
of prophylactic phenobarbitone in newborns with
perinatal asphyxia. A dose of 40 mg/kg administered
prophylactically was associated with a better neuro-
developmental outcome at 3 years of age.17 However, the
Cochrane review database systematic review by Evans et
al (2000) that included the 5 RCTs derived no difference
in the risk of death, neurodisability.18 Another study using
40 mg/kg within 1st hour showed a significant reduction
in HIE with no difference in complications. 19
Recommendation for use of prophylactic phenobarbitone
still awaits further studies.
A large number of drugs are under investigations for
neuro-protection in HIE. These need to be used in the
early period of hypoxic ischemic injury.10 They act by
causing blockade of free radical generation (allopurinol,
oxypurinol), scavenging of oxidants (superoxide
dismutase, glutathione, N-acetyl cysteine and alpha
tocopherol), calcium channel blockade (flunarizine,
nimodipine), blockage of NMDA receptors (magnesium,
MK801, dextromethorphan) and blockage of
inflammatory mediators (phospholipase A 2 ,
indomethcin). One promising modality on the horizon is
cerebral hypothermia. 12,13,14,20 Mild reductions in
temperature of the body as a whole or of the head (brain)
has been shown to minimize the effects of hypoxic
ischemic encephalopathy. It may be noted that none of the
modalities mentioned in this section are ready for routine
use as yet.
179
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R. Agarwal et al
FOLLOWUP
All the neonates with the moderate and severe asphyxia,
especially those with stage II and III HIE staging should
be followed in the High risk clinic, they should have a
complete neurological assessment and intervention if
needed during the followup. A formal psychometric
assessment at 18 months should be performed in all these
babies
LONG TERM OUTCOME
Among the infants who survive severe HIE, the sequelae
include mental retardation, epilepsy, and cerebral palsy of
varying degrees. The latter can be in the form of
hemiplegia, paraplegia, or quadriplegia. Such infants
need careful evaluation and support. They may need to
be referred to specialized clinics capable of providing
coordinated comprehensive follow-up care.
The incidence of long-term complications depends on
the severity of HIE. Up to 80% of infants who survive
severe HIE develop serious complications, 10-20%
develop moderately serious disabilities, and up to 10% are
normal. Among the infants who survive moderately
severe HIE, 30-50% may suffer from serious long-term
complications, and 10-20% with minor neurological
morbidities. Infants with mild HIE tend to be free from
serious CNS complications
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1. Costello A, Francis V, Byrne A, Puddephatt C. State of the
worlds newborns. Kinetik Communications 2001.
2. World Health Organizaton. Perinatal mortality: a listing of
available information. FRH/MSM.96.7.Geneva:WHO, 1996.
3. Report of the National Neonatal Perinatal Database (National
Neonatology Forum, India) 2000
4. Casey BM, McIntire DD, Leveno KJ. The continuing value of
the Apgar score for the assessment of newborn infants. New
Engl J Med 2001; 344 : 467-471.
5. Moster D, Lie RT, Irgens LM, Bjerkedal T, Markestad T. The
association of Apgar score with subsequent death and
cerebral palsy: A population based study in term infants. J
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6. Perlman JM, Tack ED, Martin T, Shackelford G, Amon E.
Acute systemic organ injury in term infants fter asphyxia. Am
J Dis Child 1989; 143 : 617-620.
7. Sarnat HB, Sarnat MS. Neonatal encephalopathy following
fetal distress: A clinical and electroencephalographic study.
Arch Neurol 1976; 33: 695-706.
8. Levene MI. The asphyxiated newborn infant. In Levene MI,
Lilford RJ, ed. Fetal and neonatal neurology and neuro-surgary.
Edinburgh; Churchil Livingstone, 1995: 405-426.
9. Du-Pleiss AJ, Johnston MV. Hypoxic ischemic injury in
newborn: cellular mechanism and potential strategies for
neuroprotection. Clinics in Perinatology 1997; 29: 627-654.
10. Vannucci RC. Current and potentially new management
strategies for perinatal hypoxic ischemic encephalopathy.
Pediatrics 1990; 85 : 961-968.
11. Thoresen M, Wyatt J. Keeping a cool head, post-hypoxic
hypothermia an old idea revisited. Acta Paediatr 1997; 86:
1029-1033.
12. Gluckman PD, Wyatt JS, Azzopardi D, Ballardi R, Edwards
AD, Ferreio DM et al. Selective head cooling with mild
systemic hypothermia after neonatal encephalopathy :
Multicenter randomized trial. Lancet 2005; 365: 663-670.
13. Shankaran S, Laptook AR, Ehraenkranz RA, Tyson JE, Mc
Donald SA, Donovan TF et al. Whole body hypothermia for
neonates with hypoxic ischemic encephalopathy. NEJM 2005;
353: 1574-1584.
14. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT,
Kaufman DA et al. Moderate hypothermia in neonatal
encephalopathy: efficacy outcomes. Pediatr Neurol 2005; 32:
11-17.
15. Kecskes Z, Healy G, Jensen A. Fluid restriction for term
infants with hypoxicischaemic encephalopathy following
perinatal asphyxia. In The Cochrane Library: Issue 3, 2005.
16. Lianne J, Woodward, Peter J Anderson, Nicole C Austin,
Kelly Howard, Terrie E Inder. Neonatal MRI to predict
neurodevelopmental outcomes in preterm infants. NEJM
2006; 355 : 685-694.
17. Hall RT, Hall FK, Daily DK. High-dose phenobarbital therapy
in term newborn infants with severe perinatal asphyxia: a
randomized, prospective study with three-year follow-up. J
Pediatr 1998; 132 : 345-348.
18. Evans DJ, Levene MI. Anticonvulsants for preventing
mortality and morbidity in full term newborns with perinatal
asphyxia. Cochrane Database Syst Rev 2000; CD001240.
19. Vargas-Origel A, Espinosa- Garcia JO, Muniz-Quezada E,
Vargas-Nieto MA, Aguilar-Garcia G, Prevention of hypoxic-
ischemic encephalopathy with high dose, early phenobarbitol
therepy. Gac Med Mex 2004; 140 : 147-153.
20. John S, Wyatt, Peter D, Gluckman, Ping Y, Liu, Denis
Azzopardi, Roberta Ballard, A. David Edwards et al. Gunn for
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Indian J Pediatr (2010) 77:11291135
DOI 10.1007/s12098-010-0209-8

SYMPOSIUM ON AIIMS PROTOCOLS IN NEONATOLOGY-I

Management of Neonatal Seizures

Jeeva M. Sankar & Ramesh Agarwal & Ashok Deorari &
Vinod K. Paul

Received: 28 July 2010 / Accepted: 2 August 2010 / Published online: 30 September 2010
# Dr. K C Chaudhuri Foundation 2010

Abstract Seizures in the newborn period constitute a Definition

medical emergency. Subtle seizures are the commonest
type of seizures occurring in the neonatal period. Myoclon- A seizure is defined clinically as a paroxysmal alteration in
ic seizures carry the worst prognosis in terms of long-term neurologic function, i.e., motor, behavior and/or autonomic
neurodevelopmental outcome. Hypoxic-ischemic encepha- function. This definition includes [3]:
lopathy is the most common cause of neonatal seizures.
1. Epileptic seizures: phenomena associated with
Multiple etiologies often co-exist in neonates and hence it is
corresponding EEG seizure activity e.g. clonic seizures
essential to rule out common causes such as hypoglycae-
2. Non-epileptic seizures: clinical seizures without
mia, hypocalcemia, and meningitis before initiating specific
corresponding EEG correlate e.g., subtle and general-
therapy. A comprehensive evidence based approach for
ized tonic seizures
management of neonatal seizures has been described in this
3. EEG seizures: abnormal EEG activity with no clinical
protocol.
correlation.
Keywords Seizure . Newborn . Anti-epileptic therapy

Neonatal seizures (NS) are the most frequent and Classification

distinctive clinical manifestation of neurological dysfunc-
tion in the newborn infant. The incidence of NS is 2.8 per
1000 in infants with birth weights of more than 2500 g; it
is higher in preterm low birth weight neonatesas high as
57.5 per 1000 in very low birth weight infants [1]. Infants
with NS are at high risk of neonatal death or neurological
impairment and epilepsy disorders in later life. Though,
mortality due to NS has decreased over the yrs from 40%
to about 20%, the prevalence of long-term neurodevelop-
ment sequelae has largely remained unchanged at around
30% [2]. Improper and inadequate management of
seizures could be one of the major reasons behind this
phenomenon.
J. M. Sankar : R. Agarwal (*) : A. Deorari : V. K. Paul
Division of Neonatology, Department of Pediatrics, All India
Institute of Medical Sciences,
Ansari Nagar,
New Delhi 110029, India
e-mail: aranag@rediffmail.com
Four types of NS have been identified [1] (Table 1):
Subtle seizures: They are called subtle because the
clinical manifestations are mild and frequently missed.
They are the commonest type and constitute about 50%
of all seizures. Common examples of subtle seizures
include:
1. OcularTonic horizontal deviation of eyes or
sustained eye opening with ocular fixation or
cycled fluttering
2. Oralfaciallingual movementsChewing, tongue-
thrusting, lip-smacking, etc.
3. Limb movementsCycling, paddling, boxing-jabs,
etc.
4. Autonomic phenomenaTachycardia or bradycardia
5. Apnea may be a rare manifestation of seizures.
Apnea due to seizure activity has an accelerated or
a normal heart rate when evaluated 20 sec after

1130
Table 1 Investigations Required in a Neonate with Seizures
Essential investigations (required in all with few exceptionsa)
Blood sugar
Serum Na, calcium, magnesium
Cerebrospinal fluid (CSF) examination
Cranial ultrasound (US) and
Electroencephalography (EEG) and/or amplitude integrated EEG
a
Given in the text
onset. Bradycardia is thus not an early manifesta-
tion in convulsive apnea but may occur later due to
prolonged hypoxemia.
Clonic seizures: They are rhythmic movements of
muscle groups. They have both fast and slow compo-
nents, occur with a frequency of 13 jerks per sec, and
are commonly associated with EEG changes.
Tonic seizures: This type refers to a sustained flexion
or extension of axial or appendicular muscle groups.
These seizures may be focal or generalized and may
resemble decerebrate (tonic extension of all limbs) or
decorticate posturing (flexion of upper limbs and
extension of lower limbs). Usually there are no EEG
changes in generalized tonic seizures.
Myoclonic seizures: These manifest as single or
multiple lightning fast jerks of the upper or lower
limbs and are usually distinguished from clonic move-
ments because of more rapid speed of myoclonic jerks,
absence of slow return and predilection for flexor
muscle groups. Common changes seen on the EEG
include burst suppression pattern, focal sharp waves
and hypsarrhythmia.
Myoclonic seizures carry the worst prognosis in terms
of neuro-developmental outcome and seizure recur-
rence. Focal clonic seizures have the best prognosis.
Common Causes of Neonatal Seizures [1, 48]
The most common causes of seizures as per the recently
published studies from the country are hypoxic ischemic
encephalopathy, metabolic disturbances (hypoglycemia and
hypocalcemia), and meningitis; the incidence of intraven-
tricular hemorrhage was low in both the studies [7, 8].
Etiology could, however, vary between different centres
depending upon the patient population (term vs preterm),
level of monitoring (only clinical vs electrical and clinical
seizures), etc.
198 118
Indian J Pediatr (2010) 77:11291135
Additional investigations
Hematocrit (if plethoric and/or at risk for polycythemia)
Serum bilirubin (if icteric)
Arterial blood gas and anion gap (lethargy, vomiting, family history, etc.)
Imaging: CT and/or MRI (if no etiology found after essential investigations)
TORCH screen for congenital infections
Work-up for inborn errors of metabolism
Hypoxic-Ischemic Encephalopathy (HIE) HIE secondary to
perinatal asphyxia is the commonest cause of NS. Most
seizures due to HIE (about 5065%) start within the first
12 h of life while the rest manifest by 2448 h of age.
Additional problems like hypoglycemia, hypocalcemia, and
intracranial hemorrhage may co-exist in neonates with
perinatal asphyxia and these should always be excluded.
Subtle seizures are the most common type of seizures
following HIE.
Metabolic Causes Common metabolic causes of seizures
include hypoglycemia, hypocalcemia, and hypomagnese-
mia. Rare causes include pyridoxine deficiency and inborn
errors of metabolism (IEM).
Infections Meningitis should be excluded in all neonates
with seizures. Meningoencephalitis secondary to intrauter-
ine infections (TORCH group, syphilis) may also present as
seizures in the neonatal period.
Intracranial Hemorrhage Seizures due to subarachnoid,
intraparenchymal or subdural hemorrhage occur more often
in term neonates, while seizures secondary to intraventric-
ular hemorrhage (IVH) occur in preterm infants. Most
seizures due to intracranial hemorrhage occur between 2
and 7 days of age. Seizures occurring in a term well baby
on day 23 of life is often due to subarachnoid hemorrhage.
Developmental Defects Cerebral dysgenesis and neuronal
migration disorders are rare causes of seizures in the
neonatal period.
Miscellaneous They include polycythemia, maternal nar-
cotic withdrawal, drug toxicity (e.g. theophylline, doxap-
ram), local anesthetic injection into scalp, and phacomatosis
(e.g. tuberous sclerosis, incontinentia pigmentii). Acciden-
tal injection of local anesthetic into scalp may be suspected
in the presence of unilateral fixed and dilated pupil.
Multifocal clonic seizures on the 5th day of life may be
 199
Indian J Pediatr (2010) 77:11291135
related to low zinc levels in the CSF fluid (benign
idiopathic neonatal convulsions).
Seizures due to SAH and late onset hypocalcemia carry
a good prognosis for long term neuro-developmental
outcome while seizures related to hypoglycemia, cerebral
malformations, and meningitis have a high risk for adverse
outcome.
Approach to an Infant with Neonatal Seizures [1, 46]
History
Seizure History A complete description of the seizure
should be obtained from the parents/attendant. History of
associated eye movements, restraint of episode by passive
flexion of the affected limb, change in color of skin
(mottling or cyanosis), autonomic phenomena, and wheth-
er the infant was conscious or sleeping at the time of
seizure should be elicited. The day of life on which the
seizures occurred may provide an important clue to its
diagnosis. While seizures occurring on day 03 might be
related to perinatal asphyxia, intracranial hemorrhage, and
metabolic causes, those occurring on day 47 may be due
to sepsis, meningitis, metabolic causes, and developmental
defects.
Antenatal History History suggestive of intrauterine infec-
tion, maternal diabetes, and narcotic addiction should be
elicited in the antenatal history. A history of sudden
increase in fetal movements may be suggestive of intra-
uterine convulsions.
Perinatal History Perinatal asphyxia is the commonest
cause of neonatal seizures and a detailed history including
history of fetal distress, decreased fetal movements, instru-
mental delivery, need for resuscitation in the labor room,
Apgar scores, and abnormal cord pH (<7) and base deficit
(>10 mEq/L) should be obtained. Use of a pudendal block
for mid-cavity forceps may be associated with accidental
injection of the local anesthetic into the fetal scalp.
Feeding History Appearance of clinical features including
lethargy, poor activity, drowsiness, and vomiting after
initiation of breast-feeding may be suggestive of inborn
errors of metabolism. Late onset hypocalcemia should be
considered in the presence of top feeding with cows
milk.
Family History History of consanguinity in parents, family
history of seizures or mental retardation and early fetal/
119
1131
neonatal deaths would be suggestive of inborn errors of
metabolism. History of seizures in either parent or siblings
in the neonatal period may suggest benign familial neonatal
convulsions (BFNC).
Examination
Vital Signs Heart rate, respiration, blood pressure, capillary
refill time and temperature should be recorded in all infants.
General Examination Gestation, birth-weight, and weight
for age should be recorded as they may provide important
clues to the etiologyfor e.g.,, seizures in a term well
baby may be due to subarachnoid hemorrhage while
seizures in a large for date baby may be secondary to
hypoglycemia. The neonate should also be examined for
the presence of any obvious malformations or dysmorphic
features.
CNS Examination Presence of a bulging anterior fontanel
may be suggestive of meningitis or intracranial hemor-
rhage. A detailed neurological examination should include
assessment of consciousness (alert/drowsy/comatose), tone
(hypotonia or hypertonia), and fundus examination for
chorioretinitis.
Systemic Examination Presence of hepatosplenomegaly or
an abnormal urine odor may be suggestive of IEM. The
skin should be examined for the presence of any neuro-
cutaneous markers. Presence of hypopigmented macules or
ash-leaf spot would be suggestive of tuberous sclerosis.
Investigations
Essential Investigations Investigations that should be con-
sidered in all neonates with seizures include blood sugar,
serum electrolytes (Na, Ca, Mg), cerebrospinal fluid (CSF)
examination, cranial ultrasound (US), and electroencepha-
lography (EEG). CSF examination should be done in all
cases as seizures may be the first sign of meningitis. It should
not be omitted even if another etiology such as hypoglycemia
is present because meningitis can often coexist. CSF study
may be withheld temporarily if severe cardio-respiratory
compromise is present or even omitted in infants with severe
birth asphyxia (documented abnormal cord pH/base excess
and onset within 1224 h). An arterial blood gas (ABG) may
have to be performed if IEM is strongly suspected.
One should carry out all these investigations even if one
or more investigations are positive, as multiple etiologies
may coexist, e.g. sepsis, meningitis and hypoglycemia.
 200
1132
Additional Investigations These may be considered in
neonates who do not respond to a combination of
phenobarbitone and phenytoin or earlier in neonates with
specific features. These include neuroimaging (CT, MRI),
screen for congenital infections (TORCH) and for inborn
errors of metabolism.
Imaging Neurosonography is an excellent tool for detection
of intraventricular and parenchymal hemorrhage but is
unable to detect SAH and subdural hemorrhage. It should
be done in all infants with seizures. CT scan should be done
in all infants where an etiology is not available after the first
line of investigations. It can be diagnostic in subarachnoid
hemorrhage and developmental malformations. Magnetic
resonance imaging (MRI) is indicated only if investigations
do not reveal any etiology and seizures are resistant to usual
anti-epileptic therapy. It can be diagnostic in cerebral
dysgenesis, lissencephaly, and other neuronal migration
disorders.
Electroencephalogram (EEG) EEG has both diagnostic
and prognostic role in seizures. It should be done in all
neonates who need anticonvulsant therapy. Ictal EEG may
be useful for the diagnosis of suspected seizures and also
for diagnosis of seizures in muscle-relaxed infants. It
should be done as soon as the neonate is stable enough to
be transported for EEG, preferably within first wk. EEG
should be performed for at least 1 h [9]. Inter-ictal EEG is
useful for long-term prognosis of neonates with seizures.
A background abnormality in both term and preterm
neonates indicates a high risk for neurological sequelae.
These changes include burst-suppression pattern, low
voltage invariant pattern and electro-cerebral inactivity.
Amplitude Integrated EEG This new method provides
continuous monitoring of cerebral electrical activity at the
bedside in critically sick newborns. a EEG is helpful in
evaluating the background as well in identification of
seizure activity in neonatal seizures. As with conventional
EEG, background abnormalities like burst-suppression or
continuous low voltage pattern in aEEG also help in
prognosticating the infant with seizures particularly in the
setting of HIE. Seizure activity on aEEG is characterized by
a rapid rise in both the lower and upper margins of the
trace. Some seizures that are focal or relatively brief are,
however, missed by this technique [1].
Screen for Congenital Infections TORCH screen and
VDRL should be considered in the presence of hepatosple-
nomegaly, thrombocytopenia, intrauterine growth restric-
tion, small for gestational age, and presence of
chorioretinitis.
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Indian J Pediatr (2010) 77:11291135
Metabolic Screen This includes blood and urine ketones,
urine reducing substances, blood ammonia, anion gap,
urine and plasma aminoacidogram, serum and CSF lactate/
pyruvate ratio.
Management
Initial Medical Management
The first step in successful management of seizures is to
nurse the baby in thermoneutral environment and to ensure
airway, breathing, and circulation (TABC). Oxygen should
be started, IV access should be secured, and blood should
be collected for glucose and other investigations. A brief
relevant history should be obtained and quick clinical
examination should be performed. All this should not
require more than 25 min.
Correction of Hypoglycemia and Hypocalcemia
If glucostix shows hypoglycemia or if there is no facility to
test blood sugar immediately, 2 ml/kg of 10% dextrose
should be given as a bolus injection followed by a
continuous infusion of 68 mg/kg/min.
If hypoglycemia has been treated or excluded as a cause
of convulsions, the neonate should receive 2 ml/kg of 10%
calcium gluconate IV over 10 min under strict cardiac
monitoring. If ionized calcium levels are suggestive of
hypocalcemia, the newborn should receive calcium gluco-
nate at 8 ml/kg/d for 3 days. If seizures continue despite
correction of hypocalcemia, 0.25 ml/kg of 50% magnesium
sulfate should be given intramuscularly (IM).
Anti-Epileptic Drug Therapy (AED) [1]
Anti-epileptic drugs (AED) should be considered in the
presence of even a single clinical seizure since clinical
observations tend to grossly underestimate electrical seiz-
ures (diagnosed by EEG) and facilities for continuous EEG
monitoring are not universally available. If aEEG is being
used, eliminating all electrical seizure activity should be the
goal of AED therapy [1]. AED should be given if seizures
persist even after correction of hypoglycemia/ hypocalce-
mia (Fig. 1).
Phenobarbitone (Pb)
It is the drug of choice in neonatal seizures. The dose is
20 mg/kg/IV slowly over 20 min (not faster than 1 mg/kg/
min). If seizures persist after completion of this loading
dose, additional doses of phenobarbitone 10 mg/kg may
 201 121
Indian J Pediatr (2010) 77:11291135 1133

Fig. 1 Acute management of

neonatal seizures Neonate with seizures

. Identify and characterize the seizure

. Secure airway and optimize breathing, circulation, and temperature
. Start oxygen, if seizures are continuous
. Secure IV access and take samples for baseline investigations including sugar, calcium,
. If hypoglycemic (blood sugar <40 mg/dl): administer 2 ml/kg of 10% dextrose as bolus
magnesium, sodium, potassium, arterial blood gas, hematocrit, sepsis screen

. followed by a continuous infusion of 6-8 mg/kg/min

If blood sugar is in normal range, sample for ionized calcium should be withdrawn; if
abnormal, 2 ml/kg of calcium gluconate (10%) should be given IV under cardiac monitoring

Seizures persist

Administer phenobarbitone 20mg/kg IV stat

over 20 min
Seizures continue

Repeat phenobarbitonein 10 mg/kg/dose

aliquots until 40 mg/kg dose is reached

Seizures continue

Administer phenytoin 20 mg/kg IV slowly

over 20 min under cardiac monitoring

Seizures continue

Repeat phenytoin 10 mg/kg/dose

Seizures continue

Consider Lorazepam / midazolam bolus and

midazolam infusion if needed;
Consider ventilation
Seizures continue

Consider other antiepileptic drugs,

pyridoxine, and exchange transfusion;
Consider ventilation

Seizures controlled

Wean AED slowly to maintenance phenobarbitone

be used every 2030 min until a total dose of 40 mg/kg
has been given. The maintenance dose of Pb is 35 mg/kg/
day in 12 divided doses, started 12 h after the loading
dose.
Phenytoin
Phenytoin is indicated if the maximal dose of phenobar-
bitone (40 mg/kg) fails to resolve seizures or earlier, if
adverse effects like respiratory depression, hypotension or
bradycardia ensue with phenobarbitone. The dose is
20 mg/kg IV at a rate of not more than 1 mg/kg/min
under cardiac monitoring. Phenytoin should be diluted in
normal saline as it is incompatible with dextrose solution.
A repeat dose of 10 mg/kg may be tried in refractory
seizures. The maintenance dose is 35 mg/kg/d (maximum
of 8 mg/kg/d) in 24 divided doses. Oral suspension has
very erratic absorption from gut in neonates, so it should be
avoided. Thus ,only IV route is preferred in neonates and it
should preferably be discontinued before discharge.
Fosphenytoin, the prodrug of phenytoin, does not cause
the same degree of hypotension or cardiac abnormalities,
has high water solubility (therefore can be given IM), and is
less likely to lead to soft-tissue injury when compared with
 202 122
1134 Indian J Pediatr (2010) 77:11291135

phenytoin. It is dosed in phenytoin equivalents (1.5 mg/kg
of fosphenytoin is equivalent to 1 mg/kg of phenytoin).
Benzodiazepines
This group of drugs may be required in up to 1520% of
neonatal seizures. The commonly used benzodiazepines are
lorazepam and midazolam. Diazepam is generally avoided
in neonates due to its short duration of action, narrow
therapeutic index, and because of the presence of sodium
benzoate as a preservative. Lorazepam is preferred over
diazepam as it has a longer duration of action and results in
less adverse effects (sedation and cardiovascular effects).
Midazolam is faster acting than lorazepam and may be
administered as an infusion. It causes less respiratory
depression and sedation than lorazepam. However, when
used as continuous infusion, the infant has to be
monitored for respiratory depression, apnea, and brady-
cardia (equipment for resuscitation and assisted ventila-
tion should be available at the bedside of all neonates
given multiple doses of AED).
The doses of These drugs are given below:
Lorazepam: 0.05 mg/kg IV bolus over 25 min; may
be repeated
Midazolam: 0.15 mg/kg IV bolus followed by infusion
of 0.1 to 0.4 mg/kg/hr.
According to Volpe, the expected response of neonatal
clinical seizures to anticonvulsants is 40% to the initial 20-
mg/kg loading dose of phenobarbitone, 70% to a total of

Fig. 2 Weaning of anticonvul-

sant therapy Newborn on anticonvulsant therapy

Wean all antiepileptic drugs except

phenobarbitone once seizure controlled

Perform neurological examination

prior to discharge

Normal Abnormal

Stop phenobarbitone Continue

prior to discharge phenobarbitone
for 1 month

Repeat neurological
examination at 1month

Normal
examination Abnormal examination

Evaluate EEG

Taper drugs Normal EEG Abnormal EEG

over 2 wks Taper drugs Continue drug;
over 2 wks reassess at 3 months*

*Intractable seizures may need lifelong therapy; consider switching over to other drugs (phenytoin or
carbamazepine)
 203
Indian J Pediatr (2010) 77:11291135
40 mg/kg of Pb, 85% to a 20-mg/kg of phenytoin, and 95%
to 100% to 0.05 to 0.1 mg/kg lorazepam [1].
Antiepileptic Drugs for Seizures Refractory to Above
Treatment
In exceptional circumstances when the seizures are refrac-
tory to the first-line AEDs, the following second-line drugs
might be tried.
Lidocaine It is usually administered as a bolus dose of
4 mg/kg IV followed by an infusion rate of 2 mg/kg/hr. It is
tapered over several days. Adverse effects include arrhyth-
mias, hypotension, and seizures. It should not be adminis-
tered with phenytoin.
Paraldehyde It may be used in seizures refractory to the first
line drugs. A dose of 0.10.2 ml/kg/dose may be given IM or
0.3 ml/kg/dose mixed with coconut oil in 3:1 may be used by
per rectal route. Additional doses may be used after 30 min
and q 46 hrly. Adverse effects include pulmonary hemor-
rhage, pulmonary edema, hypotension, and liver injury.
Sodium Valproate It can be used for maintenance therapy in
neonates. Per rectal route may be used in acute condition.
IV preparation is now available. Dose is 2025 mg/kg/d
followed by 510 mg/kg every 12 h. It should, however, be
used with caution in newborns given the uncertain risk of
hepatotoxicity following its use.
Vigabatrin It has been used in neonates for refractory
seizures, primarily for infantile spasms. The dose is
50 mg/kg/day.
Topiramate It shows promise in neonatal seizures because
of its potential neuroprotective effect against injury caused
by seizures. Topiramate has been used for refractory
infantile spasms in infants. The higher volume of distribu-
tion compared with other drugs requires higher initial and
maintenance doses of approximately 3 mg/kg.
Other Therapies
Pyridoxine A therapeutic trial of pyridoxine is reserved as a
last resort in refractory seizures. Intravenous route is the
preferred method; however, suitable IV preparations are not
universally available. Hence, intramuscular (IM) route may
have to be used (1 ml of neurobion has 50 mg pyridoxine and
1 ml each may be administered both the sides in either the
gluteal region or anterolateral aspect of thigh). It should ideally
be done in the NICU as hypotension and apnea can occur.
123
1135
Exchange Transfusion This is indicated in life-threatening
metabolic disorders, accidental injection of local anaesthe-
tic, trans-placental transfer of maternal drugs (e.g. chlor-
propamide), and bilirubin encephalopathy.
Maintenance Anti-Epileptic Therapy
Principles of AED used in older children and adults are
applicable to neonates also. Monotherapy is the most
appropriate strategy to control seizures. Attempts should
be made to stop all anti-epileptic drugs and wean the baby
to only phenobarbitone at 35 mg/kg/day. If seizures are
uncontrolled or if clinical toxicity appears, a second AED
may be added. The choice may vary from phenytoin,
carbamezepine, and valproic acid.
When to Discontinue AED
This is highly individualized and no specific guidelines are
available. We usually try to discontinue all medication at
discharge if clinical examination is normal, irrespective of
etiology and EEG. If neurological examination is persistently
abnormal at discharge, AED is continued and the baby is
reassessed at one month. If the baby is normal on examination
and seizure free at 1 month, phenobarbitone is discontinued
over 2 wks. If neurological assessment is not normal, an EEG
is obtained. If EEG is not overtly paroxysmal, phenobarbitone
is tapered and stopped. If EEG is overtly abnormal, the infant
is reassessed in the same manner at 3 months and then 3
monthly till 1 yr of age (Fig. 2). The goal is to discontinue
phenobarbitone as early as possible.
References
1. Volpe JJ. Neonatal Seizures .Neurology of the newborn, 5th ed.
Philadelphia: Saunders Elsevier; 2008. p. 20344.
2. Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile
and neurodevelopmental outcome of seizures in term newborn
infants. Pediatrics. 2006;117:127080.
3. Mizrahi EM, Kellaway P. Characterization and classification. In
Diagnosis and management of neonatal seizures. Lippincott-
Raven, 1998; 1535.
4. Painter MJ, Scher MS, Stein MD, et al. Phenobarbitone compared
with phenytoin for treatment of neonatal seizures. N Engl J Med.
1999;341:485899.
5. Rennie JM. Neonatal seizures. Eur J Pediatr. 1997;156:837.
6. Laroia N. Controversies in diagnosis and management of neonatal
seizures. Indian Pediatr. 2000;37:36772.
7. Iype M, Prasad M, Nair PM, Geetha S, Kailas L. The newborn with
seizuresa follow-up study. Indian Pediatr. 2008;45:74952.
8. Kumar A, Gupta A, Talukdar B. Clinico-etiological and EEG
profile of neonatal seizures. Indian J Pediatr. 2007;74:337.
9. Wical BS. Neonatal seizures and electrographic analysis: evaluation
and outcomes. Pediatr Neurol. 1994;10:2715.
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Symposium on AIIMS Protocols in Neonatology III

Sepsis in the Newborn

M. Jeeva Sankar, Ramesh Agarwal, Ashok K Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar,
New Delhi, India

ABSTRACT
Infections are the single largest cause of neonatal deaths globally. According to National Neonatal Perinatal Database (2002-
03), the incidence of neonatal sepsis in India was 30 per 1000 live-births; klebsiella pneumoniae and staphylococcus aureus
were the two most common organisms isolated. Based on the onset, neonatal sepsis is classified into two major categories:
early onset sepsis, which usually presents with respiratory distress and pneumonia within 72 hours of age and late onset
sepsis, that usually presents with septicemia and pneumonia after 72 hours of age. Clinical features of sepsis are non-specific
in neonates and a high index of suspicion is required for the timely diagnosis of sepsis. Although blood culture is the gold
standard for the diagnosis of sepsis, culture reports would be available only after 48-72 hours. A practical septic screen for
the diagnosis of sepsis has been described and some suggestions for antibiotic use have been included in the protocol.
[Indian J Pediatr 2008; 75 (3) : 261-266] E-mail: vinodpaul@neonatalhealth.com

Key words : Infections; Newborn; Sepsis screen; Antibiotics

Sepsis is the commonest cause of neonatal mortality; it is
responsible for about 30-50% of the total neonatal deaths
in developing countries1,2. It is estimated that up to 20% of
neonates develop sepsis and approximately 1% die of
sepsis related causes2. Sepsis related mortality is largely
preventable with rational antimicrobial therapy and
aggressive supportive care.
DEFINITION
Neonatal sepsis is a clinical syndrome characterized by
signs and symptoms of infection with or without
accompanying bacteremia in the first month of life. It
encompasses various systemic infections of the newborn
such as septicemia, meningitis, pneumonia, arthritis,
osteomyelitis, and urinary tract infections. Superficial
infections like conjunctivitis and oral thrush are not
usually included under neonatal sepsis.
EPIDEMIOLOGY: INDIAN DATA
The incidence of neonatal sepsis according to the data
Correspondence and Reprint requests : Dr. Vinod K. Paul,
Professor, Department of Pediatrics, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi 110029, India
[Received February 7, 2008; Accepted February 7, 2008]
from National Neonatal Perinatal Database (NNPD, 2002-
03) is 30 per 1000 live births. The database comprising 18
tertiary care neonatal units across India found sepsis to be
one of the commonest causes of neonatal mortality
contributing to 19% of all neonatal deaths3. Septicemia
was the commonest clinical category with an incidence of
23 per 1000 live births while the incidence of meningitis
was reported to be 3 per 1000 live births. Among
intramural births, Klebsiella pneumoniae was the most
frequently isolated pathogen (32.5%), followed by
Staphylococcus aureus (13.6%). Among extramural
neonates (referred from community/other hospitals),
Klebsiella pneumoniae was again the commonest
organism (27%), followed by Staphylococcus aureus (15%)
and Pseudomonas (13%).3
CLASSIFICATION OF NEONATAL SEPSIS
Neonatal sepsis can be classified into two major categories
depending up on the onset of symptoms4.
Early onset sepsis (EOS): It presents within the first 72
hours of life. In severe cases, the neonate may be
symptomatic at birth. Infants with EOS usually present
with respiratory distress and pneumonia. The source of
infection is generally the maternal genital tract. Some
maternal / perinatal conditions have been associated with
an increased risk of EOS. Knowledge about these potential
risk factors would help in early diagnosis of sepsis. Based
on the studies from India, the following risk factors seem

Indian Journal of Pediatrics, Volume 75March, 2008 261

 209
M.J. Sankar et al
to be associated with an increased risk of early onset
sepsis.4, 5
1. Low birth weight (<2500 grams) or prematurity
2. Febrile illness in the mother with evidence of bacterial
infection within 2 weeks prior to delivery.
3. Foul smelling and/or meconium stained liquor.
4. Rupture of membranes >24 hours.
5. Single unclean or > 3 sterile vaginal examination(s)
during labor
6. Prolonged labor (sum of 1st and 2nd stage of labor > 24
hrs)
7. Perinatal asphyxia (Apgar score <4 at 1 minute)
Presence of foul smelling liquor or three of the above
mentioned risk factors warrant initiation of antibiotic
treatment. Infants with two risk factors should be
investigated and then treated accordingly.
Late onset sepsis (LOS): It usually presents after 72
hours of age. The source of infection in LOS is either
nosocomial (hospital-acquired) or community-acquired
and neonates usually present with septicemia, pneumonia
or meningitis.6, 7 Various factors that predispose to an
increased risk of nosocomial sepsis include low birth
weight, prematurity, admission in intensive care unit,
mechanical ventilation, invasive procedures,
administration of parenteral fluids, and use of stock
solutions. Factors that might increase the risk of
community-acquired LOS include poor hygiene, poor
cord care, bottle-feeding, and prelacteal feeds. In contrast,
breastfeeding helps in prevention of infections.
CLINICAL FEATURES
Non-specific features: The earliest signs of sepsis are often
subtle and nonspecific; indeed, a high index of suspicion
is needed for early diagnosis. Neonates with sepsis may
present with one or more of the following symptoms and
signs (a) Hypothermia or fever (former is more common
in preterm low birth weight infants) (b) Lethargy, poor
cry, refusal to suck (c) Poor perfusion, prolonged capillary
refill time (d) Hypotonia, absent neonatal reflexes (e)
Brady/tachycardia (f) Respiratory distress, apnea and
gasping respiration (g) Hypo/hyperglycemia (h)
Metabolic acidosis.
Specific features related to various systems
Central nervous system (CNS): Bulging anterior
fontanelle, vacant stare, high-pitched cry, excess
irritability, stupor/coma, seizures, neck retraction.
Presence of these features should raise a clinical
suspicion of meningitis.
Cardiac: Hypotension, poor perfusion, shock.
Gastrointestinal: Feed intolerance, vomiting, diarrhea,
262
125
abdominal distension, paralytic ileus, necrotizing
enterocolitis (NEC).
Hepatic: Hepatomegaly, direct hyperbilirubinemia
(especially with urinary tract infections).
Renal: Acute renal failure.
Hematological: Bleeding, petechiae, purpura.
Skin changes: Multiple pustules, abscess, sclerema,
mottling, umbilical redness and discharge.
INVESTIGATIONS
Since treatment should be initiated in a neonate suspected
to have sepsis without any delay, only minimal and rapid
investigations should be undertaken.8
Blood culture: It is the gold standard for diagnosis of
septicemia and should be performed in all cases of
suspected sepsis prior to starting antibiotics. A positive
blood culture with sensitivity of the isolated organism is
the best guide to antimicrobial therapy. Therefore, it is
very important to follow the proper procedure for
collecting a blood culture. The resident doctor/staff
should wear sterile gloves prior to the procedure and
prepare a patch of skin approx. 5-cm in diameter over the
proposed veni-puncture site. This area should be cleansed
thoroughly with alcohol, followed by povidone-iodine,
and followed again by alcohol. Povidone-iodine should
be applied in concentric circles moving outward from the
centre. The skin should be allowed to dry for at least 1
minute before the sample is collected. One-mL sample of
blood should be adequate for a blood culture bottle
containing 5-10 mL of culture media. Since samples
collected from indwelling lines and catheters are likely to
be contaminated, cultures should be collected only from
a fresh veni-puncture site. All blood cultures should be
observed for at least 72 hours before they are reported as
sterile. It is now possible to detect bacterial growth within
12-24 hours by using improved bacteriological techniques
such as BACTEC and BACT/ALERT blood culture
systems. These advanced techniques can detect bacteria at
a concentration of 1-2 colony-forming unit (cfu) per mL.
Septic screen.9,10 All neonates suspected to have sepsis
should have a septic screen to corroborate the diagnosis.
However, the decision to start antibiotics need not be
conditional to the sepsis screen result, if there is a strong
clinical suspicion of sepsis. The various components of the
septic screen include total leukocyte count, absolute
neutrophil count, immature to total neutrophil ratio,
micro-erythrocyte sedimentation rate and C reactive
protein (Table 1). The absolute neutrophil count varies
considerably in the immediate neonatal period and
normal reference ranges are available from Manroes
charts.11 The lower limit for normal total neutrophil
Indian Journal of Pediatrics, Volume 75March, 2008
 210
Sepsis in the Newborn
TABLE 1. A Practical Sepsis Screen
Components Abnormal value
Total leukocyte count <5000/mm 3
Absolute neutrophil count Low counts as per Manroe
chart11 for term and
Mouzinhos chart12 for
VLBW infants
Immature/total neutrophil >0.2
Micro-ESR >15 mm in 1st hour
C reactive protein (CRP) >1 mg/dL
(ESR, erythrocyte sedimentation rate)
counts in the newborn begins at 1800/cmm, rises to 7200/
cmm at 12 hours of age and then declines and persists at
1800/cmm after 72 hours of age. For very low birth
weight infants, the reference ranges are available from
Mouzinhos charts. 12 The ratio of immature to total
neutrophils (I/T ratio) is 0.16 at birth and declines to a
peak value of 0.12 after 72 hours of age. Presence of two
abnormal parameters in a screen is associated with a
sensitivity of 93-100%, specificity of 83%, positive and
negative predictive values of 27% and 100% respectively
in detecting sepsis. Hence, if two (or more) parameters are
abnormal, it should be considered as a positive screen and
the neonate should be started on antibiotics. If the screen
is negative but clinical suspicion persists, it should be
repeated within 12 hours. If the screen is still negative,
sepsis can be excluded with reasonable certainty. For
early onset sepsis, documentation of polymorphs in the
neonatal gastric aspirate at birth could serve as a marker
of chorioamnionitis and it may be taken as one parameter
of sepsis screen.
Lumbar puncture (LP): The incidence of meningitis in
neonatal sepsis has varied from 0.3-3% in various
studies. 3,6 The clinical features of septicemia and
meningitis often overlap; it is quite possible to have
meningitis along with septicemia without any specific
symptomatology. This justifies the extra precaution of
performing LP in neonates suspected to have sepsis. In
EOS, lumbar puncture is indicated in the presence of a
positive blood culture or if the clinical picture is consistent
with septicemia. It is not indicated if antibiotics have been
started solely due to the presence of risk factors. In
situations of late onset sepsis, LP should be done in all
infants prior to starting antibiotics. Lumbar puncture
could be postponed in a critically sick neonate. It should
be performed once the clinical condition stabilizes. The
TABLE 2. Normal Cerebrospinal Fluid Examination in Neonates13
CSF Components Normal range
Cells/mm3 8 (0-30 cells)
PMN (%) 60%
CSF protein (mg/dL) 90 (20-170)
CSF glucose (mg/dL) 52 (34-119)
CSF/ blood glucose (%) 51 (44-248)
(PMN, polymorphonuclear cells; CSF, cerebrospinal fluid)
Indian Journal of Pediatrics, Volume 75March, 2008
126
cerebrospinal fluid characteristics are unique in the
newborn period and normal values are given in Table 2.13
Radiology: Chest X-ray should be considered in the
presence of respiratory distress or apnea. An abdominal
X-ray is indicated in the presence of abdominal signs
suggestive of necrotizing enterocolitis (NEC).
Neurosonogram and computed tomography (CT scan)
should be performed in all patients diagnosed to have
meningitis.
Urine culture: In early onset sepsis, urine cultures have
a low yield and are not indicated. Urine cultures obtained
by suprapubic puncture or bladder catheterization have
been recommended in all cases of LOS. Since the
procedures are painful and the yield is often poor, we do
not recommend a routine urine culture in neonates with
sepsis. However, neonates at risk for fungal sepsis and
very low birth weight infants with poor weight gain
should have a urine examination done to exclude urinary
tract infection (UTI). UTI may be diagnosed in the
presence of one of the following: (a) >10 WBC/mm3 in a
10 mL centrifuged sample (b) >104 organisms /mL in
urine obtained by catheterization and (c) any organism in
urine obtained by suprapubic aspiration
MANAGEMENT
Supportive: Adequate and proper supportive care is crucial
in a sick neonate with sepsis. He/she should be nursed in
a thermo-neutral environment taking care to avoid hypo/
hyperthermia. Oxygen saturation should be maintained
in the normal range; mechanical ventilation may have to
be initiated if necessary. If the infant is hemodynamically
unstable, intravenous fluids should be administered and
the infant is to be monitored for hypo/hyperglycemia.
Volume expansion with crystalloids/colloids and
judicious use of inotropes are essential to maintain normal
tissue perfusion and blood pressure. Packed red cells and
fresh frozen plasma might have to be used in the event of
anemia or bleeding diathesis.
Antimicrobial therapy: There cannot be a single
recommendation for the antibiotic regimen of neonatal
sepsis for all settings. The choice of antibiotics depends on
the prevailing flora in the given unit and their
antimicrobial sensitivity. This protocol does not aim to
provide a universal recommendation for all settings but
lays down broad guidelines for the providers to make a
rational choice of antibiotic combination. Decision to start
antibiotics is based upon clinical features and/ or a
positive septic screen. However duration of antibiotic
therapy is dependent upon the presence of a positive
blood culture and meningitis (Table 3).
Indications for Starting Antibiotics: The indications for
starting antibiotics in neonates at risk of EOS include any
one of the following:
263
 211
M.J. Sankar et al
TABLE 3. Duration of Antibiotic Therapy in Neonatal Sepsis
Diagnosis Duration
Meningitis (with or without positive blood/ 21 days
CSF culture)
Blood culture positive but no meningitis 14 days
Culture negative, sepsis screen positive and 7-10 days
clinical course consistent with sepsis
Culture and sepsis screen negative, but 5-7 days
clinical course compatible with sepsis
(a) presence of 3 risk factors for early onset sepsis (see
above)
(b) presence of foul smelling liquor
(c) presence of 2 antenatal risk factor(s) and a positive
septic screen and
(d) strong clinical suspicion of sepsis.
The indications for starting antibiotics in LOS include:
Fig. 1. Protocol for sepsis
264
127
(a) positive septic screen and/or
(b) strong clinical suspicion of sepsis. (Fig. 1)
Prophylactic Antibiotics: We do not use prophylactic
antibiotics in the following circumstances: infants on IV
fluids/TPN, meconium aspiration syndrome, and after
exchange transfusion(s). An exchange transfusion
conducted under strict asepsis (single use catheter, sterile
gloves, removal of catheter after the procedure) does not
increase the risk of sepsis and hence does not merit
antibiotics. However, a messy exchange transfusion could
be treated with prophylactic antibiotics. In our unit,
ventilated neonates are treated with prophylactic
antibiotics for 5-7 days.
Choice of antibiotics: Empirical antibiotic therapy should
be unit-specific and determined by the prevalent
spectrum of etiological agents and their antibiotic
sensitivity pattern. Antibiotics once started should be
Indian Journal of Pediatrics, Volume 75March, 2008
 212 128

Sepsis in the Newborn

modified according to the sensitivity reports. Guidelines
for empirical antibiotic therapy have been provided in
Table 4.
The empirical choice of antibiotics is dependent upon
the probable source of infection. For infections that are
likely to be community-acquired where resistant strains
are unlikely, a combination of ampicillin or penicillin with
gentamicin may be a good choice as a first line therapy.
For infections that are acquired during hospital stay,
resistant pathogens are likely and a combination of
ampicillin or cloxacillin with gentamicin or amikacin may
be instituted. In nurseries where this combination is
ineffective due to the presence of multiple resistant strains
of klebsiella and other gram-negative bacilli, a
combination of a third generation cephalosporin
(cefotaxime or ceftazidime) with amikacin may be
appropriate. 3 rd generation cephalosporins have very

TABLE 4. Empirical Choice of Antibiotics for Treatment of Neonatal Sepsis

Clinical situation Septicemia & Meningitis

Pneumonia

FIRST LINE Penicillin or Ampicillin and Gentamicin Add Cefotaxime

Community-acquired (Resistant strains
are unlikely)
SECOND LINE Ampicillin or Cloxacillin and Add Cefotaxime
Hospital-acquired (Some strains Gentamicin or Amikacin
are likely to be resistant)
THIRD LINE Cefotaxime or Piperacillin-Tazobactam or
Hospital-acquired sepsis (Most Ciprofloxacin Same (Avoid Ciprofloxacin)
strains are likely to be resistant) andAmikacin;

Consider Vancomycin if MRSA is suspected.

TABLE 5. Drugs, Route of Administration and Doses of Common Antibiotics Used.

Drug Route Birth Weight 2000g Birth Weight >2000g

0-7 d >7 days 0-7 days >7 days

Amikacin I/V, I/M 7.5 q12h 7.5 q8h 10 q12h 10 q8h

Ampicillin
Meningitis I/V 100 q12h 100 q8h 100 q 8h 100 q6h
Others I/V, I/M 25 q12h 25 q8h 25 q8h 25 q6h

Cefotoxime
Meningitis I/V 50 q6h 50 q6h 50 q6h 50 q6h
Others I/M, I/V 50 q12h 50 q8h 50 q12h 50 q8h

Piperacillin+ I/V 50-100 q12h 50-100 q8h 50-100 q12h 50-100 q12h

Tazobactam
Ceftriaxone I/M, I/V 50 q24h 50 q24h 50 q24h 75 q24h
Ciprofloxacin I/V, PO 10-20 q24h 10-20 q24h 10-20 q12h 10-20 q12h

Cloxacillin
Meningitis I/V 50 q12h 50 q8h 50 q8h 50 q6h
Others I/V 25 q12h 25 q8h 25 q8h 25 q6h

Gentamicin
Conventional I/V, I/M 2.5 q12h 2.5 q8h 2.5 q12h 2.5 q8h
Single dose I/M 4 q24 h 4 q24 hr 5 q24h 5 q24h

Netilmicin I/V, I/M 2.5 q12h 2.5 q8h 2.5 q12h 2.5 q8h

Penicillin G (units/kg/dose)
Meningitis I/V 75,000 q12h 75,000 q8h 75,000 q8h 75,000 q6h
-100,000 -1,00,000 -1,00,000 -1,00,000
Others I/V, I/M 25,000 q12h 25,000 q8h 25,000 q8h 25,000 q6h
Vancomycin I/V 15 q12h 15 q8h 15 q12h 15 q8h

All doses are in mg/kg/dose;

(I/V, intravenous; I/M, intramuscular; PO, per-oral; h, hourly)
Protocol for sepsis

Indian Journal of Pediatrics, Volume 75March, 2008 265

 213
M.J. Sankar et al
good CSF penetration and are traditionally thought to
have excellent antimicrobial activity against gram
negative organisms. Hence they were considered to be a
good choice for the treatment of nosocomial infections
and meningitis. However, recent reports suggest that at
least 60-70% of the gram-ve organisms are resistant to
them.14-16 More over, routine use of these antibiotics might
increase the risk of infections with ESBL (extended
spectrum beta-lactamase) positive organisms. Therefore it
is preferable to use antibiotics such as piperacillin-
tazobactam or methicillin/vancomycin in units with high
incidence of resistant strains. A combination of
piperacillin-tazobactam with amikacin should be
considered if pseudomonas sepsis is suspected. Penicillin
resistant staphylococcus aureus should be treated with
cloxacillin, nafcillin or methicillin. Addition of an
aminoglycoside is useful in therapy against
staphylococcus. Methicillin resistant staphylococcus
aureus (MRSA) should be treated with a combination of
ciprofloxacin or vancomycin with amikacin. Ciprofloxacin
has excellent activity against gram-negative organisms
also; however, it does not have good CSF penetration. It
may be used for the treatment of resistant gram-negative
bacteremia after excluding meningitis. For sepsis due to
enterococcus, a combination of ampicillin and gentamicin
is a good choice for initial therapy. Vancomycin should be
used for the treatment of enterococcus resistant to the first
line of therapy.
The dosage, route, and frequency of commonly used
antimicrobial agents are given in table 5.
Reserve antibiotics: Newer antibiotics like aztreonam,
meropenem and imipenem are also now available in the
market. Aztreonam has excellent activity against gram-
negative organisms while meropenem is effective against
most bacterial pathogens except methicillin resistant
staphylococcus aureus (MRSA) and enterococcus.
Imipenem is generally avoided in neonates because of the
reported increase in the incidence of seizures following its
use. Empirical use of these antibiotics should be avoided;
they should be reserved for situations where sensitivity of
the isolated organism warrants their use.
Adjunctive therapy
Exchange transfusion (ET): Sadana et al17 have evaluated the
role of double volume exchange transfusion in septic
neonates with sclerema and demonstrated a 50%
reduction in sepsis related mortality in the treated group.
We perform double-volume exchange transfusion with
cross-matched fresh whole blood as adjunctive therapy in
septic neonates with sclerema.
Intravenous Immunoglobulin (IVIG): Non-specific pooled
IVIG has not been found to be useful.18
266
129
Granulocyte-Macrophage colony stimulating factor (GM-
CSF): This mode of treatment is still experimental.19
REFERENCES
1. Bang AT, Bang RA, Bactule SB, Reddy HM, Deshmukh MD.
Effect of home-based neonatal care and management of sepsis
on neonatal mortality: field trial in rural India. Lancet 1999;
354 : 1955-19861.
2. Stoll BJ. The global impact of neonatal infection. Clin Perinatol
1997; 24 : 1-21.
3. Report of the National Neonatal Perinatal Database (National
Neonatology Forum) 2002-2003.
4. Singh M, Narang A, Bhakoo ON. Predictive perinatal score in
the diagnosis of neonatal sepsis. J Trop Pediatr 1994; 40 : 365-
368.
5. Takkar VP, Bhakoo ON, Narang A. Scoring system for the
prediction of early neonatal infections. Indian Pediatr 1974; 11
: 597-600
6. Baltimore RS. Neonatal nosocomial infections. Semin Perinatol
1998; 22 : 25-32.
7. Wolach B. Neonatal sepsis: pathogenesis and supportive
therapy. Semin Perinatol 1997; 21 : 28-38.
8. Gerdes JS, Polin R. Early diagnosis and treatment of neonatal
sepsis. Indian J Pediatr 1998; 65 : 63-78.
9. Polinski C. The value of white blood cell count and
differential in the prediction of neonatal sepsis. Neonatal Netw
1996; 15 : 13-23
10. Da Silva O, Ohlsson A, Kenyon C. Accuracy of leukocyte
indices and C-reactive protein for diagnosis of neonatal sepsis:
a critical review. Pediatr Infect Dis J 1995; 14 : 362-366.
11. Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. The
neonatal blood count in health and disease. I.Refernce values
for neutrophilic cells. J Pediatr 1979; 95 : 89-98.
12. Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Revised
reference ranges for circulating neutrophils in very-low-birth-
weight neonates. Pediatrics 1994; 94 : 76-82.
13. Sarff LD, Platt LH, McCracken GH Jr. Cerebrospinal fluid
evaluation in neonates: Comparison of high-risk neonates
with and without meningitis. J Pediatr 1976; 88 : 473-477.
14. Upadhyay A, Aggarwal R, Kapil A, Singh S, Paul VK, Deorari
AK. Profile of neonatal sepsis in a tertiary care neonatal unit
from India: A retrospective study. J Neonatology 2006; 20 : 50-
57.
15. Deorari Ashok K. For the Investigators of the National
Neonatal Perinatal Database (NNPD). Changing pattern of
bacteriologic profile in Neonatal Sepsis among intramural
babies. J Neonatology 2006; 20 : 8-15.
16. Zaidi AK, Huskins WC, Thaver D, Bhutta ZA, Abbas Z,
Goldmann DA. Hospital-acquired neonatal infections in
developing countries. Lancet 2005; 365 : 1175-1188.
17. Sadana S, Mathur NB, Thakur A. Exchange transfusion in
septic neonates with sclerema: effect on immunoglobulin and
complement levels. Indian Pediatr 1997; 34 : 20-25.
18. Jenson HB, Pollock HB. The role of intravenous
immunoglobulin for the prevention and treatment of neonatal
sepsis. Semin Perinatol 1998; 22 : 50-63.
19. Goldman S, Ellis R, Dhar V, Cairo MS. Rationale and potential
use of cytokines in the prevention and treatment of neonatal
sepsis. Clin Perinatol 1998; 25 : 699-710.
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Indian J Pediatr (April 2012) 79(4):501509
DOI 10.1007/s12098-010-0279-7

SYMPOSIUM ON AIIMS PROTOCOLS IN NEONATOLOGY

Retinopathy of Prematurity
Deepak Chawla & Ramesh Agarwal & Ashok Deorari &
Vinod K. Paul & Parijat Chandra & Rajvardhan V. Azad

Received: 17 August 2010 / Accepted: 13 October 2010 / Published online: 27 October 2010
# Dr. K C Chaudhuri Foundation 2010

Abstract Retinopathy of prematurity (ROP) occurs due to
abnormal proliferation of retinal vessels. The most impor-
tant risk factors which predispose to development of ROP
include oxygen therapy, anemia needing blood transfusion,
sepsis and apnea. Very low birth weight neonates, those
born at 32 week of gestation and other preterm neonates
with risk factors must be screened for ROP. As a general
rule first screening should be done at 1 month of postnatal
age. If screening detects ROP not needing treatment follow
up should be planned according to location and stage of
ROP. Better visual outcomes are observed with earlier
treatment at lower threshold. Peripheral retinal ablation
with diode laser under adequate analgesia and sedation is
the preferred method for treatment of severe ROP. Guide-
lines regarding the procedure of dilatation, ophthalmic
examination and treatment (if required) have been provided
D. Chawla
Department of Pediatrics, Government Medical College,
Chandigarh, India
P. Chandra : R. V. Azad
Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic
Sciences, All India Institute of Medical Sciences,
Ansari Nagar,
New Delhi 110029, India
R. Agarwal : A. Deorari : V. K. Paul
Division of Neonatology & WHO Collaborating Centre for
Training & Research in Newborn Care, Department of Pediatrics,
All India Institute of Medical Sciences,
Ansari Nagar,
New Delhi 110029, India
A. Deorari (*)
Department of Pediatrics, All India Institute of Medical Sciences,
Ansari Nagar,
New Delhi 110029, India
e-mail: ashokdeorari_56@hotmail.com
in the protocol. Close co-operation between the ophthal-
mologist and neonatologist is essential for successful
management of ROP.
Keywords Prematurity . Risk factors . Retinopathy of
prematurity
Introduction
Retinopathy of prematurity (ROP) is a vasoproliferative
disorder of the retina among premature babies. ROP begins
to develop between 32 and 34 week after conception,
regardless of gestational age at delivery and has two distinct
phases [1]. During the acute first phase, the normal
vasculogenesis of the retina is disturbed by the relative
hyperoxia of the extrauterine environment. This causes
vaso-obliteration and non-vascularization of some areas of
the anterior retina [2]. The subsequent hypoxia causes a
second chronic phase, characterized by the proliferation of
vascular and glial cells, arteriovenous shunt formation,
occasionally leading to involution or permanent cicatricial
changes and visual impairment [3, 4]. In its more severe
forms, it results in severe visual impairment or blindness,
both of which carry a high financial cost for the community
but also a high individual cost by affecting the normal
motor, language, conceptual, and social development of the
child.
Epidemiology
Studies from India reporting incidence of ROP provide
interesting insights. Although screening criteria differ
across different units and time-periods, overall incidence
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502 Indian J Pediatr (April 2012) 79(4):501509

of ROP varies from 20% to 52% (Table 1) with more recent
studies reporting lower rates of ROP ranging from 20% to
30% [514]. An important lesson is learnt from units
reporting ROP in different time periods [9]. Initial low
incidence of ROP rises with better screening protocols,
availability of assisted ventilation services and survival of
sicker, smaller neonates. In this phase, even sick but
relatively mature (late preterm) neonates have been reported
to develop ROP. This period is followed by gradual decline
in incidence of ROP especially of more severe variety.
Prematurity is the single most important risk factor
responsible for retinopathy of prematurity. Incidence of
ROP increases with decreasing gestation and birth weight.
However, not all preterm neonates develop ROP. Important
risk factors which increase the probability of developing
ROP are oxygen therapy, anemia needing blood transfu-
sion, sepsis and apnea [5, 7, 9, 11]. Nevertheless, a very
preterm extremely low birth weight neonate can develop
ROP even without exposure to oxygen or presence of these
risk factors.
In general, more than 50% of preterm infants weighing
less than 1,250 g at birth show evidence of ROP and about
10% of the infants develop severe ROP. However, retinal
detachment occurs and leads to visual loss in only a few
percent of infants with severe ROP, and in most cases, ROP
regresses spontaneously. The most conspicuous question is
why ROP in some premature infants progresses despite
rigorous and timely intervention, while in other cases with
similar clinical characteristics it regresses. Evidence has
suggested that African-American infants are less prone to
severe outcome ROP than white infants and Alaskan
natives develop threshold ROP earlier than non-natives.
This racial variation suggests that genetic, socioeconomic,
or dietary factors may be involved [15]. Poor early weight
gain in postnatal period has been observed to be a risk
factor for development of severe ROP [16, 17].
Diagnosis
A screening program is needed for early diagnosis and
secondary prevention of visual loss due to ROP in at-risk
neonates. For documentation of the deterioration or
regression of ROP, classification of degrees of severity for
therapeutic interventions, and consistent reporting in clinical
trials the International Classification of ROP (ICROP) is used

Table 1 Incidence and risk factors of retinopathy of prematurity

First author Year Screening criteria n Incidence Risk factors

Chaudhari S 2009 [5]
Charan R 1995 [6]
Gupta VP 2004 [7]
Maheshwasri R 1996 [8, 9]
Dutta S 2004 [10]
Rekha S 1996 [11]
Gopal L 1995 [12]
Varughese S 2001 [13]
Sharma P 2009 [14]
Gestation 32 week or birth weight 552 ROP: 22.3% (123/552) Apnea, septicemia and
<1,500 g or additional risk factors Threshold ROP: oxygen therapy
7.4% (41/552)
Birth weight 1,700 g and admitted 165 ROP: 47% (78/165) Not studied
to the neonatal unit
Gestation <35 week or birth 60 ROP: 21.7% Apnea, sepsis,
weight <1,500 g oxygen therapy
Gestation <35 week or birth weight 66 ROP: 20% (13/66) Not studied
<1,500 g or premature neonate Threshold ROP:
needing oxygen for more than 24 h 6/66 (9.1%)
Gestation 32 week or birth weight 108 Not reported Administration of packed
1,700 g or premature babies of any cells and double-volume
gestation who have received prolonged exchange transfusion
oxygen therapy (30 days)
Gestation <35 week or birth 100 ROP: 46% (46/100) Anemia, duration of
weight <1,500 g Threshold ROP: oxygen therapy
9/100 (9%)
Premature neonates with birth 50 ROP: 38% (19/50) No formal analysis. All
weight <2,000 g Threshold ROP: with threshold ROP had
16% (8/50) received oxygen and 6 of 8
had received blood transfusion.
Gestation <34 week or birth 79 ROP: 52% (41/79) Not studied
weight <1,500 g Threshold ROP:
6.3% (5/79)
Preterm infants with birth weight 1,500 g 704 ROP: 11.9% (84/704) Respiratory distress syndrome
or gestation 32 week. Infants with birth 33 (4.7%) infants had
weight 1,5011,800 g or gestation 3334 severe ROP requiring
week screened if additional risk laser therapy
factors present
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Indian J Pediatr (April 2012) 79(4):501509 503

(Table 2) [18]. ICROP describes vascularization of the retina
and characterizes ROP by its position (zone, Fig. 1), severity
(stage), and extent (clock hours).
Some definitions used in relation to ROP are as follows:
Aggressive Posterior ROP (AP-ROP) A rapidly progressing,
severe form of ROP. If untreated, it usually progresses to stage
5 ROP. The characteristic features of this type of ROP are its
posterior location, prominence of plus disease, and the ill-
defined nature of the retinopathy. This may not have classical
ridge or extraretinal fibrovascular proliferation. This rapidly
progressing retinopathy has been referred previously as type
II ROP and Rush disease.It is observed most commonly in
Zone I, but may also occur in posterior Zone II.
Threshold Disease Presence of stage 3 with plus disease in
Zone I or II, extending in 5 or more contiguous or
8 cumulative clock hours (30 degree sectors).
appears at 36 week of post-menstrual age and threshold
disease at 37 week. Vascularization is complete by 40 week
of gestation. Thus the crucial period for detection of ROP is
from 32 week to 40 week of post-menstrual period. The
critical phase is from 3435 week to 3738 week age
during which the progression of the disease takes place and
treatment may have to be instituted. It may also be noted
that ROP usually does not develop before 2 week of
postnatal age.
Which Babies Should be Screened?
Selecting neonates for screening depends on incidence of
ROP at different gestation ages. Gestation and birth weight
cut-off for screening shifts lower as smaller and sicker
neonates start surviving. Based on current incidence and
risk factors reported in Indian literature following group of
neonates should be screened.

Pre-threshold Disease Presence of less than threshold
disease in Zone 1, or stage 2 plus disease in Zone 2, or
stage 3 (without plus) disease in Zone 2, or stage 3 plus
disease with extent less than that for threshold disease.
Protocol for Screening
The aim of the screening programme is to detect ROP early,
follow it up closely during its evolution and treat if it
reaches a potentially serious severity.
What is the Screening Window
Progression of ROP follows a distinct time-table according
to the post-menstrual age of the baby. Hardly any ROP is
detected before 32 week of gestation. The median age for
detection of stage 1 ROP is 34 week. Pre-threshold ROP
& Babies with Birth Weight <1,500 g
& Babies Born at 32 week of Gestation
& Selected preterm infants with a birth weight between
1,500 and 2,000 g or gestational age of more than 32 week
with sickness like need of cardiorespiratory support,
prolonged oxygen therapy, apnea of prematurity, anemia
needing blood transfusion and neonatal sepsis or believed
by their attending pediatrician or neonatologist to be at
high risk. This third criterion is important as it brings in
many more larger babies into the screening guidelines
without raising the screening parameters [19].
When and How Often to Screen
First screening examination should be carried out at
31 weeks of gestation or 4 week of age, whichever is later
(Table 3) [20]. A good rule to remember is first screening at

Table 2 Classification of retinopathy of prematurity

1. Location Zone I Circle with optic nerve at centre and a radius of twice the distance from optic nerve to macula
Zone II From edge of Zone I to the nasal ora serrata nasally and equator temporally
Zone III Lateral most crescent shaped area from Zone II to ora-serrata temporally
2. Severity Stage 1 Presence of thin white demarcation line separating the vascular from avascular retina
Stage 2 The line becomes prominent because of lifting of retina to form a ridge having height and width
Stage 3 Presence of extra retinal fibro-vascular proliferation with abnormal vessels and fibrous tissue arising
from the ridge and extending into vitreous
Stage 4 Partial retinal detachment; not involving macula (4A) or involving macula (4B)
Stage 5 Complete retinal detachment
3. Plus disease Presence of dilatation and tortuosity of posterior retinal vessels. Associated with vitreous haze,
pupillary rigidity
4. Extent Extent of involvement of the retina as expressed as clock hours (30 degree sectors)
5.Pre-plus disease Vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease
but that demonstrate more arterial tortuosity and more venous dilatation than normal
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504 Indian J Pediatr (April 2012) 79(4):501509

Fig. 1 International classifica-

tion of retinopathy of
prematurity (ICROP) zones

1 month of postnatal age in babies born at >26 week of Stage 1 or 2 ROP: Zone III
gestation age. Regressing ROP: Zone III
Follow-up examinations should be recommended by the
Findings that suggest further examinations are not
examining ophthalmologist on the basis of retinal findings.
needed include:
& 1-week or less follow-up
& Zone III retinal vascularization attained without previ-
Stage 1 or 2 ROP: Zone I ous Zone I or II ROP
Stage 3 ROP: Zone II & Full retinal vascularization
& 1- to 2-week follow-up & Postmenstrual age of 45 week and no prethreshold
disease (defined as stage 3 ROP in Zone II, any ROP in
Immature vascularization: Zone Ino ROP Zone I) or worse ROP is present
Stage 2 ROP: Zone II & Regression of ROP
Regressing ROP: Zone I
& 2-week follow-up Where to Examine the Baby?
Stage 1 ROP: Zone II
Regressing ROP: Zone II Neonates are best examined in the neonatal unit itself under
supervision of attending pediatrician. It is not wise to
& 2- to 3-week follow-up
transport small babies to ophthalmic outpatient or ward for
Immature vascularization: Zone IIno ROP examination.

Table 3 Timing of first screening

eye examination based on gesta- Gestation age at birth (weeks) Age at initial examination
tional age at birth [20]
Postmenstrual age (wks) Chronological age (wks)

22 31 9
23 31 8
24 31 7
25 31 6
26 31 5
27 31 4
28 32 4
29 33 4
30 34 4
31 35 4
32 36 4
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Indian J Pediatr (April 2012) 79(4):501509 505

How to Dilate the Pupils?
Pupils are dilated with Phenylephrine 2.5% and Tropica-
mide 0.5%. One drop of Tropicamide is instilled every 10
15 min for 4 times starting 1 h before the scheduled time
for examination. This is followed by phenylephrine, one
drop just before examination. Phenylephrine is available in
10% concentration; it should be diluted 4 times before use
in neonates. Repeated instillation of phenylephrine is
avoided for the fear of hypertension.
What Does the Examination Entail?
Screening of ROP involves indirect ophthalmoscopy using
20 D or 28/30 D lens by an experienced ophthalmologist.
After instilling a topical anesthetic drop like Proparacaine, a
wire speculum is inserted to keep the eye-lids apart. First
the anterior segment of the eye is examined to look for
tunica vasculosa lentis, pupillary dilation, and lens/media
clarity; followed by the posterior pole to look for plus
disease; followed by sequential examination of all clock
hours of the peripheral retina. A scleral depressor is often
used to indent the eye externally to examine areas of
interest, rotate and stabilize the eye.
How to Record Findings During Screening?
Ophthalmological notes should be made after each ROP
examination, detailing zone, stage and extent in terms of
clock hours of any ROP and the presence of any pre-plus or
plus disease (Fig. 2). These notes should include a
recommendation for the timing of the next examination (if
any) and be kept with the babys medical record.
What Precautions are Taken During Examination?
ROP screening examinations can have short-term effects on
blood pressure, heart rate and respiratory function in the

Fig. 2 Retinopathy of prematu-

rity screening examination
record sheet Neonatal Ophthalmology Examination Record

Gestation: Birth Weight:

Name:

CR. No:

DoB: __/__/____ Gender: M/F weeks grams

Risks:

Stage 1: Stage 2: Stage 3: Stage 4/5: Laser: AP-ROP:

Date: R L

Postmenstrual Age:

Follow-up:

Examiner: Zone: Stage: Preplus: Y / N Zone: Stage: Preplus: Y / N

Plus: Y / N Plus: Y / N
Comments:
 223
506
premature baby [21]. The examinations should be kept as
short as possible and precautions taken to ensure that
emergency situations can be dealt with promptly and
effectively.
Eye examination during screening lasts several minutes
and may cause considerable pain to the neonate. A
systematic review and meta-analysis comprising four
studies has reported that oral sucrose reduces pain during
eye examination [21]. Of the two studies reporting the role
of topical proparacaine drops, one has observed significant
pain reduction.
Discomfort to the baby should be minimized by
administering oral sucrose just before examination, pre-
treatment of the eyes with a topical proparacaine and
swaddling the baby. Baby should not have been fed just
before examination to avoid vomiting and aspiration. Hand
washing should be done and asepsis maintained.
Use of Wide-Field Digital Camera (RetCam) for Screening
A wide-field digital camera (RetCam) capable of retinal
imaging in preterm infants has been evaluated as an
alternative to indirect ophthalmoscopy for screening.
Retinal images taken by camera can be stored, transmitted
to expert, reviewed, analyzed and sequentially compared
over time and are useful for telemedicine purposes. Studies
comparing RetCam with the indirect ophthalmoscope have
reported variable sensitivity and good specificity [22].
However, due to high cost and due to limitations in
diagnostic sensitivity, specificity, and accuracy when image
quality is poor, it is not recommended to replace bedside
ophthalmoscopic examination. Digital fundus images can
be used as a useful adjunct to conventional bedside ROP
screening by indirect ophthalmoscopy.
Treatment
What is the Indication?
Early Treatment of Retinopathy of Prematurity (ETROP)
trial recruited neonates at 26 centres in the US and
compared early treatment of high-risk prethreshold with
conventional threshold treatment [23]. 401 babies meeting
the criteria for high-risk of an unfavourable outcome with
prethreshold in at least one eye, were randomized to receive
either early or conventional treatment. The level of risk was
determined by a risk analysis programme which used,
among other factors, degree of ROP (stage, zone and
presence of plus), rate of ROP progression, birthweight,
gestational age and ethnicity to classify eyes as at either
high-risk (i.e. 15% chance) or low-risk (<15% chance) treated under adequate sedation and analgesia in an
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Indian J Pediatr (April 2012) 79(4):501509
of an unfavourable outcome without treatment. The results
showed an overall significant benefit for the early treatment
of eyes with high-risk prethreshold disease. Based on
results of ETROP, two new terminologies have been
suggested:
Type 1 ROP: & Zone I, any stage ROP with plus
disease
& Zone I, stage 3 ROP with or
without plus disease
& Zone II, stage 2 or 3 ROP with
plus disease
Type 2 ROP: & Zone I, stage 1 or 2 ROP without
plus disease
& Zone II, stage 3 ROP without plus
disease
Peripheral retinal ablation should be carried out for all
cases with type 1 ROP and continued serial examinations
are advised for type 2 ROP.
What are Treatment Modalities Available and What
are Their Advantages and Disadvantages?
Peripheral retinal ablation of avascular retina anterior to the
ridge can be done by either cryotherapy or diode laser.
Diode laser ablation has replaced cryotherapy due to lower
rate of postoperative ocular and systemic complications and
less damage to the adjacent tissues compared with
cryotherapy. Other advantages are that the laser spots are
visible during treatment minimizing the risk of missing
areas requiring treatment, and that laser equipment is
portable allowing use outside of the operating theatre. The
procedure can be carried out under general anesthesia or
under sedation depending on the feasibility and expertise.
Treatment for ROP should include the entire avascular
retina anterior to the ridge with burn spacing of between 0.5
to 1 burn-widths apart.
Pre-anesthetic Medication
Oral feeds should be discontinued 3 h prior to the procedure
(Table 4). Baby should be started on intravenous fluids, and
put on cardio-respiratory monitor. Dilatation of pupil is
done by using 0.5% Tropicamide and 2.5% phenylephrine
as described in the section on protocol for screening.
Anesthesia/Sedation
Topical anaesthesia alone provides insufficient analgesia for
ROP treatment and should not be used. Babies may be
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Indian J Pediatr (April 2012) 79(4):501509
Table 4 Preparation for laser ablative therapy
Take consent
Ensure good pupillary dilatation
Nil by mouth 3 h prior to procedure
Start on intravenous fluids
Put on vital sign monitor/pulse oximeter
Warmer for maintaining temperature
Arrange equipment and check functioning thereof
Intubation equipment
Endotracheal tubes No. 2.5, 3, 3.5
Resuscitation bag and face masks
Oxygen delivery system
Syringes
Infusion pumps
Ventilator
Arrange drugs, fill syringes in advance with drugs in appropriate
dilution and label them: morphine, midazolam, normal saline 10%
dextrose, adrenaline
operation theatre if this can be arranged in a timely way. If
shifting to operation theatre is not possible or is causing
delay in treatment, babies may be treated more rapidly in
the neonatal unit under adequate sedation and analgesia.
Procedure
Both the eyes can be treated at the same sitting time unless
contraindicated by instability of the baby. If baby is not
tolerating the procedure, consider abandoning the proce-
dure for the time being. Vital signs and oxygen saturation
should be monitored very closely.
Monitoring After Laser Therapy
After laser therapy, first examination should take place 5
7 days after the treatment and should be continued at least
weekly for signs of decreasing activity and regression. Re-
treatment should be performed usually 1014 days after initial
treatment when there has been a failure of the ROP to regress.
Post-operative Care
& The baby should be closely monitored. If condition
permits, oral feeds can be started shortly after the
procedure.
& Premature babies, especially those with chronic lung
disease may have increase or re-appearance of apneic
episodes or an increase in oxygen requirement. There-
fore, they should be carefully monitored for 4872 h
after the procedure.
136
507
& Antibiotic drops (such as chloramphenicol) should be
instilled 68 hrly for 23 days.
Prevention
Judicious Oxygen Therapy
Oxygen is a drug and it should be administered in a
quantity that is absolutely necessary. Each neonatal care
unit should have a written policy outlining appropriate use
of oxygen therapy. If a preterm neonate born at <32 weeks
gestation needs resuscitation at birth, inhaled oxygen
concentration (FiO2) should be titrated to prevent hyperoxia
and achieve gradual increase in oxygen saturation (70% at
3 min and 80% at 5 min after birth) [24]. During acute care
of a sick preterm neonate, ROP is more likely to develop if
partial pressure of oxygen in arterial blood is more than
80 mm Hg [25]. Oxygen level in blood should be
continuously monitored using pulse oximeter. It has been
observed that if oxygen saturation in a baby on oxygen
therapy is kept between 85% and 93%, in about 90%
samples partial pressure of oxygen is in desirable range
(4080 mm Hg) [26]. Various observational studies have
reported that incidence and severity of ROP is lowered if
oxygen saturation targets are kept in desirable range and if
units implement written policies regarding oxygen admin-
istration and monitoring [27, 28]. During recovery phase of
respiratory illness in preterm neonates, targeting higher
oxygen saturations has been associated with increased
incidence/severity of bronchopulmonary dysplasia without
any benefit in stopping progression of ROP or improving
growth and development [29, 30].
Judicious Use of Blood Transfusions
Transfusion of packed RBCs is another risk factor of ROP.
Adult RBCs are rich in 2,3 DPG and adult Hb binds less
firmly to oxygen, thus releasing excess oxygen to the
retinal tissue. Packed cell transfusions should be given
when hematocrit falls below following ranges: ventilated
babies 40%, babies with cardio-pulmonary disease but not
on ventilators 35%, sick neonates but not having cardio-
pulmonary manifestations 30%, symptomatic anemia 25%
and asymptomatic anemia 20%.
Vitamin E Supplementation
Very low birth weight neonates should receive 1525 IU of
vitamin E daily as supplement. However, higher doses
given by intravenous route have been associated with
increased risk of neonatal sepsis [31].
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508
Prenatal Steroids
Use of prenatal steroids is a well-known approach to
prevent respiratory distress and intraventricular hemor-
rhage, two important risk factors of ROP. Although there
are some concerns that prenatal steroids may induce ROP,
this is not borne out by other studies. The authors believe
prenatal steroids prevent acute illnesses in premature babies
and should be administered to all mothers with preterm
labor between 2434 weeks of gestation. The preferred
preparation of steroids for prenatal used is betamethasone in
two doses of 12 mg each given intramuscularly, 24 h apart.
Bevacizumab
Intravitreal injection of bevacizumab, a neutralizing anti-
VEGF molecule has been demonstrated to diminish the
neovascular response significantly in animal models [32].
However, due to uncertainties with respect to the dosing,
frequency, timing, and adjunct therapies to be used and
potential to cause serious systemic adverse effects, use of
bevacizumab is not recommended outside the scope of
clinical trial.
Quality Improvement
Roles and Responsibilities
& All units caring for babies at risk of ROP should have a
written protocol in relation to the screening for, and
treatment of, ROP. This should include responsibilities
for follow-up of babies transferred or discharged from
the unit before screening is complete.
& If babies are transferred either before ROP screening is
initiated or when it has been started but not completed,
it is the responsibility of the consultant neonatologist to
ensure that the neonatal team in the receiving unit is
aware of the need to start or continue ROP screening.
& Whenever possible ROP screening should be completed
prior to discharge. There should be a record of all
babies who require review and the arrangements for
their follow-up.
& For babies discharged home before screening is com-
plete, the first followup out-patient appointment must
be made before hospital discharge and the importance
of attendance explained to the parents.
Auditing
Following outcomes should be regularly audited in units
with ROP screening and treatment programme.
137
Indian J Pediatr (April 2012) 79(4):501509
& Completeness of screening programme: Percentage of
babies <32 week GA or <1,501 g birthweight who
receive at least one ROP eye examination.
& Timing of first screen: Percentage of babies <27 week
GA receiving a first ROP screening examination by
4 week of postnatal age.
& ROP Treatment: Percentage of babies with any zone 1
ROP who receive treatment.
& Timing of treatment: Percentage of babies needing ROP
treatment for their ROP who are treated within 48 h of
the decision to treat being made.
References
1. Flynn JT. The premature retina: a model for the in vivo study of
molecular genetics? Eye. 1992;6:1615.
2. Kushner BJ, Essner D, Cohen IJ, Flynn JT. Retrolental fibroplasia
II. Pathologic correlation. Arch Ophthalmol. 1977;95:2938.
3. Chan-Ling T, Tout S, Hollander H, Stone J. Vascular changes and
their mechanisms in the feline model of retinopathy of prematu-
rity. Invest Ophthalmol Vis Sci. 1992;33:212847.
4. Chan-Ling T, Gock B, Stone J. The effect of oxygen on
vasoformative cell division. Evidence that physiological hypoxia
is the stimulus for normal retinal vasculogenesis. Invest Oph-
thalmol Vis Sci. 1995;36:120114.
5. Chaudhari S, Patwardhan V, Vaidya U, Kadam S, Kamat A.
Retinopathy of prematurity in a tertiary care centerincidence,
risk factors and outcome. Indian Pediatr. 2009;46:21924.
6. Charan R, Dogra MR, Gupta A, Narang A. The incidence of
retinopathy of prematurity in a neonatal care unit. Indian J
Ophthalmol. 1995;43:1236.
7. Gupta VP, Dhaliwal U, Sharma R, Gupta P, Rohatgi J.
Retinopathy of prematurityrisk factors. Indian J Pediatr.
2004;71:88792.
8. Maheshwari R, Kumar H, Paul VK, Singh M, Deorari AK, Tiwari
HK. Incidence and risk factors of retinopathy of prematurity in a
tertiary care newborn unit in New Delhi. Natl Med J India.
1996;9:2114.
9. Aggarwal R, Deorari AK, Azad RV, et al. Changing profile of
retinopathy of prematurity. J Trop Pediatr. 2002;48:23942.
10. Dutta S, Narang S, Narang A, Dogra M, Gupta A. Risk factors of
threshold retinopathy of prematurity. Indian Pediatr. 2004;41:665
71.
11. Rekha S, Battu RR. Retinopathy of prematurity: incidence and
risk factors. Indian Pediatr. 1996;33:9991003.
12. Gopal L, Sharma T, Ramachandran S, Shanmugasundaram R,
Asha V. Retinopathy of prematurity: a study. Indian J Ophthalmol.
1995;43:5961.
13. Varughese S, Jain S, Gupta N, Singh S, Tyagi V, Puliyel JM.
Magnitude of the problem of retinopathy of prematurity. experi-
ence in a large maternity unit with a medium size level-3 nursery.
Indian J Ophthalmol. 2001;49:1878.
14. Sharma P. DM dissertation: Risk factors for severe retinopathy of
prematurity in preterm low birth weight neonates Department of
Pediatrics. New Delhi: All India Institute of Medical Sciences
2009 (Submitted for publication to Indian Journal of Pediatrics).
15. Saunders RA, Donahue ML, Christmann LM, et al. Racial
variation in retinopathy of prematurity. The cryotherapy for
retinopathy of prematurity cooperative group. Arch Ophthalmol.
1997;115:6048.
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16. Hellstrom A, Hard AL, Engstrom E, et al. Early weight gain
predicts retinopathy in preterm infants: new, simple, efficient
approach to screening. Pediatrics. 2009;123:e63845.
17. Hellstrom A, Ley D, Hansen-Pupp I, et al. New insights into the
development of retinopathy of prematurityimportance of early
weight gain. Acta Paediatr 2010;99:5028.
18. The International Classification of Retinopathy of Prematurity
revisited. Arch Ophthalmol. 2005;123:99199.
19. Azad R, Chandra P, Patwardhan SD, Gupta A. Importance of
the third criterion for retinopathy of prematurity screening in
developing countries. J Pediatr Ophthalmol Strabismus.
2009;46:3324.
20. Screening examination of premature infants for retinopathy of
prematurity. Pediatrics. 2006;117:572576.
21. Sun X, Lemyre B, Barrowman N, OConnor M. Pain management
during eye examinations for retinopathy of prematurity in preterm
infants: a systematic review. Acta Paediatr. 2010;99:32934.
22. Kemper AR, Wallace DK, Quinn GE. Systematic review of digital
imaging screening strategies for retinopathy of prematurity.
Pediatrics. 2008;122:82530.
23. Early Treatment For Retinopathy Of Prematurity Cooperative Group.
Revised indications for the treatment of retinopathy of prematurity:
results of the early treatment for retinopathy of prematurity
randomized trial. Arch Ophthalmol. 2003;121:168494.
24. Finer N, Leone T. Oxygen saturation monitoring for the preterm
infant: the evidence basis for current practice. Pediatr Res.
2009;65:37580.
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25. Flynn JT, Bancalari E, Snyder ES, et al. A cohort study of
transcutaneous oxygen tension and the incidence and severity
of retinopathy of prematurity. N Engl J Med. 1992;326:1050
4.
26. Castillo A, Sola A, Baquero H, et al. Pulse oxygen saturation
levels and arterial oxygen tension values in newborns receiving
oxygen therapy in the neonatal intensive care unit: is 85% to 93%
an acceptable range? Pediatrics. 2008;121:8829.
27. Tin W, Milligan DW, Pennefather P, Hey E. Pulse oximetry,
severe retinopathy, and outcome at one year in babies of less than
28 weeks gestation. Arch Dis Child Fetal Neonatal Ed. 2001;84:
F10610.
28. Chow LC, Wright KW, Sola A. Can changes in clinical practice
decrease the incidence of severe retinopathy of prematurity in very
low birth weight infants? Pediatrics. 2003;111:33945.
29. Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. Oxygen-
saturation targets and outcomes in extremely preterm infants. N
Engl J Med. 2003;349:95967.
30. Supplemental Therapeutic Oxygen for Prethreshold Retinopathy
Of Prematurity (STOP-ROP), a randomized, controlled trial. I:
primary outcomes. Pediatrics. 2000;105:295310.
31. Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for
prevention of morbidity and mortality in preterm infants.
Cochrane Database Syst Rev. 2003:CD003665.
32. Micieli JA, Surkont M, Smith AF. A systematic analysis of the off-
label use of bevacizumab for severe retinopathy of prematurity. Am J
Ophthalmol. 2009;148:53643. e532.
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 231 139

Symposium on AIIMS Protocols in Neonatology IV

Parenteral Nutrition
Deepak Chawla, Anu Thukral, Ramesh Agarwal, Ashok K. Deorari and Vinod K. Paul

Division of Neonatology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New
Delhi, India

ABSTRACT
Nutritional insufficiency, leading to early growth deficits has long-lasting effects, including short stature and poor
neurodevelopmental outcomes. Early enteral feeding is commonly limited by immaturity of gastrointestinal motor function in
preterm neonates. To ensure that a stressed premature infant receives an adequate but not excessive amount of glucose,
the amount of carbohydrate delivered in the form of dextrose is commonly initiated at the endogenous hepatic glucose
production and utilization rate of 4 to 6 mg/kg/min; and 8 to 10 mg/kg/min in ELBW infants. The early provision of protein is
critical to attain positive nitrogen balance and accretion as premature babies lose ~1% of their protein stores daily. Aminoacid
can be used at concentrations of 3-3.5g/kg/day and lipid at 3.5-4g/kg/day as long as the fat intake remains less than 60% of
nonprotein calories. Sodium, potassium, chloride, calcium, magnesium and phosphorus need to be provided in PN solution
as per their daily needs. Hospital-acquired infection (HAI) is a major complication of PN. All efforts should be made to avoid
it. [Indian J Pediatr 2008; 75 (4) : 377-383] E-mail: ashokdeorari_56@hotmail.com

Key words : Parentral nutrition neonates; Lipid; Glucose; Aminoacids; Non protein calories

The goal of nutrition management in neonates, especially
very low birth weight (VLBW) infants is the achievement
of postnatal growth at a rate that approximates the
intrauterine growth of a normal fetus at the same
postconceptional age. Although, this is best achieved
with optimal enteral nutrition, early enteral feeding is
commonly limited by immaturity of gastrointestinal
motor function, manifested principally as delayed
stomach emptying, gastro-esophageal reflux, abdominal
distension, and infrequent stooling. Nutritional
insufficiency, leading to early growth deficits has long-
lasting effects, including short stature and poor
neurodevelopmental outcomes (Table 1) 1. Likewise,
establishing an alternative source of nutrition becomes a
life-sustaining intervention in surgical neonates with
congenital or acquired disease causing gastrointestinal
failure. Parenteral nutrition (PN), first introduced in the
late 1960s, has been used extensively in neonatal intensive
care units (NICU) of developed countries. With
improving survival of extremely premature neonates and
increasing number of NICUs in India, need of parenteral
nutrition is being widely recognized among health care
providers. This recognition of need is accompanied by the
Correspondence and Reprint requests : Dr. Ashok K. Deorari,
Professor, Department of Pediatrics, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi 110029, India.
[Received March 13, 2008; Accepted March 13, 2008]
fact that with availability of optimum nutrient sources,
early administration of PN is now both safe and
efficacious.
Indications
PN should be considered in neonates who are not on
significant enteral feeds for more than 3-5 days or are
anticipated to be receiving less than 50% of total energy
requirement by day 7 of life (Table 2).
Energy
Determination of appropriate energy and nutritional
requirements of a newborn infant is the first step in
formulating PN. Preterm infants have very low energy
reserves due to low amounts of fat as well as low
glycogen reserves. Cessation of placental nutrient
supplies and low reserves results in metabolic shock and
protein catabolism if appropriate amounts of energy and
proteins are not provided soon after birth.2 A daily energy
intake of 120-130 kcal/kg is needed to meet the metabolic
demands of a healthy premature neonate and to allow for
growth rate comparable to intrauterine growth rate (Table
3)3. Energy requirement of term neonate is 100-120 kcal/
kg/day. Energy intake of sick neonates (e.g., acute
respiratory illness, chronic lung disease, necrotizing
enterocoliltis) is not exactly known but is likely to be near
upper limits of the energy requirement of preterm infant.3
10% dextrose solution provides 0.34 kcal/ml. 10% lipid

Indian Journal of Pediatrics, Volume 75April, 2008 377


solution provides 0.9 kcal/ml and 20% lipid solution
provides 1.1 kcal/ml. If sufficient amount of non-protein
energy is not provided, amino acids are catabolised for
energy production. Adequate balance between nitrogen
and non-protein energy sources (Protein/Energy ratio: 3-
4 gm/100 kcal) is needed to promote protein accretion.2
Balance between carbohydrates and fat is needed to
prevent excessive fat deposition and excessive production
of CO2. The ideal distribution of calories should be 50-55%
carbohydrate, 10-15% proteins and 30-35% fats.
Amino acids
Amino acids (AA) are building blocks of the body. The
amount needed, calculated using factorial approach is
3.0-3.5 gm/kg/day (0.3 gm/kg/d to mimic intrauterine
changes in body composition + 2.2 to 2.5 gm/kg/d for
normal growth + 1 gm/kg/d obligatory urinary and
dermal protein loss). An optimal AA solution should
contain essential (valine, leucine, isoleucine, methionine,
phenylalanine, threonine, lysine and histidine) and
conditionally essential (cysteine, tyrosine, glutamine,
arginine, proline, glycine and taurine) AAs, should not
have excess of glycine and methionine and should not
contain sorbitol. AA infusion can be started between 0
and 36 h of birth. The amount started on day 1 of PN has
varied from 0.5 to 3.0 gm/kg/d in different studies. To
avoid negative protein balance, one should start with at
least 1 to 1.5 gm/kg/d and then increase by 1 gm/kg/d
to maximum of 3.5 gm/kg/d. With this regimen, there
have been no reports of side effects like metabolic
acidosis, hyperaminoacidemia, azotemia or
hyperammonaemia.1 Studies in preterm babies who
TABLE 1. Consequences of Suboptimal Nutrient Intake 1
Short term
Increased vulnerability to infections
Free-radical mediated damage
Greater need of ventilator support
TABLE 2. Indications of Parenteral Nutrition
Indications of parenteral nutrition
Birth weight less than 1000 gm
Birth weight 1000-1500 gm and anticipated to be not on significant feeds for 3 or more days
Birth weight more than 1500 gm and anticipated to be not on significant feeds for 5 or more days
Surgical conditions in neonates: Necrotizing enterocolitis, Gastroschisis, Omphalocele, Tracheo-esophageal fistula, Intestinal atresia,
Mal-rotation, Short bowel syndrome, and Meconium ileus
TABLE 3. Daily Energy Intake Recommended for Preterm Infants3
Committee
American Academy of Pediatrics
Canadian Pediatric Society
European Society of Gastroenterology and Nutrition
Life Sciences Research Office
378
232 140
D. Chawla et al
receive TPN suggest that protein accretion occurs by
amino acid stimulation of protein synthesis rather than by
suppression of protein breakdown. 4, 5 Protein
requirements for the neonate tend to be inversely related
to gestational age and size due to more rapid growth rates
and greater protein losses in the smaller, more premature
infants.6 The early provision of protein is critical to attain
positive nitrogen balance and accretion, as premature
babies lose ~1% of their protein stores daily.7 Benefits
include improvement in nitrogen balance, stable plasma
AA profile and better growth in neonatal period. AA
solutions are available as 10% and 20% preparations
(appendix).
Carbohydrates
Carbohydrates are the main energy substrate for the
neonates receiving PN. Although, glucose is routinely
administered to VLBW infants beginning soon after birth,
the main objective of this established practice is to
maintain euglycemia. During PN, glucose infusion rate is
gradually advanced and objective is the achievement of
higher energy intake. Glucose is available as 5%, 10%,
25% and 50% solutions.
To ensure that a stressed premature infant receives an
adequate but not excessive amount of glucose, the
amount of carbohydrate delivered in the form of dextrose
is commonly initiated at the endogenous hepatic glucose
production and utilization rate of 4 to 6 mg/kg/min; and
8 to 10 mg/kg/min in ELBW infants. It provides 40 to 50
kcal/kg/d and preserves carbohydrate stores.
Frequently smaller, more unstable premature infants
Long term
Poor growth
Poor neurodevelopment outcome
Susceptibility to cardiovascular diseases
Reduced cell growth in specific organ systems (heart, kidney, pancreas)
Recommended energy intake (kcal/kg/day)
105-130
105-135
98-128
110-135
Indian Journal of Pediatrics, Volume 75April, 2008
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Parenteral Nutrition

develop hyperglycemia due to decreased insulin
production and insulin resistance. Glucose infusion rates
(GIR) for these babies may need to be limited to 4 mg/
kg/min or less, while larger preterm infants or term
infants can often tolerate up to 8 mg/kg/min initially.8, 9
Once the GIR supports acceptable serum glucose values,
it is advanced in a gradual, stepwise fashion (0.5 to 1 mg/
kg/min) to a suggested maximum glucose oxidative rate
for neonates of 12 to 13 mg/kg/min to support growth
and maintained there unless serum glucose values change
significantly.
Excessive carbohydrate delivery above the amount
that can be oxidized for energy and glycogen storage will
lead to an increase in basal metabolic rate,10 fat deposition,
cholestasis,11 hepatic steatosis,12 or overfeeding.
Insulin has been used along with glucose to serve two
distinct purposes. One is to manage hyperglycemia if
infant is developing high glucose levels despite glucose
infusion rate of 4-6 mg/kg/minute. In this case, insulin is
stopped as soon as euglycemia is achieved. Second
objective is to achieve higher glucose infusion rate and
promote growth. Later approach does not result in
increased AA accretion, can induce lactic acidosis and is
therefore not recommended.13
Lipids
kg per day by day 4, has been well tolerated without
noticeable adverse effects. Consider avoiding lipids for a
short period in the unstable, late preterm infant who has
evidence of increased PVR. Lipids may be restricted in
patients with hyperbilirubinemia in minimum amounts
that will provide only the essential fatty acids. Because
both lipids and bilirubin are transported in the blood by
albumin, lipids competing for binding sites on albumin
may result in insufficient binding of bilirubin to facilitate
excretion. 16 Persistently high bilirubin values may
increase the risk of kernicterus from the deposition of
bilirubin in brain cells. A free fatty acid to albumin ratio
(FFA:albumin) greater than 6:1 is thought to be clinically
significant.
IVL emulsions are aqueous suspensions containing
neutral triglycerides derived from soybean, safflower oil,
egg yolk to emulsify and glycerine to adjust tonicity.
Hydrolysis of triglycerides by hepatic and lipoprotein
lipase results in formation of free fatty acids. IVL
emulsions are available in two strengths: 10% and 20%
(Appendix). Use of 20% lipid emulsion is preferable to a
10% solution to decrease the risk of hypertriglyceridemia,
hypercholesterolemia, and hyperphospholipidemia
(Fig. 1). When lipids are exposed to light, they form
potentially toxic lipid hydroperoxides. Hence lipid

Lipids are essential components of parenteral nutrition for

preterm infants to provide essential fatty acids (EFAs) and
to meet high energy needs. Parenteral lipids are an
attractive source of nutrition in the first postnatal days
because of their high energy density, energy efficiency,
isotonicity with plasma, and suitability for administration
through a peripheral vein. Parenteral lipid emulsions
enable the delivery of fat-soluble vitamins. Even a short
delay of 3 to 7 days in supplying lipids to parenterally fed
preterm infants leads to biochemical EFA deficiency.14
Such deficiency increases antioxidant susceptibility in
preterm infants. EFA deficiency can be prevented with
Fig. 1. Metabolism of intravenous lipid emulsions. Lipoprotein X
introduction of as little as 0.5 to 1.0 g/kg per day of lipid
inhibits the clearance of remnant particles
infusion. Fluid-restricted, growth-compromised patients
or those limited to peripheral line access may require as Appendix
high as 3.5 to 4 grams fat/kg/d to achieve adequate Sources of Parenteral Solutions
energy for growth and protein sparing. This intake is
Component Source Concentration
appropriate as long as the fat intake remains less than 60%
of nonprotein calories.15 Proteins Aminoven 6% and 10%
Primene
The routine use of intravenous lipid (IVL) emulsions Lipids Intralipid 10%, 10% PLR
has not been universally accepted in critically ill, (phospholipids reduced), 20%
ventilated VLBW infants because of potential Glucose Dextrose 5%, 10%, 25%, 50%
complications like adverse effects on gas exchange and NaCl NaCl 0.9%, 3%
KCl KCl 15%
displacement of bilirubin from albumin. Proper use of IVL
Calcium Calcium gluconate 10%
emulsions includes slow infusion rates (<0.15 g/kg per Multivitamin Adult MVI -
hour), slow increases in dosage, and avoidance of unduly Trace elements Celcel -
high doses (>3.0 g/k per day). Studies have shown that TMA
administration of IVLs, beginning on day 1 at a dose of 1.0 Magnesium Magnesium sulfate 50%
g/kg per day and increasing in stepwise fashion to 3.0 g/ sulfate

Indian Journal of Pediatrics, Volume 75April, 2008 379

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D. Chawla et al

syringes and tubing should be covered by wrapping it in TABLE 4. Daily Requirement of Minerals
aluminum foil.
Mineral Requirement
Lipids may be restricted in patients with
Sodium 0-3 meq/kg/d (1st week of life)
hyperbilirubinemia in minimum amounts that will 3-6 meq/kg/d (beyond 1 st week)
provide only the essential fatty acids. Some clinicians will Potassium 0-2 meq/kg/d (1st week of life)
reduce or withhold lipids if rising bilirubin trends 1-3 meq/kg/d (beyond 1 st week)
approach levels requiring exchange transfusions. Because Chloride 2-3 meq/kg/d
both lipids and bilirubin are transported in the blood by Calcium 150-200 mg/kg/day
Magnesium 15-25 mg/d
albumin, lipids competing for binding sites on albumin
Phosphate 20-40 mg/kg/d
may result in insufficient binding of bilirubin to facilitate
excretion. 16 Persistently high bilirubin values may
TABLE 5. Recommended Vitamin Intake
increase the risk of kernicterus from the deposition of
bilirubin in brain cells. A free fatty acid to albumin ratio Vitamin Term (daily dose) Preterm (dose/kg/day)
(FFA:albumin) greater than 6:1 is thought to be clinically
Vitamin A (IU) 2300 1640
significant.
Vitamin D (IU) 400 160
Minerals Vitamin E (IU) 7 2.8
Vitamin K (g) 200 80
Sodium, potassium, chloride, calcium, magnesium and Vitamin B6 (g) 1000 180
phosphorus need to be provided in PN solution as per Vitamin B12 (g) 1 0.3
Vitamin C (mg) 80 25
their daily needs (Table 4). Except phosphate, all these
Biotin (g) 20 6
minerals are easily available in India. Sodium, potassium, Folic acid (g) 140 56
and chloride are essential to life and requirements are Niacin (mg) 17 6.8
dependent on obligatory losses, abnormal losses, and Pantothenic acid (mg) 5 2
amounts necessary for growth. Estimated and advisable Riboflavin (g) 1400 150
intakes are based on accretion studies and urinary and Thiamin (g) 1200 350
fecal losses from balance studies completed in the late
1970s. 17 Dosage of zinc to be provided is 150-400 microgram/kg/
d even with short-term PN, but a suitable preparation is
Calcium, phosphorus, and magnesium are the most difficult to find in Indian market.
abundant minerals in the body. They are closely
interrelated to each other in metabolism, the formation of Fluids
tissue structure, and function.
Intravenous fluid is the carrying medium for PN. It is
Vitamins started at 60-80 ml/kg/d and advanced by 15-20 ml/kg/
d to maximum of 150 ml/kg/d by end of first week of
Vitamins are added in PN solution to meet the daily life. Fluid therapy is regulated by monitoring hydration
requirement (Table 5). Separate preparations of fat-soluble status of the infant (weight gain/loss, serum sodium,
and water-soluble vitamins suitable for neonates are not urinary specific gravity, urine output and osmolality of
available in India. Multivitamin injection (MVI), when plasma and urine.
added in a dose of 1.5 ml/kg to AA-glucose solution
meets the need of vitamin A and most other vitamin. Evidence-based recommendations
Furthermore, intravenous vitamin delivery may be less Evidence-based recommendations for use of PN
due to photodegradation of vitamins A, D, E, K, B2, B6, B12, constituents are summarized in Table 6.
C, and folic acid and adsorption of vitamins A, D, and E
into the vinyl delivery bags and tubing. Vitamin K needs Dispensing PN solution
to be given separately as weekly intramuscular injections. In developed countries PN solution is prepared by central
Although vitamin B12 is not present in MVI, its deficiency pharmacy and delivered ready to be used. But this facility
is not manifested unless the neonate is on long-term PN. is usually not available in most of Indian hospitals and
physicians and nurses have to chart and prepare PN.
Trace elements Steps for calculation and preparing PN are as follows (a
Trace elements like zinc, copper, manganese, selenium, PN chart is provided in appendix):
fluorine and iodine should be provided in PN solutions. Determine total fluid requirement for the day
Zinc is universally recommended from day one of TPN, Subtract amount of fluid to be used for medications
whereas the other trace minerals are generally provided (e.g., diluting and infusing antibiotics) and enteral
after two, four, or 12 weeks of TPN without any feeds
appreciable enteral feeding. Copper, selenium,
molybdenum, and iron can be delivered separately also. Plan AA, IVL and glucose to be given over 24 h

380 Indian Journal of Pediatrics, Volume 75April, 2008

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Parenteral Nutrition

TABLE 6. Evidence-based Recommendations for Parenteral Nutrition

Component Recommendations

Fluids Day 1: 60-80 mL/kg/d.

Postnatal weight loss of 5% per day to a maximum of 15% is acceptable. This is achieved by progressively
increasing the fluid intake to 120-150 mL/kg/d by one week of age.
Energy An intake of 50 kcal/kg/d is sufficient to match ongoing expenditure, but it does not meet additional
requirements of growth.
The goal energy intake is 120 kcal/kg/d (higher in infants with chronic lung disease)
Protein Optimal parenteral amino acid intake is 3.5 g/kg/d.
Parenteral amino acids can begin from day 1 at 1-1.5 gm/kg/d
Carbohydrates From day 1, 6 mg/kg/min can be infused, increased by 2 mg/kg/min/d to 12-14 mg/kg/min and adjusted to
maintain euglycemia
Insulin is only used in infants who continue to have hyperglycemia associated with glycosuria and osmotic
dieresis even after the glucose intake has been reduced to 6 mg/kg/min. Insulin is given as a continuous infusion
commencing at a rate of 0.05 units/kg/h, increasing as required for persistent hyperglycemia.
Fat Intravenous fat, 1 g/kg/d can be started from day 1, at the same time as when intravenous amino acids are
started. This is increased to 2 g/kg/d and 3 g/kg/d over the next two days.
It is delivered as a continuous infusion of 20% intravenous fat via a syringe pump, separate from the infusate
containing the amino acids and glucose. The syringe and infusion line should be shielded from ambient light.
Minerals and Trace Minerals should include: sodium, chloride, potassium, calcium, phosphorus, magnesium.
Elements Trace elements should include: zinc, copper, selenium, manganese, iodine, chromium, and molybdenum.
Vitamins Vitamins must be added to the fat emulsion to minimize loss during administration due to adherence to tubing
and photo-degradation.

Take IVL suspension in one syringe and add MVI in
to it.
In second syringe mix AA, dextrose, electrolytes and
trace elements
IVL+MVI suspension is infused separately from AA-
Glucose-Minerals solution, although they can be
mixed at the site of infusion using a three-way
adapter.
For calculating amount of each PN component, use
following formula:
Amount to be given per kg body weight Body weight
Amount of component =
Strength of solution
For example, for a baby weighing 1.5 kg to be given 3
meq/kg of sodium, amount of 3% NaCl to be used is:
3 meq/kg 1.5 kg
Amount of 3% NaCl = = 9 ml
0.5 meq/ml
Route of administration
PN can be delivered through peripheral or central venous
lines. The limiting factor in deciding route of delivery is
osmolarity of the AA-glucose solution which is dependent
on dextrose concentration. A dextrose concentration
greater than 12.5% has an acidic pH and can be irritating
to the peripheral veins. In addition to dextrose,
electrolytes and minerals added to the solution increase
the osmolarity of the solution. Hypertonic solution need
to be administered through central venous line. Increasing
use of peripherally inserted central catheters (PICC) has
facilitated administration of PN while avoiding many
potential complications of surgically inserted central lines.
Short-term PN can be given through peripheral venous
line. Another attractive option in neonates is central line
inserted through umbilical vein. Position of central line
should be confirmed by X-ray before starting infusion
through it. The venous access used for PN should not be
interrupted for giving antibiotics or other medications.
For this a separate intravenous line should be established.
Peripheral access offers the advantage of a lower risk of
infection due to the greater distance of the catheter from
the central circulation as well as a smaller risk of
mechanical complications. However, nutrition delivery is
limited with peripheral lines due to constraints created by
a solutions osmolarity. Osmolality refers to the number of
particles per weight of water in kilograms and is typically
used to describe enteral feedings and a standard in
describing blood. 18 Osmolarity refers to the number of
millimoles of liquid or solid in a liter of solution and is the
preferred term for TPN. The sample worksheet of TPN is
shown in Table 7. In peripheral access concentration
greater than 900-1000 mOsm/ L are to be avoided. With
central access, solutions greater than 1,000 mOsm/L are
acceptable.
Monitoring and complications
Meticulous monitoring is needed in a neonate receiving
PN. Monitoring protocol and its rationale is summarized
in Table 8. Monitoring should be more frequent in the
initial stages. Once a steady metabolic stage has been
achieved, monitoring can be reduced to once a week.
Complications of PN can be nutrient-related or venous
access-related. Nutrient related complications include
hypoglycemia (plasma sugar < 54 mg%), hyperglycemia
(plasma sugar > 150 mg%) (glucose related); azotemia,

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D. Chawla et al

TABLE 7. TPN Worksheet

TABLE 8. Monitoring Schedule for a Neonate on Parenteral metabolic acidosis (protein-related); hypertriglyceridemia
Nutrition
(triglyceride > 200 mg/dl) (lipid-related), cholestasis and
Parameter Frequency trace element deficiency. Most of these complications can
be avoided by proper monitoring and provision of
Blood sugar 2-3 times a day while increasing
nutrients. PN-related cholestasis is usually complication
glucose infusing rate
Once a day while on stable glucose of long-term PN and can be avoided by provision of at
infusion rate least minimal-enteral nutrition. Catheter-related
Urine sugar Each urine sample ideally complications include dislodgement and infection.
Serum electrolytes Twice a week initially, then weekly
Blood urea Twice a week initially, then weekly Prevention of infection
Calcium, magnesium Weekly
and phosphorous Hospital-acquired infection (HAI) is a major complication
Serum albumin Weekly
of PN. All efforts should be made to avoid HAI.
Packed cell volume Weekly
Liver function tests Weekly Aseptic precautions during preparation of PN
Serum triglycerides Weekly
ANTHROPOMETRY Use of laminar flow
Weight Daily at the same time No compromise on disposables
Length Weekly
Trained staff
Head circumference Weekly
FLUID ml/kg/day - Daily No reuse of the PN solutions
Nutrient Intake Calculation Energy in Kcal per kg day No interruption of the venous line carrying PN
Protein in grams per kg per day
Use of bacterial filter in AA-glucose line

382 Indian Journal of Pediatrics, Volume 75April, 2008

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Parenteral Nutrition
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