Outcome of Infants Born to Women with

Chronic Kidney Disease

Douglas L. Blowey and Bradley A. Warady
Pregnancy in women with chronic kidney disease is not uncommon and is not without risk to the
mother and child. This article reviews the literature on the outcome of infants from pregnancies
in women with chronic kidney disease (CKD), including those receiving dialysis and those living
with a functional kidney transplant. Pregnancy in women with CKD and end-stage renal disease
(ESRD) is associated with a higher rate of premature birth and small-for-gestational-age (SGA)
infants, with resultant increase in neonatal mortality. Although congenital anomalies or long-term
developmental issues do not appear to be a significant risk, these areas deserve further study,
especially as newer immunosuppressive medications are employed in kidney transplant recipi-
ents.
© 2007 by the National Kidney Foundation, Inc.
Index Words: Neonatal; outcome; pregnancy; chronic kidney disease; dialysis; transplantation

T he term chronic kidney disease (CKD)

was advanced during the development of
clinical practice guidelines by the National
Kidney Foundation’s Kidney Disease Out-
comes Quality Initiative (K/DOQI).1 The ini-
tiative presented a uniform definition and
classification of the stages of CKD. The guide-
lines define CKD as (1) the presence of kidney
damage (irrespective of the underlying cause)
for 3 months or more, with or without de-
creased glomerular filtration rate (GFR), or
(2) GFR less than 60 mL/min/1.73 m2 for 3
months or more, with or without kidney dam-
age. Kidney damage is considered to be
present when structural or functional abnor-
malities of the kidney exist, such as abnormal-
ities in the composition of the urine (eg, pro-
teinuria), or abnormalities are seen in imaging
tests. Table 1 shows the classification of the
stages of CKD. The stages are defined by the
level of GFR, ranging from 1 to 5, with higher
stages representing lower GFR values. Kidney
failure, or stage 5 CKD, is characterized by an
estimated GFR less than 15 mL/min/1.73 m2
and is usually accompanied by signs and
symptoms of uremia and a requirement for
the initiation of renal replacement therapy,
that is, dialysis or transplantation. In turn,
stage 5 CKD is similar to, but not synonymous
with, the definition of end-stage renal disease
(ESRD). In the United States, ESRD is an ad-
ministrative term used to categorize patients
who are receiving dialysis or have a function-
ing kidney transplant. Because the staging of
CKD is based on GFR, a patient who receives
dialysis is categorized as having stage 5 CKD,
but a patient with a well-functioning kidney
transplant is likely to be categorized as having
stage 1 or 2 CKD.
The term CKD captures a diverse range of
kidney pathology, from isolated proteinuria
to progressive glomerular involvement asso-
ciated with a systemic process (eg, lupus ne-
phritis). Likewise, ESRD encompasses pa-
tients who receive various regimens of
hemodialysis or peritoneal dialysis, as well as
kidney transplant recipients with wide-rang-
ing levels of kidney function and diverse im-
munosuppressive therapies. Thus, individu-
als categorized as having CKD or ESRD
comprise a heterogeneous group of individu-
als with respect to their quality and quantity
of kidney function, the underlying cause of
kidney disease, and comorbid conditions,
such as proteinuria, cardiovascular disease,
hypertension, hyperlipidemia, diabetes, gas-
trointestinal and liver disease, anemia, and
poor nutrition, all of which may indepen-
dently have impacts on pregnancy and subse-
quent neonatal outcome.
From the Departments of Pediatrics, Pediatric Nephrology,
and Clinical Pharmacology, Children’s Mercy Hospitals &
Clinics, University of Missouri at Kansas City, Kansas City,
MO.
Address correspondence to Douglas L. Blowey, MD, 2410
Gillham Road, Kansas City, MO 64108. E-mail: dblowey@
cmh.edu
© 2007 by the National Kidney Foundation, Inc.
1548-5595/07/1402-0012$32.00/0
doi:10.1053/j.ackd.2007.01.014

Advances in Chronic Kidney Disease, Vol 14, No 2 (April), 2007: pp 199-205 199
200
Table 1. Stages of Chronic Kidney Disease
Stage GFR (mL/min/1.73 m ) 2
1 ⬎90
2 60-89
3 30-59
4 15-29
5 ⬍15
In the United States,11 million individu-
als aged 20 to 39 years have decreased kid-
ney function, defined as a GFR less than 90
mL/min/1.73 m2.1 Assuming that half of
these individuals are women, as many as 5.5
million women of reproductive age have
CKD. In addition, approximately 77,000
women 15 to 39 years of age are receiving
dialysis or living with a functioning kidney
transplant.2
Although pregnancy rates for women with
CKD and ESRD are lower than that observed
in the general population,2 pregnancy is not
uncommon3 and raises many questions about
the risks of pregnancy to both the mother
and the child. The maternal health risks of
pregnancy in women with ESRD have been
previously reviewed4,5 and include new or
worsening hypertension, diabetes, infection,
preeclampsia, and, for kidney transplant re-
cipients, the additional risks of graft rejection
and a decline in graft function. The maternal
health risks of pregnancy associated with
CKD are less well defined, especially in
women with mild to moderate CKD (eg, stage
2 to 4), but include an increased risk of
new or worsening hypertension, preeclamp-
sia, eclampsia, and deterioration of kidney
function.6-14 The impact of maternal CKD and
ESRD on the developing child, centered on
neonatal morbidity and mortality, congenital
malformations, and childhood development,
is the focus of the remainder of this review.
Table 2. Summary of the Studies Assessing Neonatal Outcome in Pregnancies Associated with Chronic
Kidney Disease and End-Stage Renal Disease
General Population
Preterm (⬍37 weeks) 12.3%
SGA — 33%-45%
Neonatal mortality 0.68%
BW ⬍2,500 g 8%
Abbreviations: BW, birth weight; CKD, chronic kidney disease; SGA, small for gestational age.
Blowey and Warady
Accordingly, a PubMed search for articles re-
lated to neonatal outcome in women with
CKD, transplantation, or dialysis was com-
pleted. Publications dating 1980 forward were
reviewed for applicability, and the bibliogra-
phy was searched for articles not noted in the
PubMed search.
Neonatal Mortality
According to the most recent national vital
statistics report,15 the two leading causes of
infant death in the United States are congeni-
tal malformations and complications of pre-
mature birth, accounting for 20% and 17% of
infant deaths, respectively. Overall, infant
mortality in the United States in 2003 was
0.68%, but the rates were much higher for
preterm infants, especially in those born be-
fore 32 weeks of gestational age. Whereas
mortality in full-term infants (37 weeks or
more) was 0.25%, it was 0.85% in those born
between 32 and 36 weeks of gestational age
and increased considerably (18.8%) in those
born at less than 32 weeks of gestational age.
Small-for-gestational-age (SGA) infants, de-
fined as a birth weight of less than the 10th
percentile for gestational age, also have a
higher mortality than an appropriately sized
infant of the same gestational age.16,17
Compared with the general population, ba-
bies born to mothers with CKD and ESRD are
more likely to be born premature or SGA
(Table 2) and are at an increased risk for
death during the neonatal period. Informa-
tion about the neonatal outcome of pregnan-
cies in renal transplant recipients comes
from the National Transplantation Pregnancy
Registry (NTPR),18-20 a United States– based
registry, the European Dialysis and Trans-
plant Association (EDTA) Registry,3,21 the
Transplant Dialysis CKD
50%-54% 67% 16%-59%
37% 7%-37%
1%-3% 10%-11% 3%-10%
46%-50% 94% 37%
 Outcome of Infants Born to Women with CKD
United Kingdom Transplant Pregnancy Reg-
istry,22 and a few small case series.23,24
Neonatal Outcome in Mothers with
Kidney Transplants
The NTPR describes 1,097 pregnancies in kid-
ney transplant recipients, 702 of whom re-
ceived either cyclosporine (90%) or tacrolimus
(10%) as part of their immunosuppressive reg-
imen. The registry reports a 1% to 2% neonatal
mortality, defined as death within the first 30
days of life. Of the pregnancies that result in a
live birth (76%), 52% to 54% of infants were
preterm (⬍37 weeks), and 46% to 50% had a
birth weight less than 2,500 g. Although the
details are not reported, the mean gestational
age of 36 weeks and mean birth weight of
approximately 2,400 g suggest that the major-
ity of infants were only mildly premature (eg,
32 to 36 weeks). No apparent difference were
seen in neonatal outcome between cyclospo-
rine-based and tacrolimus-based immunosup-
pressive regimens.20 A previous report by the
NTPR revealed that the relative risk of having
an SGA infant was increased in the setting of
a transplant recipient mother with either hy-
pertension, a prepregnancy serum creatinine
greater than 1.5 mg/dL, or declining kidney
function during the pregnancy.18
Of live-born children from pregnancies in
kidney transplant recipients described in the
EDTA registry, neonatal mortality was 2.8%,
and the majority of deaths were attributed to
disorders of prematurity. Prematurity was
common and occurred in 50% of all infants.
Similar to the finding in the NTPR report, only
a small percentage (5%) of the births were
extremely premature (⬍30 weeks of gesta-
tional age). The incidence of SGA infants was
14%, and 45% of all infants had a birth weight
less than 2,500 g. Finally, the United Kingdom
Transplant Pregnancy Registry, which has
information on 193 pregnancies in kidney
transplant recipients, reports that 50% of the
live births were premature.22 Similar to that
reported by the EDTA Registry, the risk of
preterm birth was associated with maternal
hypertension and a prepregnancy serum
creatinine greater than 1.7 mg/dL (150
␮mol/L).
201
Neonatal Outcome in Mothers Receiving
Dialysis Therapy
Although the number of pregnancies reported
is limited, the neonatal outcome of babies
born to women receiving dialysis is similar to
the transplant experience in that an increased
incidence of neonatal mortality, prematurity,
and SGA infants occurred, as compared with
the general population.3,4,21,25,26 Although the
718 babies described in the EDTA Registry are
largely babies born to mothers with a func-
tioning kidney transplant (88%), the report
also describes the pregnancy outcome of a
small number of mothers receiving hemodial-
ysis (11%) and peritoneal dialysis (0.5%).
Compared with babies born to mothers
with a functioning kidney transplant, the birth
weights of babies born to mothers receiving
dialysis were lower, and almost all babies had
a birth weight less than 2,500 g. The neonatal
mortality in pregnancies associated with dial-
ysis was higher than that noted in transplant
patients and was reported to be 10%.21 Hou4
also reported a similar neonatal mortality of
11% in pregnancies complicated by chronic
maternal dialysis. In this report, 67% of babies
were born premature, and 37% were SGA
infants. Interestingly, 43% of the SGA infants
were exposed to severe maternal hyperten-
sion,4 an association noted previously in
mothers with12,27 and without6,28 CKD.
Neonatal Outcome in Mothers with
Chronic Kidney Disease
Information on the pregnancy outcome of
mothers with CKD is less well organized than
the registry data available for ESRD. The CKD
information comes mainly from retrospective
case series and collectively contains about
1,300 pregnancies from mothers with varied
etiologies and stages of CKD.7-14,27-29 The
reported neonatal mortality in these series
ranges from 3% to 12%, the rate of preterm
births is 16% to 59%, and the incidence of SGA
infants is 7% to 37%. Similar to the ESRD data,
the rate of preterm delivery and SGA births in
women with CKD appears to increase with
worsening maternal kidney function, severe
proteinuria, and hypertension.8,9,12-14,27,29
202 Blowey and Warady
Neonatal Morbidity
No detailed information is available on short-
term neonatal morbidity in infants born to
mothers with CKD or ESRD, aside from the
reported generic “newborn complication” rate
of 41% to 54% in babies born to women with
a functioning kidney transplant.20 Despite the
lack of specific details on neonatal morbidity
associated with pregnancies complicated by
ESRD and CKD, one can infer the potential
outcomes by recognizing the morbidity asso-
ciated with prematurity, the most common
outcome of pregnancies associated with ESRD
and CKD. Despite the achievement of sub-
stantial advances in neonatal care over the
past decade, premature infants, especially
very-low-birth-weight infants (⬍1,500 g), con-
tinue to be at high risk for a variety of clinical
complications, such as pneumothorax, respi-
ratory distress syndrome, sepsis, necrotizing
entercolitis, chronic lung disease, deafness,
and intraventricular hemorrhage.30,31 Fortu-
nately, although the risk of extreme prematu-
rity appears to be small in infants born
to mothers with ESRD and CKD, significant
morbidity can still occur in even the most
mature (⬎2,500 g) of the premature infant
population.
Congential Anomalies
CKD patients are treated with medications
that have teratogenic risks that can poten-
tially be responsible for congenital anomalies.
Whereas the fetotoxic effects of angiotensin-
converting enzyme (ACE) inhibitors are well
characterized, the potential adverse effects as-
sociated with immunosuppressive medica-
tions can range from major malformations to
subtle defects such as immunologic or neuro-
cognitive defects that are not evident until
several years after birth. The incidence of ma-
jor structural malformations reported in preg-
nant women without disease is 3%. The EDTA
Registry reported a 3% to 5% incidence of
congenital malformations in live-born chil-
dren of women who are renal transplant re-
cipients,3 a rate that is similar to that in the
general population. Similarly, The National
Transplantation Pregnancy Registry reported
a 4% prevalence of major structural malforma-
tions in 164 children born to mothers with
solid-organ transplants, but long-term fol-
low-up of the children was not described.19,20
This estimate, while reassuring, is limited,
as it does not take into account the potential
for anomalies in pregnancies considered un-
successful, and it does not account for subtle
defects or immunologic and cognitive defects
that may not be evident until an older age.
The majority of pregnancies from these re-
ports occurred during the era of cyclosporine
and minimal data are available on the preg-
nancy risks associated with the newer immu-
nosuppressive medications such as tacroli-
mus, mycophenolate mofetil, sirolimus, and
the ever-expanding array of monoclonal anti-
bodies. The rate of congenital anomalies in
pregnancies of patients with CKD or in those
who receive dialysis has not been character-
ized.
The limited amount of information avail-
able on the rate of congenital anomalies in
children born to mothers with ESRD or CKD
makes determination of an increased risk of
birth defects in this population difficult. At
present, a significant increase in congenital
anomalies does not appear to occur; however,
this conclusion should be viewed with cau-
tion, as the reports are limited by methodol-
ogy that may lead to an underestimation of
the true rate of congenital anomalies. Limita-
tions include the exclusion of pregnancies
considered unsuccessful (eg, stillborn, miscar-
riages, and terminations), the lack of a com-
prehensive or systematic assessment of anom-
alies, and the availability of only short-term
follow-up assessments. The last is of particu-
lar importance in the consideration of poten-
tial abnormalities in development, as well as
toxicities that result in complications such
as autoimmune disorders, malignancies, and
germ-cell abnormalities in offspring, prob-
lems that may only be captured by detailed
studies performed in late childhood or even as
the population ages into adulthood.
Teratogenic Risks
ACE inhibitors and angiotensin-receptor block-
ers (ARBs), alone or in combination, are com-
monly recommended for diabetic kidney
disease and nondiabetic kidney diseases, even
 Outcome of Infants Born to Women with CKD
in the absence of hypertension. They are pre-
scribed for patients with all stages of CKD, in
kidney transplant recipients, and in dialysis
patients as a means to control blood pressure
and help preserve residual kidney function.
These agents are contraindicated in preg-
nancy because of the well-characterized feto-
toxic effects of ACE inhibitors. ACE inhibitor
fetopathy, characterized by fetal hypotension,
anuria-oliogohydramnios, growth restriction,
pulmonary hypoplasia, renal tubular dyspla-
sia, and hypocalvaria, may occur with second-
trimester or third-trimester exposure to ACE
inhibitors.32-35 The neonatal mortality for in-
fants with ACE-inhibitor fetopathy may be as
high as 25%.33 Historically, first-trimester ex-
posure to ACE inhibitors has not been per-
ceived as a risk for adverse birth outcomes;
however, a recent study suggests that first-
trimester exposure to ACE inhibitors does in-
crease the risk of major congenital malforma-
tions.36
Developmental Outcome
The long-term cognitive, developmental, and
functional outcome of infants born to mothers
with CKD is of importance to the parents, as
well as to the medical community that must
provide the appropriate support services. Un-
fortunately, very little information is available
on the developmental outcome of children
born to mothers with CKD, to those receiving
dialysis, or to those with a functioning kidney
transplant. An exploratory phone survey of
women registered in the NTPR found that
16% of children born to transplant recipients
receiving cyclosporine had developmental de-
lays or required educational support.37 Al-
though no formal developmental or control
group testing was conducted, the study high-
lights the potential for subtle developmental
abnormalities and the need for further explo-
ration. Willis et al.38 completed a cross-sec-
tional prevalence survey on the general health
and developmental state of 48 children born
to kidney transplant recipients. The survey
included a basic physical and developmental
assessment, the latter of which consisted of an
assessment of the attainment of developmen-
tal milestones and academic achievement. The
median age of follow-up was 5.2 years (range:
203
9 months to 18 years). Of the 48 infants in the
survey, 94% were considered to be in good
general health, 95% had a normal physical
examination (1 child with cerebral palsy and 1
child with a claw-hand deformity), and 98%
were considered developmentally normal. As
no formal developmental testing was done,
subtle developmental abnormalities could not
be excluded. In a much smaller study of chil-
dren who underwent a more detailed assess-
ment of development, all 6 children (aged 1 to
6 years) born to mothers with a functioning
kidney transplant were considered to have
normal development.39 Although these data
do not suggest any severe health challenges,
one must keep in mind, as mentioned previ-
ously, that children born to mothers with
ESRD or CKD are more likely to be born pre-
mature and that extremely low-birth-weight
babies (eg, ⬍1,000 g) have considerable long-
term health and educational needs and can
have significant neurodevelopment impair-
ment.40,41 Fortunately, although babies born
to mothers with ESRD or CKD tend to be
premature, most infants are apparently born
after 32 weeks of gestational age and do not
incur the same neurodevelopmental risks as
extremely low-birth-weight infants.
Summary
The ability to provide an accurate assessment
of neonatal outcome of infants born to women
with CKD is made difficult by the lack of good
data. Currently, we are aware that pregnancy
in women with CKD and ESRD is associated
with high rate of preterm birth and SGA in-
fants with resultant increased risk of neonatal
mortality. Whether the risks are caused by the
specific underlying maternal kidney disease,
factors unique to kidney transplantation or
dialysis, or one of the many comorbid condi-
tions or required medications is not clear and
requires further investigation. Although an
increased risk of congenital anomalies does
not appear to occur in this population, the
information should be viewed with caution
until more specific studies can be done to
assess the short-term impact of the newer
immunosuppressive regimens and the com-
pletion of long-term studies to assessing the
204 Blowey and Warady
potential for developmental anomalies and
delayed toxicity.
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