doi:10.1111/jog.

13424
doi:10.1111/jog.13424 J. Obstet.
J. Obstet. Gynaecol. Res. Vol. 43, No. 10: Gynaecol.
1543–1549, Res. 2017
October

Safety and efficacy of low dose intramuscular magnesium

sulphate (MgSO4) compared to intravenous regimen for
treatment of eclampsia

Pradip Kumar Saha1 , Jasbinder Kaur2, Poonam Goel3, shalija Kataria3, Rimpy Tandon3 and
Lekha Saha4
Departments of 1Obstetrics and Gynecology, 4Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), and
Departments of 2Biochemistry, 3Obstetrics and Gynaecology, Government Medical College and Hospital, Chandigarh, India

Abstract
Aim: This study was performed to compare the safety and efficacy of low dose intramuscular magnesium sul-
phate (MgSO4) (Dhaka regimen) and intravenous (IV) MgSO4 (Zuspan regimen) for the prevention of eclampsia
recurrence and to compare serum magnesium concentration.
Methods: Forty one eligible patients with eclampsia were randomly divided into two groups: group I patients
received IV MgSO4 according to the Zuspan regime, while group II patients received intramuscular (IM) MgSO4
according to the Dhaka regimen (i.e. low dose MgSO4). The total dose MgSo4 requirements per patient were cal-
culated and serum MgSo4 level was measured. Maternal and fetal outcomes were compared between the groups.
Results: The mean total dose of MgSO4 required for the treatment of eclampsia was higher in group I compared
to group II (32 ± 6.8 g vs 25.4 ± 8.8 g, respectively; P < 0.5). The mean serum MgSO4 levels were significantly
higher (P < 0.003) in group I compared to group II, although there were no significant differences in seizure recur-
rence. Statistically, more patients in group I experienced a loss of knee jerk reaction and required dose deferral
compared to group II. There was a significantly higher number of babies with poor Apgar scores in group I. Over-
all the maternal and fetal outcomes were comparable between the groups.
Conclusions: A low dose IM regimen (Dhaka regimen) of MgSo4 is equally efficacious and safe compared to an
IV regimen (Zuspan regimen) for the control and prevention of seizures in patients with eclampsia.
Key words: eclampsia, intramuscular, intravenous, low dose MgSO4.

Introduction both affluent and poor countries but eclampsia is more

Hypertensive disorders of pregnancy are a major cause
of maternal and perinatal morbidity and mortality, com-
plicating 7–10% of all pregnancies.1 Eclampsia affects 1
in 2000–4000 deliveries in developed countries, but this
statistic is several times higher in developing
countries.1,2
Maternal mortality as a result of eclampsia ranges
from 0% to 14%. Perinatal mortality is very high, ranging
from 10% to 28%.2 Pre-eclampsia incidence is the same in
common in poor countries because of the lack of antena-
tal care.2 Standard practice is to use an anticonvulsant to
control the immediate fit and prevent further seizures,
followed by delivery. Magnesium sulfate (MgSo4) is
the drug of choice for both prevention and treatment of
eclampsia.3,4 Dose related MgSo4 toxicity is a major
concern.5–10 Potential complications of MgSo4 treatment
include maternal hypotension, respiratory depression,
respiratory arrest and although rare, cardiac arrest.11,12
Apprehension regarding these toxicities leads to the

Received: September 18 2016.

Accepted: May 14 2017.
Correspondence: Associate Professor Pradip Kumar Saha, Department of Obstetrics and Gynecology, Postgraduate Institute of Medical
Education and Research (PGIMER), Chandigarh, Pin 160012, India. Email: pradiplekha@yahoo.co.in

© 2017 Japan
Japan Society
Societyof
ofObstetrics
Obstetricsand
andGynecology
Gynecology 1543
1
P. K. Saha et al.
limited use of this drug in many developing countries.7,9
Reduction of MgSo4 toxicity without compromising
efficacy (such as control of seizures and fatality rate) re-
mains a major challenge.7,8 The most commonly used
regimens of MgSO4 administration are Pritchard et al.’s
standard intramuscular (IM) regimen and Zuspan and
Sibai et al.’s intravenous (IV) regimen.13–15 Several stud-
ies have been carried out, particularly in developing
countries, to determine the lowest effective dose of
MgSO4, which would potentially offer lower toxicity
than the standard regimens.7,16–18 A low dose regimen
may ensure greater safety and in developing countries
like India where cost is an important determinant of
accessibility to qualitative health services, lower cost if
it is proven lower doses could be an alternative.
The pharmacokinetic basis of MgSO4 dosing regimens
for eclampsia prophylaxis and treatment is not clearly
established.19 Minimum effective serum magnesium
concentrations for eclampsia prophylaxis are lower than
the generally accepted therapeutic level.19
The goal of magnesium sulfate infusion is to control
eclamptic convulsions. Our hypothesis for this study is
that a regimen with a significantly lower serum magne-
sium level compared to the established Zuspan regimen
would still be able to achieve this clinical objective.
The aim of this study was to compare the safety and
efficacy of a low dose IM MgSO4 (Dhaka regimen) with
an IV MgSO4 (Zuspan regimen) for the treatment of
eclampsia and to measure Serum (Sr) MgSO4 in two
different protocols.
Methods
This randomized clinical trial was conducted in the
Departments of Obstetrics and Gynecology and
Biochemistry at the Government Medical College and
Hospital, Chandigarh, India. The institute ethical commit-
tee approved the study (no: GMC/TA-1(19D)/ 22 033
May 29, 2009), which was registered in the clinical trial
registry of India (No: CTRI/ 2009 000339, 05–08-2009).
Criteria
Patients with antepartum and intrapartum eclampsia
were included in the study.
Patients with eclampsia who experienced complica-
tions such as coma, pulmonary edema, oliguria, intracra-
nial bleeding and patients who had already received
MgSO4, phenytoin and diazepam before attending the
hospital were excluded from the study.
21544
At the time of admission, a detailed history was taken
and physical examination, including an obstetric exami-
nation, was performed. Blood samples were taken for
hemoglobin, platelet count, coagulation profile, kidney
and liver function tests, serum electrolytes and random
blood sugars. A fundus eye examination was also
performed. Eclampsia was diagnosed if a patient with
pre-eclampsia or hypertension experienced convulsions
after 20 weeks of gestation. Eclamptic patients who were
admitted to the labor ward and met the inclusion criteria
were included in this study. After the patients’ relatives
granted written consent the patients were randomized
according to computer generation into two groups.
Group I patients received a standard IV dose regimen
of MgSo4 (Zuspan regimen), which is standard practice
in this medical college.14 Group II patients received a
low dose IM regimen of MgSo4 (Dhaka regimen).16
The study group consisted of 41 women with
antepartum and intrapartum eclampsia randomly allocated
to either group I or II. Group I patients received 4 g of IV
MgSO4 as 20% solution followed by 1 g IV per h as
continuous IV infusion. Group II patients initially
received a 10 g loading dose of MgSO4 (4 g IV as 20%
solution, 6 g IM 50% solution, 3 g in each buttock with
1% of 1 ml of lidocaine) followed by 2.5 g IM every 4 h
as maintenance therapy.In both groups, MgSo4 was
continued for 24 h after the last seizure or 24 h after
delivery, whichever occurred last.
In cases of convulsion recurrence in either group, an
additional 2 g of 20% IV MgSo4 was administered.
Before each maintenance dose of IM MgSO4, respiratory
rate, knee jerk reaction and urine outputs were observed.
These were observed every h in Group I. The maintenance
dose was deferred if the knee jerk reaction was absent,
urine output was < 100 ml in the last 4 h or < 30 ml/h
and respiratory rate < 16/min. In both groups, blood sam-
ples were drawn to estimate the serum magnesium levels;
the first sample was taken 4 h after the loading dose was
administered and the second sample 24 h after delivery.
The total MgSO4 dose and serum magnesium level
was detected by colorimetric method using a commer-
cially available Magnesium Colorimetric Assay Kit
according to the manufacturer’s instructions.
Oral nifedipine was administered to control
hypertension.
The following maternal and neonatal outcomes were
observed.
Maternal
Recurrence of seizures; signs of magnesium toxicity,
such as loss of knee jerk reaction; respiratory depression;
©©2017
2017Japan
JapanSociety
Societyof
ofObstetrics
Obstetrics and
and Gynecology
 Lowdose
Low dose MgSO4
MgSO4 for
for eclampsia

oliguria; and any other maternal complications, such as Clinical presentations

coagulation failure, renal failure and pulmonary edema
were recorded. The details of labor and delivery were
also recorded.
Neonatal
Neonatal outcomes, such as stillborn, live born, Apgar
score, hypotonia, respiratory depression and cord pH
were recorded. Requirements for calcium gluconate,
neonatal intensive care unit admission and neonatal
jaundice were also recorded.
The mean age, mean body weight, height and body mass
index were comparable between the groups. Weight was
taken after delivery at the time of discharge, as it was
technically not possible to take weight on admission.
The majority of patients in both groups were primigrav-
ida. Proteinuria was present in 91% of women. The mean
systolic and diastolic blood pressure and other character-
istics, such as type of eclampsia and gestational age at
presentation, were also comparable between the groups
(Table 1).

Serum magnesium
We also measured the Sr magnesium level in both
groups. For statistical analysis, student t and chi-square
tests were used. A P value < 0.05 was considered statis-
tically significant.
Results
Initially, 50 patients were recruited but a total of 41 pa-
tients who satisfied the inclusion criteria were random-
ized. Twenty patients were included in group I and 21
in group II (Fig. 1).
Obstetric outcomes and treatment complications
The majority of the patients (60% in group I and 63% in
group II ) experienced spontaneous onset of labor
(Table 2). The mode and type of delivery were similar
in both groups.
A significantly higher number of patients in group I
(80%) experienced loss of knee jerk reflex (P < 0.05) and
dose deferral (P < 0.05). The same regimen returned on
appearance of knee jerk and desirable urine output and
respiratory rate. There was no significant difference in
seizure recurrence in either group. None of the patients
experienced hematoma or pain at the local injection site.

Figure 1 Flow chart for patient

allocation.

© 2017 Japan
Japan Society
Societyof
ofObstetrics
Obstetricsand
andGynecology
Gynecology 1545
3
P. K. Saha et al.

Table 1 Baseline characteristics of women with eclampsia

Clinical parameters Group I (Zuspen regimen) (n = 20) Group II (Dhaka regimen) (n = 21)
Age (years) (M ± SD) 24 ± 2.2 24 ± 3.8
BMI (M ± SD) 23.3 ± 5 23.2 ± 6
Weight (kg) (M ± SD) 55.4 ± .6.3 54.9 ± 6.7
Height (cm) (M ± SD) 154 ± 6.6 153.6 ± 7.9
Gravida
Primi 16 (80%) 17 (81%)
≥2 4 (20%) 4 (19%)
Type of eclampsia N (%) N (%)
Antepartum 18 (90%) 18 (85.7%)
Intrapartum 2 (20%) 3 (14.3%)
Mean gestational age (weeks) (M ± SD) 36.5 ± 3.3 35.4 ± 3.8
Mean Systolic BP (mm Hg) (M ± SD) 148 ± 12.3 150.38 ± 11.6
Mean diastolic BP (mm Hg) (M ± SD) 102 ± 7.8 100 ± 8.6
BMI, body mass index; BP, blood pressure; M, mean; SD, standard deviation.

Table 2 Obstetric outcomes and treatment complications in women with eclampsia

Group I Group II
(Zuspen regimen) (Dhaka regimen)
Parameters (n = 20) N (%) (n = 21) N (%)
Labor
Spontaneous 12 (60%) 13 (63%)
Induced 8 (40%) 8 (37%)
Mode of delivery
Vaginal – unaided 13 (65%) 14 (66.6%)
Forceps 2 (10%) 0
Cesarean 5 (25%) 7 (33.4%)
Complications
Loss of knee jerk reflex 13 (65%)* 3 (14.3%)
Seizure recurrence 2 (10%) 1 (4.8%)
Number of deferred doses 16 (80%)* 5 (23.8%)
*P < 0.05 when compared between groups.

Perinatal outcomes Eleven patients in group I achieved therapeutic

The mean birth weight of infants was comparable be-
tween the groups (Table 3). There were four stillbirths
in group I and one in group II and two neonatal deaths
in group II compared to one in group I; however, the
difference was not statistically significant. There was no
significant difference in the requirement for neonatal in-
tensive care, respiratory distress or neonatal jaundice.
Significantly more babies had a low Apgar store (<7)
at 1 min in group I. More babies had hypotonia in group
I; however, this result was not statistically significant.
Maternal serum magnesium level
The total MgSo4 dose required in group I was signifi-
cantly higher than in group II (P < 0.05) (Table 4). In
group I, the serum magnesium level was significantly
higher at 4 h and 24 h compared to group II (P < 0.003)
(Table 5).
MgSo4 level in 4 h and 12 patients in 24 h. In group II,
six patients achieved therapeutic MgSo4 level at 4 h
and five patients at 24 h, based on the therapeutic level
for treatment of eclamptic convulsions suggested by Lu
et al. with a concentration of 1.8 to 3.0 mmol/L
(4.2 mg/dl to 7.2 mg/dl) (Table 6).20
Discussion
Eclampsia is one of the leading causes of maternal mor-
bidity and mortality. This condition affects 1 in 2000–
4000 deliveries in developed countries but is several
times higher in developing countries.1,2
Eclampsia is a major obstetric emergency that requires
adequate and timely management to avoid catastrophic
outcomes. MgSO4 is the treatment of choice for the pre-
vention and treatment of eclamptic convulsions.3

41546 ©©2017
2017Japan
JapanSociety
Societyof
ofObstetrics
Obstetrics and
and Gynecology
 Lowdose
Low dose MgSO4
MgSO4 for
for eclampsia

Table 3 Perinatal outcomes following maternal treatment with magnesium sulphate

Parameters Group I (Zuspen regimen) (n = 20) N (%) Group II (Dhaka regimen) (n = 21) N (%)
Birth weight (kg) (M± SD) 1.93 ± 0.64 1.85 ± 0.72
Stillbirths 4 (20%) 1 (5%)
Neonatal deaths 1 (5%) 2 (10%)
NICU requirement 5 (25%) 4 (19%)
Respiratory distress 5 (25%) 4 (19%)
Hypotonia 4 (20%) 2 (9.5%)
Jaundice 5 (25%) 4 (19%)
Cord pH < 7.2 5 (25%) 4 (19.0%)
Apgar score 9 (45%)* 3 (14.2%)
< 7 at 1 min
< 7 at 5 min 5 (25%) 2 (9.5%)
*P < 0.05 when compared between groups. M, mean; NICU, neonatal intensive care unit; SD, standard deviation.

Table 4 Comparison of total dose requirement between groups

Group I (Zuspen regimen) (n = 20) Group II (Dhaka regimen) (n = 21)
Mean total dose of magnesium 32 ± 6.8 25.4 ± 8.8
per patient (g) (Mean ± SD)
P < 0.05 when compared between groups. M, mean; SD, standard deviation.

Table 5 Maternal serum magnesium level (Mg/dl) in Seth et al. conducted a study to evaluate the efficacy of
women treated with magnesium sulphate for eclampsia three different regimens of MgSO4 therapy (Pritchard
Group I Group II regimen, IM low dose and single IV or IM loading dose)
(Zuspen regimen) (Dhaka regimen) P
Time (n = 20) (n = 21) Value in patients with antepartum eclampsia.16 They found
that low dose MgSO4 regimens for the control of
4h 4.25 ± 0.86 3.41 ± 0.79 0.003
24 h 4.33 ± 0.93 3.32 ± 0.90 0.003 eclamptic convulsions provided less toxicity and im-
proved neonatal outcomes without significant adverse
Values are given as mean ± standard deviation.
effects.
Bangal et al. also found a low dose MgSO4 regimen to
be safe and effective for eclampsia.17 The average total
Table 6 Number of patients who achieved therapeutic dose of MgSO4 required to control convulsions was 20 g
magnesium sulphate
(i.e. 54.4% less than that of the standard Pritchard regi-
Group I Group II men). In our study, the mean total dose requirement in
4h 11 6 the IM low dose group was 25.4 g.
24 h 12 5 Begum et al. conducted a study at Dhaka Medical
College and Hospital, Bangladesh and found that half
of the standard dose of MgSO4 appeared to be sufficient
Although MgSO4 has been proven to have high efficacy to effectively control convulsions and serum levels of
among the antiepileptic drugs used, such as phenytoin magnesium remained lower than levels that produce
and diazepam, the toxicity associated with MgSO4 toxicity.7 The Sr MgSo4 levels achieved at different time
remains a concern. Considering the small maternal size intervals were similar to our results.
of Indian women, few studies have compared low with Shilva et al. also compared the safety and efficacy of
standard high doses of MgSo4 to examine whether the low dose MgSO4 in the treatment of eclampsia and con-
MgSo4 dose can be reduced to alleviate toxicity cluded that seizures can be safely controlled in women
without decreasing efficacy. However, these few studies with eclampsia with a lower dose of MgSO4 with the ad-
have proved that toxicity can be reduced by giving low vantage of lower toxicity.10 Fewer patients experienced
dose MgSO4 without decreasing efficacy. Our results loss of knee jerk reaction or required deferred doses.
are consistent these results.7,16–18 These results are consistent with our findings.

© 2017 Japan
Japan Society
Societyof
ofObstetrics
Obstetricsand
andGynecology
Gynecology 1547
5
P. K. Saha et al.
Jana et al. conducted a similar study to assess the
safety and efficacy of a very low dose MgSo4 regimen
for the treatment of eclampsia in Indian women.18 Their
initial loading dose of 8 g MgSo4 was even lower than
the original Dhaka regime of 10 g, which we used in this
study. However the maintenance doses were same in
both groups.
The maternal serum magnesium levels in women
treated with MgSo4 in group I were 4.25 ± 0.86 mg/dl
and 4.33 ± .93 mg/dl in 4 h and 24 h, respectively, while
in group II these were 3.41 ± 0.79 mg/dl and
3.32 ± 0.90 mg/dl for the same time interval. Although
the serum MgSo4 level in the low dose Dhaka regimen
is significantly lower than the Zuspan regimen, but the
recurrence of seizures were the same in both groups.
Serum concentrations between 2 and 3.5 mmol/l
(4–7 mEq/l) are generally thought to be therapeutic
and have directly and indirectly driven clinical practice
for decades.19
A concentration of 1.8 to 3.0 mmol/L (4.2 mg/dl to
7.2 mg/dl) is the suggested therapeutic level for treat-
ment of eclamptic convulsions.20 If we consider this a
surrogate marker for the prevention of convulsions,
45% of patients in group I and 70% in group II did not at-
tain this value, although their seizures were controlled. It
appears that MgSO4 can be protective even at lower
serum concentrations than the generally accepted thera-
peutic level.
Okusanya et al. examined the clinical pharmacoki-
netic properties of MgSO4 in women with pre-
eclampsia and eclampsia and concluded that the actual
magnesium dose and concentration needed for prophy-
laxis has never been estimated.19 It it appears that
MgSO4 can be protective even at serum concentrations
of < 2 mmol/l.
The strength of our study is that we measured the
MgSo4 serum level at 4 h and 24 h, as well as the total
dose received. However, the small size of our study
sample meant that our results are underpowered for
eclampsia recurrence.
The greater number of babies with a low Apgar score
in group I could have resulted from prolonged labor or
an increased serum MgSo4 level.
Conclusion
Low dose IM MgSo4 (Dhaka regime) is as effective as
IV MgSo4 (Zuspan regime) for the treatment of eclamp-
sia. We concluded that eclamptic seizures can be safely
controlled by administering low dose IM MgSO4
without increasing the risk of MgSO4 toxicity. The
efficacy of both regimens in controlling convulsions is
comparable. There is less likelihood of dose deferral in
61548
the low dose IM regimen; however, seizure recurrence
was the same using both regimens. An IM low dose
could be used in small maternal size in resource limited
countries where intensive monitoring may not be possi-
ble. The minimum effective serum MgSO4 concentration
for eclampsia prophylaxis may be lower than the gener-
ally accepted therapeutic level; however, further re-
search is needed in a larger sample size determine the
optimum dose of MgSo4 depending on maternal weight.
Acknowledgments
The study was funded by a research grant from the
Department of Science and Technology (DST
Government Organization), Chandigarh Administra-
tion, Chandigarh, India.
Disclosure
None declared.
References
1. Sibai BM. Preeclampsia - eclampsia. Curr Probl Obstet Gynecol
Fertil 1990; 13: 1–45.
2. Villar MA, Sibai BM. Eclampsia. Obstet Gynecol Clin North Am
1988; 15: 355–377.
3. The Eclampsia Trial Collaborative Group. Which anticonvul-
sant for women with eclampsia? Evidence from the Collabora-
tive Eclampsia Trial. (Published erratum appears in Lancet
1995; 346:258). Lancet 1995; 345: 1455–1463.
4. Altman D, Carroli G, Duley L et al. Do women with pre-
eclampsia, and their babies, benefit from magnesium sulphate?
The Magpie Trial: A randomized placebo-controlled trial. Lancet
2002; 359: 1877–1890.
5. Begum R, Begum A, Bullough CH, Johanson RB. Reducing ma-
ternal mortality from eclampsia, using magnesium sulphate.
Eur J Obstet Gynecol Reprod Biol 2000; 92: 223–224.
6. Bhalla AK, Dhall GI, Dhall K. A safer and more effective regi-
men for eclampsia. Aust N Z J Obstet Gynaecol 1994; 34: 144–148.
7. Begum R, Begum A, Johanson R, Ali MN, Akhter S. A low dose
(“Dhaka”) magnesium sulphate regime for eclampsia: Clinical
findings and serum magnesium levels. Acta Obstet Gynecol
Scand 2001; 80: 998–1002.
8. Sardesai SP, Maira S, Patil A, Patil U. Low dose magnesium sul-
phate therapy for eclampsia and imminent eclampsia: Regime
tailored for Indian women. J Obstet Gynecol India 2003; 53:
546–550.
9. Mahajan NN, Thomas A, Soni RN, Gaikwad NL, Jain SM.
‘Padhar regime’ – A low dose magnesium sulphate treatment
for eclampsia. Gynecol Obstet Invest 2009; 67: 20–24.
10. Shilva, Saha SC, Kalra J, Prasad R. Safety and efficacy of low-
dose MgSO4 in the treatment of eclampsia. Int J Gynaecol Obstet
2007; 97: 150–151.
©©2017
2017Japan
JapanSociety
Societyof
ofObstetrics
Obstetrics and
and Gynecology
 Lowdose
Low dose MgSO4
MgSO4 for
for eclampsia

11. Witlin AC. Prevention and treatment of eclamptic convulsion.
Clin Obstet Gynecol 1999; 42: 507–518.
12. Idama TO, Lindow SW. Magnesium sulphate: A review of clin-
ical pharmacology as applied to obstetrics. Br J Obstet Gynaecol
1998; 105: 260–268.
13. Pritchard JA, Cunningham FG, Prichard SA. The Parkland Me-
morial Hospital protocol for treatment of eclampsia: Evaluation
of 245 cases. Am J Obstet Gynecol 1984; 148: 951–963.
14. Zuspan FP. Problems encountered in the treatment of
pregnancy-induced hypertension. A point of view. Am J Obstet
Gynecol 1978; 131: 591–597.
15. Sibai BM, Lipshitz J, Anderson GD, Dilts PV Jr. Reassessment of
intravenous MgSO4 therapy in preeclampsia-eclampsia. Obstet
Gynecol 1981; 57: 199–202.
16. Seth S, Nagrath A, Singh DK. Comparison of low dose, single
loading dose, and standard Pritchard regimen of magnesium
sulfate in antepartum eclampsia. Anatol J Obstet Gynecol 2010;
2: 1–4.
17. Bangal V, Kwatra A, Raghav S, Jadhav S. Low dose magnesium
sulphate regime for eclampsia. Pravara Med Rev 2009; 1(3).
18. Jana N, Dasgupta S, Das AK, Santra D, Samanta B. Experience
of a low-dose magnesium sulfate regimen for the management
of eclampsia over a decade. Int J Gynaecol Obstet 2013; 122:
13–17.
19. Okusanya BO, Oladapo OT, Long Q et al. Clinical pharmacoki-
netic properties of magnesium sulphate in women with pre-
eclampsia and eclampsia. BJOG 2016; 123: 356–366.
20. Lu J, Nightingale CH. Magnesium sulfate in eclampsia and pre-
eclampsia: Pharmacokinetic principles. Clin Pharmacokinet 2000;
38: 305–314.

© 2017 Japan
Japan Society
Societyof
ofObstetrics
Obstetricsand
andGynecology
Gynecology 1549
7