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The route of delivery in eclampsia is controversial. We hypothesized that adverse maternal and perinatal outcomes may not be improved by early cesarean delivery.
This was a randomized controlled exploratory trial carried out in a rural teaching institution. In all, 200 eclampsia cases, carrying ≥34 weeks, were allocated to either cesarean or vaginal delivery. Composite maternal and perinatal event rates (death and severe morbidity) were compared by intention-to-treat principle.
Groups were comparable at baseline with respect to age and key clinical parameters. Maternal event rate was similar: 10.89% in the cesarean arm vs 7.07% for vaginal delivery (relative risk, 1.54; 95% confidence interval, 0.62–3.81). Although the neonatal event rate was less in cesarean delivery–9.90% vs 19.19% (relative risk, 0.52; 95% confidence interval, 0.25–1.05)–the difference was not significant statistically.
A policy of early cesarean delivery in eclampsia, carrying ≥34 weeks, is not associated with better outcomes.
Antihypertensives to control the blood pressure, magnesium sulfate as anticonvulsant, and delivery of the patient after stabilization are well-accepted interventions in this condition. However, there is controversy regarding the mode of delivery–whether vaginal or by cesarean section. Some contend that in eclampsia, delivery should occur within 12 hours of the onset of convulsions.
In noneclamptic women, serious morbidity is less common when delivery is vaginal. We hypothesized that undertaking cesarean section to achieve immediate delivery when the patient is not in labor, or in early labor, does not produce better outcomes.
The best way to test this hypothesis would be to conduct a randomized controlled trial based on noninferiority design. No randomized clinical trial has ever evaluated the optimum method of delivery for women with eclampsia. We conducted an open-label randomized controlled study to compare maternal and neonatal outcomes of early cesarean section and planned vaginal delivery in cases of antepartum or early intrapartum eclampsia. However, the sample size required to conduct this trial actually with a noninferiority design, that is to establish that planned vaginal delivery would be no worse than cesarean delivery with regard to maternal and neonatal outcome, is very large and we conducted our study with a smaller sample. Therefore we present this study as an exploratory controlled trial.
Materials and Methods
Study setting and approvals
The study was conducted from April 1, 2010, through March 31, 2011, in a rural teaching hospital in West Bengal, India, which serves as a tertiary referral hospital. During this period a total of 542 eclampsia cases were admitted, of which 340 (62.73%) were antepartum and intrapartum eclampsia and 202 (37.27) were postpartum eclampsia. The study protocol was approved by the institutional review board. Since written informed consent requires a clear mind and many patients were confused or unconscious, we sought written informed consent from next of kin, generally the spouse.
The sample consisted of women with clinical diagnosis of antepartum or intrapartum eclampsia, presenting at gestational age ≥34 weeks, with singleton pregnancy, os <3 cm dilated, normal fetal heart rate (by auscultation), cephalic presentation, normal coagulation profile, and no other obstetric complications. We believed that once a patient is in active phase of labor, that is os >3 cm, she is likely to achieve vaginal delivery within a reasonably short period. Cesarean delivery in some of these women would have been inappropriate, although it might also have benefited some of them. The gestational age was determined on the basis of history, antenatal records, clinical examination and, where available, second trimester ultrasonography (USG) records. Women with known contraindication to labor and vaginal delivery (eg, placenta previa, cephalopelvic disproportion diagnosed clinically) or any medical complications such as heart disease, diabetes mellitus, or chronic renal disease or known lethal fetal congenital anomalies, were excluded. Large proportion of patients had USG reports from antenatal period, which allowed exclusion of cases with congenital anomalies. USG was not done at or after admission. We depended on clinical findings, such as grossly small-for-date uterus, excessive uterine tonicity, and fetal heart rate abnormalities on auscultation, to exclude women with compromised fetuses and abruption. HELLP syndrome cases with low platelet count were also excluded as many cases were to undergo cesarean section under spinal anesthesia.
Eligible subjects whose next of kin consented to participate in the trial were randomly allocated to either planned cesarean delivery (group A) or to vaginal delivery (group B) arms. Randomization was done in blocks of 20 using computer-generated random number lists. The delivery mode was noted on cards that were then individually placed in opaque serially numbered envelopes and sealed. A telephone-based alternative to this traditional allocation concealment technique was not logistically feasible in our setting. The mode was revealed immediately prior to commencing the treatment for a subject. The randomization was performed by a statistician not otherwise involved in the conduct of the study.
The baseline parameters recorded for the study were maternal age, parity, whether cared for by health care providers during the antenatal period, first convulsion to admission interval, number of convulsions before admission, blood pressure, and consciousness level at the time of admission. The birthweight was recorded for every baby delivered, even if stillborn.
All women received magnesium sulfate as anticonvulsant as per the institutional protocol: 3 g (20%) was given intravenously and 2.5 g (50%) was given intramuscularly in each buttock on admission (total 8 g). Subsequently 2.5 g (50%) was given intramuscularly to alternate buttock every 4 hours. If there was recurrence of convulsions, another 2 g (20%) was administered intravenously. Magnesium sulfate was continued for 24 hours postpartum, with clinical monitoring, that is periodic assessment of respiratory rate, knee jerk, and urine output. Serum magnesium levels were not monitored. Antihypertensive was given if systolic blood pressure was >160 mm Hg or diastolic blood pressure was >110 mm Hg, targeting systolic blood pressure between 140-160 mm Hg and diastolic blood pressure between 90-100 mm Hg. Labetalol was the antihypertensive agent used: 20-80 mg was given intravenously in incremental doses every 20 minutes as needed. After delivery, oral labetalol was used as soon as the patient was able to take drugs orally, and continued in both groups. The blood pressure was controlled, although not normalized in all cases, by use of labetalol. Intravenous fluids were restricted to a maximum of 85 mL/h.
For women allocated to vaginal delivery group, a pre-agreed protocol for management of labor was followed. Induction was achieved with misoprostol 25 μg vaginally every 4 hours for a maximum of 5 doses. Fetal heart rate and condition of cervix were assessed before giving each dose of misoprostol. As soon as the woman went into labor or the Bishop score was >5, misoprostol was stopped. The membranes were ruptured when os was at least 2-3 cm dilated, cervical effacement was >80%, and head engaged. Labor was augmented with intravenous oxytocin if there were ineffective uterine contractions. Oxytocin was administered at least 4 hours after the last dose of misoprostol. Adequate progress of labor in the first stage was defined as cervix dilating at a rate of at least 0.5 cm per hour after the onset of active labor. The fetal heart rate was monitored intermittently by stethoscope (every 15 minutes in the first stage and every 5 minutes in the second stage of labor). If labor failed to progress satisfactorily even after augmentation with oxytocin or if fetal heart rate abnormality occurred, cesarean delivery was undertaken; otherwise labor was allowed to progress and baby was delivered vaginally, either spontaneously or with the help of instruments. Epidural analgesia was not used in labor as this is not used in our institution. Instead, tramadol 100 mg was administered intravenously. The vaginal deliveries were conducted by residents under supervision of senior obstetricians.
Women allocated to cesarean delivery group underwent cesarean section as early as possible after initial stabilization and necessary assessment that included full blood cell count (including platelets) and clotting time (clot observation test) examination. Cesarean delivery was performed by consultants either under spinal anesthesia or under general anesthesia as decided by the anesthetist in charge of the patient. At birth, the neonate was assessed by the pediatrician on call. Mothers and their babies were followed up for 7 days.
The ideal primary outcome measures for such a study are maternal and perinatal deaths. However, since these are relatively rare events, we decided to use 2 composite end points–one pertaining to the mother, the other to the newborn–as our primary outcome measures. The “maternal composite event” included maternal death and severe maternal morbidity indicated by ≥1 among the following: respiratory depression, need for ventilator support, pulmonary edema, pneumonia, renal failure, hepatic failure, coagulopathy, cerebrovascular accident, and admission to intensive care unit. Respiratory depression was diagnosed by clinical findings: respiratory rate <12/min and oxygen saturation <92%. Pulmonary edema was diagnosed by clinical findings, pulse oximetry, and chest x-ray. Pneumonia was diagnosed by clinical findings, chest x-ray, and leukocytosis. Renal failure was diagnosed clinically by oliguria along with raised serum creatinine level. Hepatic failure was diagnosed by clinical findings, serum bilirubin level, and liver enzyme values. Coagulopathy was diagnosed from bleeding manifestations and laboratory coagulation profile. For neonates, the composite event included perinatal death and severe neonatal morbidity indicated by Apgar score <7 at 5 minutes, delivery room intubation, or admission to special care baby unit for >7 days. In addition, some other events related to labor and mode of delivery were recorded as secondary outcome measures. These included need for blood transfusion, wound infection (infected abdominal or episiotomy wound), puerperal febrile morbidity (temperature >38°C on ≥2 occasions in any 48-hour period, excluding the first 24 hours after delivery), evacuation of hematoma (rectus sheath hematoma or vulval hematoma), and intraoperative trauma (including uterine artery laceration; laceration of the bladder, bowel, or ureter; or extension of the uterine incision in cesarean delivery cases and cervical tear or third- or fourth-degree perineal tear in instrumental delivery cases). The length of hospital stay, total magnesium sulfate dose, and recurrence of convulsions after admission were also treated as secondary outcome measures.
Sample size and statistical analysis
The primary measure of interest for this study was taken as the composite adverse maternal and adverse neonatal outcomes. Survey of our hospital records for the past 2 years showed that the rate for the combined composite outcome was around 30% for vaginal delivery. Logically, a reduction in the event rate by 10% in case of cesarean delivery would be sufficient grounds for considering cesarean section to be the preferred mode of delivery in eclampsia cases. It was estimated that 294 women would be required in each group to demonstrate a 10% difference in composite outcome with 80% power and 5% probability of type 1 error. For detecting 5% reduction in the event rate, the sample size went up to 1251 women in each arm. Since a marked difference in composite event rate was not likely for the 2 modes of delivery in eclamptic mothers, this situation was suited for a noninferiority trial. Assuming a noninferiority margin of 5% it was estimated that 986 women would be required in each arm to establish noninferiority of vaginal delivery in comparison to cesarean delivery with 80% power and 5% probability of type 1 error.
Since we were constrained by the fact that long-term availability of the investigator team was not assured due to administrative reasons, and recruitment of so many subjects was not feasible in a short time in our single-center setting, we decided a priori to include 100 subjects in each group, over a period of 1 year, to assess actual event rates through randomized intervention. Therefore, we viewed this trial as exploratory, allowing informed estimates for a larger definitive trial or as a first study for potential inclusion in a metaanalysis of similar studies. The experience gained from this study, in terms of barriers to recruitment, compliance with treatment protocols, and data collection teamwork, would also allow better conduct of a later definitive trial.
The results were analyzed according to intention-to-treat principle, and all women who were randomized were included in the analysis. Numerical variables were compared between groups by Student unpaired t test, and categorical variables by Fisher exact test or χ2 test as appropriate. A 2-sided P value < .05 was considered statistically significant. Event rates associated with cesarean delivery were compared with those in vaginal delivery to calculate relative risk (RR) with 95% confidence interval (CI). Software (Statistica, version 6; Stat Soft Inc, Tulsa, OK; and Graph Pad Prism, version 4; Graph Pad Software Inc, San Diego, CA) was used for statistical analysis.
Of the 340 antepartum and intrapartum eclamptic women admitted during the study period, 233 women were eligible for the study. Of these, spouses of 200 women gave consent to participate in the trial. Of these 200 cases, 101 women were allocated to cesarean delivery (group A) and 99 to vaginal delivery (group B). For women randomized to group A, 3 delivered vaginally; the reasons were disappearance of fetal heart sound just before doing cesarean section (1) and request for vaginal delivery by the relatives (2). For those randomized to group B, 72 delivered vaginally and the remaining 27 were delivered by cesarean section. The reasons for cesarean delivery were nonprogress of labor (13), fetal heart rate abnormality (8), and request by the patient or relatives (6). The subject flow is depicted in the Figure. All multiparous women allocated to vaginal delivery arm succeeded in achieving vaginal delivery. Cesarean delivery for nonprogression of labor was needed only in the nulliparous women. For the 72 women who delivered vaginally in group B, 19 (26.39%) required augmentation of labor with oxytocin and 29 (40.28%) delivered within 12 hours of induction of labor; 63 (87.50%) women delivered vaginally spontaneously and the remaining 9 (12.50%) required instrumental vaginal delivery.
Baseline characteristics of the women and their babies are depicted in Table 1. That these trial participant factors are comparable suggests that randomization was largely successful.
TABLE 1Comparison of baseline maternal and neonatal characteristics
Cesarean delivery arm (n = 101)
Vaginal delivery arm (n = 99)
21.1 ± 1.53
21.1 ± 2.56
Antenatal care received (at least 3 antenatal visits)
As seen in Table 2, there were no significant differences in maternal mortality or in any of the measures of serious maternal morbidity between the 2 groups. The composite maternal event rates were comparable: 10.89% in the cesarean delivery arm vs 7.07% in the vaginal delivery arm (RR, 1.54; 95% CI, 0.62–3.81). Maternal deaths occurred in 1.98% and 2.02% cases (RR, 0.98; 95% CI, 0.14–6.83), respectively, in the 2 arms.
TABLE 2Primary maternal outcome measures in 2 study arms
Prespecified as composite of respiratory depression, ventilation, pulmonary edema, pneumonia, renal failure, hepatic failure, coagulopathy, admission to ICU, and maternal death–some women may have had overlapping complications in which case they have contributed only once to composite event rate;
Values denote counts (%). RR is calculated as risk in cesarean delivery in comparison to vaginal delivery; 95% CI denotes 95% CI of RR.
CI, confidence interval; ICU, intensive care unit; RR, relative risk.
Seal. Choosing delivery route in eclampsia. Am J Obstet Gynecol 2012.
a Prespecified as composite of respiratory depression, ventilation, pulmonary edema, pneumonia, renal failure, hepatic failure, coagulopathy, admission to ICU, and maternal death–some women may have had overlapping complications in which case they have contributed only once to composite event rate;
Perinatal outcomes in the 2 groups were also comparable, as shown in Table 3. Although the composite event rate showed slightly better outcome in the cesarean delivery group–9.90% vs 19.19% (RR, 0.52; 95% CI, 0.25–1.05)–the difference was not significant statistically. The perinatal deaths in the 2 arms were, however, similar.
Prespecified as composite of Apgar score <7 at 5 min, delivery room intubation, admission to SCBU for >7 d, and perinatal death. Some babies may have had overlapping complications in which case they have contributed only once to composite event rate.
Values denote counts (%). RR is calculated as risk in cesarean delivery in comparison to vaginal delivery. Vaginal deliveries included 9 forceps deliveries. Four babies from instrumental vaginal birth had complications: perinatal death = 2 (1 stillbirth, 1 died after 48 h of delivery); Apgar <7 at 5 min = 3 (delivery room intubation = 3, admission to SCBU >7 d = 1, 1 died after 48 h).
CI, confidence interval; RR, relative risk; SCBU, special baby care unit.
Seal. Choosing delivery route in eclampsia. Am J Obstet Gynecol 2012.
a Prespecified as composite of Apgar score <7 at 5 min, delivery room intubation, admission to SCBU for >7 d, and perinatal death. Some babies may have had overlapping complications in which case they have contributed only once to composite event rate.
Table 4 provides a summary of the maternal and perinatal deaths that were encountered. There were 4 maternal deaths: 1 case each due to pulmonary edema and cerebrovascular accident in both study arms. It is noteworthy that the majority of subjects in this study were semiconscious or comatose at the time of admission (around 70% in each arm) but survived. All mothers who died in this series were comatose at admission and had experienced >5 seizure episodes. The exact length of time from onset of seizure to initiation of treatment was not available. There were 8 perinatal deaths in the series. Three babies died in the cesarean delivery group and 5 in the vaginal delivery arm. There were marginally more stillbirths in the vaginal delivery group compared with cesarean delivery group: 3/99 (3.03%) vs 1/101 (0.99%). In the cesarean delivery group the reason for stillbirth was disappearance of the fetal heart rate just before undertaking cesarean section and the baby was allowed to deliver vaginally. There were 4 neonatal deaths, 2 in each group. Intracranial hemorrhage following difficult instrumental vaginal delivery (1 case) and respiratory problem (1 case) precipitated the deaths in the vaginal delivery group. In the cesarean delivery group 1 baby died of respiratory distress and another due to septicemia.
TABLE 4Descriptive summary of maternal and perinatal deaths
Allocated delivery method
Actual delivery method
Maternal deaths (n = 4)
Cesarean section done 18 h after admission due to nonprogress of labor; died 20 h after delivery due to pulmonary edema
Delivered 15 h after admission; died 32 h after delivery due to cerebrovascular accident (intracerebral hemorrhage)
Died 5 d after delivery due to cerebrovascular accident (leukoencephalopathy of brain)
Died 26 h after delivery due to pulmonary edema
Perinatal deaths (n = 8)
Difficult forceps; weight 2.8 kg; neonatal death after 48 h due to intracranial hemorrhage
Delivered 16 h after admission; fetal heart sound disappeared in second stage; stillbirth; weight 2.3 kg
Delivered 14 h after admission; cord prolapsed; stillbirth; weight 2.9 kg
Difficult forceps; stillbirth; weight 3.1 kg
Fetal heart rate abnormality; weight 2.2 kg; respiratory problem after delivery; neonatal death after 48 h
Fetal heart sound disappeared before undertaking cesarean section; stillbirth; weight 2.4 kg
Weight 1.8 kg; respiratory problem after delivery; neonatal death after 72 h
Weight 2.3 kg; septicemia; neonatal death after 5 d
Seal. Choosing delivery route in eclampsia. Am J Obstet Gynecol 2012.
Regarding the secondary outcome measures, the rates of blood transfusion, wound infection, puerperal febrile morbidity, hematoma evacuation, intraoperative trauma, and recurrence of convulsion following administration of magnesium sulfate were comparable between groups, as depicted in Table 5. Of the 6 women who developed recurrence of convulsion in the vaginal delivery arm, 5 took >12 hours to deliver. The duration of hospital stay was shorter by 1.5 days on average (P < .001) but dose of magnesium sulfate higher by 7.3 g on average (P < .001) in the vaginal delivery arm.
TABLE 5Selected secondary maternal outcome measures in 2 study arms
Includes any one of following: uterine artery tear, extension of uterine incision (in cesarean delivery cases), or cervical tear, third- or fourth-degree perineal tear (in instrumental vaginal delivery cases).
Duration of hospital stay, d
6.1 ± 1.4
4.6 ± 1.2
Magnesium sulfate dose, g
25.5 ± 0.28
32.8 ± 3.2
Recurrence of convulsion after magnesium sulfate
Values of hospital stay and magnesium sulfate dose are stated as mean ± SD; rest are counts (%). RR is calculated as risk in cesarean delivery in comparison to vaginal delivery; 95% CI denotes 95% CI of RR.
CI, confidence interval; RR, relative risk.
Seal. Choosing delivery route in eclampsia. Am J Obstet Gynecol 2012.
a Includes any one of following: uterine artery tear, extension of uterine incision (in cesarean delivery cases), or cervical tear, third- or fourth-degree perineal tear (in instrumental vaginal delivery cases).
Our study shows that undertaking cesarean section in eclampsia patients when they are not in labor, or are in early labor with cervical dilatation <3 cm, provides maternal and perinatal outcomes comparable to attempted vaginal delivery. The perinatal outcomes tended to be slightly better but the differences did not attain statistical significance.
Some authors have recommended that all women with eclampsia should be delivered within 12 hours of admission.
To achieve quick delivery cesarean section has been preferred when the cervix is unfavorable and the woman is unlikely to deliver early. The incidence of cesarean delivery in antepartum and intrapartum eclampsia cases varies widely. Pritchard et al
In our series of eclampsia cases, the maternal mortality rate is around 2%. The reason for high maternal deaths in vaginal delivery in observational studies from developing countries may be due to the fact that moribund cases are allowed to go for a vaginal delivery. All women who died in our series had history of multiple convulsions (>5 convulsions) and were in a comatose state at the time of admission. Thus, the condition of the woman at admission is important and most women die due to complications that arise before admission.
Maternal morbidities related to eclampsia were marginally higher in cesarean delivery group; more women required ventilatory support and transfer to intensive care unit. The duration of hospital stay was also longer in cesarean delivery group and this difference was statistically significant. Some maternal morbidities such as need for blood transfusion, evacuation of hematoma, and intraoperative trauma arose mainly in those allocated to vaginal delivery group, but the subjects ended up in either cesarean delivery or operative vaginal delivery. This may have been due to increased morbidity related to cesarean delivery in late labor,
Our study had slightly higher perinatal deaths in vaginal delivery group (5.05% vs 3.97%). However, the overall perinatal mortality was less compared to other studies. This is almost certainly due to exclusion of cases with gestational age <34 weeks or absent fetal heart sound. We had 2 perinatal deaths where difficult instrumental delivery might have contributed.
Although a cesarean delivery may have improved the fetal outcome, on the other hand cesarean delivery in second stage of labor is known to increase the maternal morbidity.
The neonates delivered vaginally were more likely to require intubation and admission to special care nursery. Access to continuous electronic fetal heart monitoring might have improved perinatal outcomes but we had limited access to this facility and therefore did not use it in the study subjects. Although this might fall short of the standard of care in developed countries, we believe that this situation is representative of resource-constrained settings in which the great majority of eclampsia cases occur. Limited diagnostic facilities also prompted us to rely on Apgar at 5 minutes, delivery room intubation, and admission to special care baby unit for >7 days as markers of severe perinatal morbidity rather than “hard” outcomes like necrotizing enterocolitis, intraventricular hemorrhage, or respiratory distress syndrome. Lack of epidural analgesia during labor is another issue that limits the generalizability of the study to developed country settings.
Although exploratory in nature, this randomized controlled trial has shown that a policy of early cesarean delivery in eclamptic mothers, carrying ≥34 weeks, is not associated with better outcomes compared to planned vaginal delivery. Neonatal outcomes showed a trend toward improvement with early cesarean delivery, with the caveat that facility for continuous electronic fetal monitoring was lacking. This pilot study has also demonstrated that a definitive randomized controlled trial of cesarean vs vaginal delivery in eclampsia is feasible, and the results could be utilized in sample size calculation for such a study in future.
Maternal mortality in 2005 estimates developed by WHO, UNICEF, UNFPA, and the World Bank.
Cite this article as: Seal SL, Ghosh D, Kamilya G, et al. Does route of delivery affect maternal and perinatal outcome in women with eclampsia? A randomized controlled pilot study. Am J Obstet Gynecol 2012;206:484.e1-7.