Side effects of oral misoprostol for the prevention of postpartum hemorrhage: Results of a community-based randomised controlled trial in rural India

Abstract

Objective.

To investigate the side effects of 600 μg oral misoprostol given for the mother and the newborn to prevent postpartum hemorrhage (PPH).

Methods.

One thousand six hundred twenty women delivering at home or subcentres in rural India were randomised to receive misoprostol or placebo in the third stage of labour. Women were evaluated for shivering, fever, nausea, vomiting and diarrhea at 2 and 24 h postpartum. Newborns were evaluated within 24 h for diarrhea, vomiting and fever. Symptoms were graded as absent, mild-to-moderate or severe.

Results.

Women who received misoprostol had a significantly greater incidence of shivering (52% vs. 17%, p < 0.001) and fever (4.2% vs. 1.1%, p < 0.001) at 2 h postpartum compared with women who received placebo. At 24 h, women in the misoprostol group experienced significantly more shivering (4.6% vs. 1.4%, p < 0.001) and fever (1.4% vs. 0.4%, p < 0.03). There were no differences in nausea, vomiting or diarrhea between the two groups. There were no differences in the incidence of vomiting, diarrhea or fever for newborns.

Conclusions.

Misoprostol is associated with a significant increase in postpartum maternal shivering and fever with no side effects for the newborn. Given its proven efficacy for the prevention of PPH, the benefits of misoprostol are greater than the associated risks.

Introduction

Postpartum hemorrhage (PPH) accounts for ~25–30% of maternal deaths in India [1]. Various clinical trials and meta-analyses have shown that uterotonic agents such as oxytocin and ergot preparations employed in the third stage of labour can reduce the incidence of PPH by 50% [2]. However, these agents have to be administered parenterally and have the disadvantage of instability in tropical climates where refrigeration is not available. In addition, ergot derivatives may induce a rise in blood pressure and are contraindicated in women with hypertension. These drugs are not within the reach of a vast majority of women in the rural areas of the resource-poor countries, where home deliveries, generally conducted by unskilled birth attendants, still account for 30–50% births [3,4].

Over recent years, misoprostol has gained wide attention as an effective agent in the prevention of PPH. It is relatively inexpensive, thermostable, easy to use and can be administered by oral, sublingual, vaginal or rectal routes. Several randomised trials have compared oral [5] or rectal [6] misoprostol with placebo and with oxytocin or ergometrine [7]. Most trials have evaluated the incidence of PPH and/or other maternal-related outcomes such as use of additional uterotonics, change in hematocrit, transfer rate to higher level facilities or need for blood products as primary outcomes. Overall, these studies have found that oral misoprostol was associated with a significant decrease in acute PPH and mean blood loss as well as the need for further interventions or transfer to higher level facilities. Low cost, ease of administration, stability and a positive efficacy and safety profile make misoprostol an attractive option in resource-poor settings [8–10].

Several studies have reported on the adverse effects of misoprostol and have found that shivering and pyrexia are the major side effects with symptoms varying by dose and route of administration [11–14]. A WHO trial assessed two doses of misoprostol (400 and 600 μg) or oxytocin (10 IU) for the prevention of PPH [11]. Shivering and pyrexia were greater with the 600 μg dose of misoprostol (28 and 7.8%, respectively) compared with 400 μg misoprostol (19 and 2%) or the oxytocin group (12.5 and 3%). Similarly, a South African trial which compared 600 μg of oral misoprostol to placebo for prevention of PPH found an increase in the incidence of shivering (44% vs. 11%) [12]. Pyrexia was also reported to be significantly higher in the misoprostol group compared with placebo (38% vs. 6%) in the active study arm [12]. Hyperpyrexia has generally been limited to the use of higher doses of oral misoprostol (800 μg and higher) for treatment of PPH or medical abortion [15,16].

Misoprostol administered rectally appears to be associated with lower peak levels and a reduction in side effects compared with oral administration. A trial from United Kingdom reported a higher incidence of shivering with 600 μg of oral misoprostol compared with 600 μg of rectal misoprostol [17]. However, there were no dose-dependent differences in the side effects with 400 μg and 600 μg of rectal misoprostol.

The published studies to date on side effects have been largely hospital based, with skilled attendants present. There is very little data on the safe administration of oral misoprostol for women delivering in community-based settings where physicians are not in attendance. To our knowledge, there have also been no studies that have reported on the possible side effects on the neonates among mothers who were given misoprostol and who nursed immediately post-delivery.

We report on a community-based randomised placebo controlled trial of 600 μg of oral misoprostol administered for prevention of PPH to women in the third stage of labour. This efficacy trial found that oral misoprostol reduced the incidence of PPH by nearly 50% in resource-poor communities where a physician was not in attendance [8]. As part of this efficacy trial, safety data were also collected to assess the maternal and neonatal side effects after administration of oral misoprostol at 2 and 24 h postpartum.

Methods

This analysis was part of a randomised placebo controlled trial of 1620 women undertaken in four primary health centre areas of Belgaum District, Karnataka, India. Each woman was randomly assigned to receive either a single oral dose of 600 μg of misoprostol (three tablets) or placebo (three tablets) that were identical in appearance, administered after delivery of baby and within 5 min of clamping and cutting of the umbilical cord. The third stage of labour was managed expectantly, which was the standard practice in rural areas at that time. After the drug was administered, both women and neonates were monitored by the auxiliary nurse midwife (ANM) for a minimum of 2 h postpartum as well as receiving a visit at 24 h after delivery as per the guidelines of the Ministry of Health, Government of India. Details of the research design for this study have been previously published [8].

All side effects were assessed for mother and newborn at both 2 and 24 h. Data were collected by the ANM on the occurrence of nausea, vomiting, shivering, fever and diarrhea on all women through direct observation and by interviews of the mothers and family members. Side effects, including diarrhea, vomiting and fever, of maternally ingested misoprostol on the breast-fed newborn were assessed on postpartum day 1. Symptoms were graded as absent, mild-to-moderate or severe. Mild-to-moderate was by subjective assessment of the ANM or report of the woman. Any side effect necessitating treatment was marked as severe.

Descriptive statistics were calculated for maternal and neonatal side effects and their severity by treatment group. Comparisons between study drug and placebo groups were performed using Chi-square and Fisher exact tests. Data were analysed using SAS software, version 9.1.3 (SAS Institute Inc., Cary, NC).

The study was approved by the institutional review boards at the University of Missouri-Kansas City, the collaborating Indian site, Jawaharlal Nehru Medical College, Belgaum, Karnataka, India, as well as both the US National Institutes of Health, the Indian Council of Medical Research and Research Triangle Institute, the data coordinating centre.

Results

A total of 1620 women were randomised; 812 women received 600 μg of oral misoprostol and the remaining 808 received placebo. Demographic, clinical and perinatal characteristics were similar in both groups. The rate of acute PPH (blood loss ≥500 mL within 2 h of delivery of the baby) among women receiving misoprostol was 6.4% compared with 12% in the placebo group representing a 47% reduction in acute PPH for those women in the misoprostol group (p < 0.0001). These data have been previously published [8].

At 2 h after delivery, women receiving misoprostol had an increased incidence of shivering (52.2% vs. 17.3%) (n = 422 and 140; p < 0.001) and fever (4.2% vs. 1.1%) (n = 34 and 9; p < 0.001). Shivering was of mild-to-moderate intensity in the majority of women (49.7%) and severe in only 2.5% of the women who received misoprostol. In the placebo group, shivering intensity was generally mild-to-moderate. No differences were observed between the two groups in the rates of nausea, vomiting or diarrhea within 2 h of delivery (Table I).

Table I.

Maternal side effects at 2 h.

	Misoprostol (n = 812)	Placebo (n = 808)	p-value
Nausea	35 (4.3)	29 (3.6)	0.472
Vomiting	28 (3.5)	25 (3.1)	0.653
Shivering	422 (52.2)	140 (17.3)	<0.001
Fever	34 (4.2)	9 (1.1)	<0.001
Diarrhea	9 (1.1)	5 (0.6)	0.290

Values in parentheses are represented in percentage.

At 24 h postpartum, symptoms of shivering were greatly reduced in all women, although women in the misoprostol group reported a significantly higher rate of shivering than the placebo group (4.6% vs. 1.4%; p < 0.001). Similarly, the incidence of fever, although lower, was also significantly higher for the women in the misoprostol group (1.4% vs. 0.4%; p < 0.030). There were no differences in the rates of nausea, vomiting or diarrhea on postpartum day 1 (Table II).

Table II.

Maternal side effects at 24 h.

	Misoprostol (n = 812)	Placebo (n = 808)	p-value
Nausea	5 (0.6)	3 (0.4)	0.562
Vomiting	12 (1.5)	4 (0.5)	0.050
Shivering	37 (4.6)	11 (1.4)	<0.001
Fever	11 (1.4)	30 (0.4)	0.030
Diarrhea	9 (1.1)	2 (0.6)	0.170

Values in parentheses are represented in percentage.

Of the 1620 women, 55% (883 women) had at least one side effect. Thirty-two per cent of women (280) were provided medication to address adverse symptoms; 28% of women in the misoprostol group and 37% in the placebo group. Antipyretics, antispasmodics and antihistaminic were the most commonly administered medications. However, in almost all cases, no medical treatment was required by 24 h.

Four women who received misoprostol required transfer to a higher level health care facility as compared with 12 women from the placebo group (0.5% vs. 1.5% respectively, p < 0.05). However, none of the transfers were related to shivering, hyperpyrexia or other known symptoms associated with misoprostol use.

Manual removal of placenta was required in one woman randomised to misoprostol as compared with three women in the placebo group. There were no statistically significant differences in the rates of infection between the two groups (15.5% vs. 18.6%). There was one non-hemorrhagic death in the placebo group which was due to empyema. No differences between groups in systolic or diastolic blood pressure at 2 h post-delivery were noted.

The side effects of oral misoprostol on the early breast-fed newborn were also monitored because misoprostol acid has been reported in the colostrum within 1 h of its oral ingestion [18]. There were no differences in the incidence of fever, vomiting and diarrhea on postpartum day 1 between newborns whose mothers were given misoprostol as compared with placebo (Table III).

Table III.

Neonatal side effects at 24 h.

	Misoprostol (n = 812)	Placebo (n = 808)	p-value
Vomiting	24 (3.0)	33 (4.1)	0.234
Fever	5 (0.3)	3 (0.4)	0.555
Diarrhea	2 (0.3)	1 (0.1)	0.342

Values in parentheses are represented in percentage.

Discussion

The findings of our study, similar to that of the previous trials confirm that shivering and pyrexia are the most common side effects of 600 μg of oral misoprostol when used in the third stage of labour. In this, just over 50% of women administered misoprostol experienced shivering, a rate significantly higher than women in the placebo group. Other studies have reported rates ranging from 19% [5] to a high of 62% [14].

The occurrence of misoprostol-induced shivering has not been observed in non-puerperal situations. Misoprostol administered for induction of termination of pregnancy in a single dose of up to 800 μg oral and a total dose of up to 2200 μg was not associated with shivering [16]. Shivering after delivery is a common clinical experience for many women. Perhaps, misoprostol administration increases the incidence of shivering by lowering the threshold for physiological shivering or be related to a prostaglandin E1 effect on central thermoregulatory mechanisms [5].

Most of the earlier studies have monitored women for a period limited to 1 h. The WHO trial assessed side effects at 1, 2–6 and at 24 h and found that women in the misoprostol group had a significantly higher incidence of shivering within 1 h and the 2 to 6 h after delivery. However, after 6 h, the prevalence of shivering was very low and there were no clinically relevant differences between the misoprostol and placebo groups [13]. In the current study being reported, side effects were monitored for 2 h after delivery and at 24 h postpartum. Shivering was observed in 52% of women at 2 h and in 4.5% of women at 24 h indicating the transient nature of the symptom. There were no cases of severe shivering reported at 24 h.

Our study, similar to other trials, also reports a higher incidence of pyrexia in the misoprostol group [11,12]. Pyrexia was seen in 4.2% of women treated with misoprostol at 2 h but was only observed in 1.4% of women at 24 h. In the WHO misoprostol dose ranging trial, pyrexia was reported to be more common with the 600 μg dose compared with either the 400 μg dose or to 10 IU oxytocin given parentally (7.5% vs. 2% vs. 3%, respectively) [11].

Diarrhea is a well-known prostaglandin-related side effect. However, we report no differences in the incidence of nausea, vomiting and diarrhea between the two groups. Previous studies have failed to report on this side effect because the data collection was limited to 1 h after delivery. The WHO study reported a higher incidence of nausea and vomiting in the misoprostol group, but these differences were not statistically significant. In the WHO trial, diarrhea became apparent after 1 h, peaked during the 2–6 h interval with 5% of women reporting diarrhea during that time [19].

There was one case of non-hemorrhagic maternal death in our study (placebo group) with death attributed to empyema of the lung. Worldwide, three maternal deaths have been reported with the use of misoprostol [20]. In two cases, the drug was used for illegal unsafe abortion, and in the third case maternal death occurred following uterine rupture, after misoprostol was given for induction of labour. There are no reported cases of maternal death related to use of misoprostol for the prevention of PPH.

Although the effect of misoprostol on blood pressure was not one of the primary safety concerns of this study, we did monitor blood pressure in our study population. Our results show that there were no significant differences between the systolic and diastolic blood pressures recorded at the time of admission to delivery and at 2 h postpartum. Two other studies have reported on blood pressure changes with use of misoprostol. One prospective observational study of 600 μg of oral misoprostol administered in the third stage of labour did not find significant difference between pre- and post-delivery systolic and diastolic blood pressure [14]. However, one double-blind placebo-controlled trial employing 600 μg of misoprostol found that at 1 h postpartum both systolic and diastolic pressure was significantly higher with misoprostol administration compared with placebo [12]. The authors attribute the increased trend in the blood pressure to be secondary to the uterotonic effect of misoprostol. Several other randomised trials evaluating the efficacy and safety of misoprostol have included patients with hypertensive disorders of pregnancy and have reported no untoward side effects. Misoprostol appears to be safe in women with hypertensive disorders and is clearly preferable to ergot derivatives in this subset of women.

As misoprostol acid, the pharmacologically active metabolite is excreted in colostrum, it is possible that breast-fed infants could experience side effects associated with the early administration of misoprostol to the mother. One study measured serum and colostrum misoprostol acid levels after the administration of 600 μg misoprostol orally in the postpartum period. Misoprostol was detected in the breast milk within 30 min of oral administration. The peak concentration was attained in 1 h and the level dropped rapidly afterwards and was undetectable by 4–5 h after ingestion [18]. The misoprostol acid level in breast milk is only one-third of that in the plasma. In our trial, there were no adverse side effects of misoprostol in breast-fed newborns.

In this current analysis, 600 μg of misoprostol was shown to be safe for both the mother and newborn when used for prevention of PPH. Misoprostol was associated with transient increase in the rate of postpartum shivering and fever, but no other serious side effects were noted. Administration of misoprostol is a simple intervention that can reduce the incidence of PPH and ultimately of maternal morbidity and mortality. Oral misoprostol can be used in the prevention of PPH, particularly in situations such as community-based settings and home births where parenteral medications are not available or feasible for use.