Misoprostol in pregnancy and breastfeeding


Risk Factor: XM
Class: Gastrointestinal agents/ Antisecretory agents

Contents of this page:
Fetal Risk Summary
Breast Feeding Summary

Fetal Risk Summary

Misoprostol, a synthetic prostaglandin E1 analogue, is used to prevent gastric ulcers induced by nonsteroidal anti-inflammatory agents. It is contraindicated in pregnancy because of the risk of uterine bleeding and contractions that may result in abortion. Although not indicated for such, misoprostol is routinely used for cervical ripening in term pregnancies and for pregnancy termination.

In reproduction studies reported by the manufacturer, misoprostol was not teratogenic in rats and rabbits at doses 625 and 63 times the maximum recommended human dose (MRHD), respectively (1). At 6.25625 times the MRHD, however, dose-related pre- and postimplantation losses and a significant decrease in the number of live pups were seen in rats (1). In another study, however, teratogenicity observed in pregnant rabbits given doses of 3001500 g/kg on days 719 included spinal bifida, caudal vertebral defects, umbilical hernia, and gastroschisis (2).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 5 newborns had been exposed to misoprostol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (20.0%) major birth defect was observed (none expected), a cardiovascular defect.

During the initial clinical trials, menstrual complaints were higher among nonpregnant women treated with misoprostol (3.7%) than with placebo (1.7%) (3). In a clinical study designed to assess the effect of misoprostol on the pregnant uterus, 111 women, who had consented to an elective 1st-trimester abortion, were treated with either placebo or one or two 400-g doses of the prostaglandin. All 6 of the women who aborted spontaneously the day following treatment had received misoprostol. Uterine bleeding occurred in 45% (25 of 56) of the women treated with misoprostol compared with 4% (2 of 55) of the placebo-treated women (3).

Misoprostol has been combined with the antiprogestogen mifepristone (RU 486) to induce legal abortion (see also Mifepristone) (4,5,6 and 7). Some of the advantages of this prostaglandin analogue over similar agents are that it is effective, active by the oral route, inexpensive, and stable at room temperature (4,5). In one study, 40 women were treated with 400 g of the drug 7 days before surgical termination of pregnancy (6). Only two of the women from this group had a complete abortion. In a second part of the study, 21 women were given 2001000 g of misoprostol 48 hours after a 200-mg dose of mifepristone, resulting in a complete abortion in 18 women (6). Similar effectiveness was found in a large study published in 1993 involving 895 women who received misoprostol either 4 or 48 hours after a dose of mifepristone (7).

A 1991 Reference cited the use of misoprostol as an illegal abortifacient in Brazil (8). The drug is freely available as an over-the-counter product in that country, where abortions are illegal. At one university hospital maternity unit, 20 women sought emergency treatment for uterine bleeding in 1988 after an unsuccessful attempt to induce abortion with misoprostol. In 1990, the number rose to 525. The usual dose consumed was 800 g (two 200-g tablets orally plus two tablets vaginally), but some women may have taken as much as 9200 g (46 tablets) (8).

Five infants with congenital malformations who had been exposed during the 1st trimester to misoprostol in unsuccessful attempts at abortion were described in a 1991 case report (9). The total dose was 1200 g in two of the mothers and 400600 g in the other three cases. The five infants had an unusual defect of the frontotemporal region of the skull consisting of an asymmetric, well-circumscribed anomaly of the cranium and overlying scalp, exposing the dura mater and underlying cerebrum. Surgical correction of the defect was attempted within 4 days of birth in each of the cases, but one infant died of severe infection. Although the authors conceded that a later acting agent was suggested by the nature of the defect, three of the mothers denied any further attempts to terminate their pregnancies after the use of misoprostol (9). In a later publication, two of the authors described more fully the defects of the scalp and cranium in three of the newborns (10).

Two additional reports describing the use of misoprostol as an abortifacient by Brazilian women appeared in 1993 (11,12). In Rio de Janeiro during a 9-month period of 1991, of 803 women admitted to hospitals with abortion complications, 458 (57%) had self-administered misoprostol to induce abortion (11). Most (80%) of these women had used the drug alone. The median dose used was 800 g (range 20016,800 g), with 65% taking it orally, 29% orally and vaginally, and 6% vaginally only. The most frequently cited reasons by the women for seeking medical care were vaginal bleeding (80%) and uterine cramps (78%). Only 8% of the women reported vomiting and diarrhea. Morbidity among the 458 women included heavy bleeding (19%) (1% required blood transfusion), infection (17%), curettage required (85%), uterine perforation after curettage (1%), and systemic collapse (1%). In Fortaleza, Brazil, misoprostol use accounted for 444 (75%) of 593 incomplete abortions treated in a hospital by uterine evacuation during 1991 (12). Complications observed in the 444 women included 144 (32%) with infection, 1 with septic shock, 3 with hypovolemic shock, and 1 with uterine perforation.

A 1992 report from Brazil questioned the teratogenicity of misoprostol (13). Since 1990, 29 women had contacted a teratogen information counseling service after unsuccessful attempts at inducing abortion with misoprostol during the 1st trimester. The mean dose used by these women was 4000 g (20 tablets), with a range of 200 g (one tablet) to 11,200 g (56 tablets). The women were monitored with ultrasonography during the remainder of their pregnancies. The results of the pregnancies were spontaneous abortions (2nd trimester)3; still pregnant3; lost to follow-up6; normal infants17 (one with preauricular tag). Of the 17 normal infants, 8 were examined by the authors, 4 were examined by pediatricians not associated with the authors, and in 5 cases verbal information was received from the mothers (13). The absence of data for the 9 (31%) cases, however, lessens the ability to interpret this report.

Seven cases of limb defects involving the hands and feet following 1st-trimester use of misoprostol (dose range 6001800 g) as an unsuccessful abortifacient were described in a 1993 report (14). Four of the infants demonstrated bilateral palsy of cranial nerves, leading to a diagnosis of Mbius sequence (6th and 7th nerve palsies). An additional five cases (one with limb deficiency, one with limb deficiency and Mbius sequence, and three with Mbius sequence) following failed abortion attempts with misoprostol were appended to the report, but specific details were not given. In the seven pregnancies with sufficient detail, misoprostol exposure was thought to have occurred between 30 and 60 days following conception. The investigators attributed the anomalies to misoprostol-induced vascular disruption (14). In a 1993 invited editorial on the strengths and weaknesses of case reports, the publication of the above research was thought to be valid because the association with birth defects was biologically plausible and there were other reports supporting a causal association (15).

A brief report (16) and abstract (17) suggested that a possible mechanism for Mbius syndrome was flexion of the embryo in the area of cranial nuclei 6 and 7 that resulted in vascular disruption of the region bent. The cranial nuclei 6 and 7 are located in a region of the embryo that would be bent if there was pressure in a cephalocaudal direction. The hypothesis proposed that flexing of the region would result in decreased blood flow and hemorrhage and/or cell death of the cranial nuclei. It was hypothesized that misoprostol-induced uterine contractions early in gestation, before there was sufficient amniotic fluid to cushion the embryo, would cause the flexing if the embryo was correctly positioned. Experiments in rat embryos confirmed that hemorrhage would occur in this region after mechanical flexion in the proposed direction. Although limb reduction defects are often associated with Mbius syndrome and may also be due to mechanical factors, the author’s hypothesis could not reasonably explain these defects (16,17).

A 1998 study (18) and earlier abstract (19) compared the frequency of 1st-trimester misoprostol use in 96 infants with Mbius syndrome with 96 infants with neural tube defects (NTD). In the 96 infants with Mbius syndrome, there were no differences in the clinical appearance between those exposed to misoprostol (N=47; 46 for attempted abortion) and those not exposed (N=49): bilateral facial-nerve (cranial nerve 7) paralysis, 34 vs. 36; unilateral facial-nerve paralysis, 13 vs. 13; abducens-nerve (cranial nerve 6) paralysis, 39 vs. 37; other cranial nerve palsy, 10 vs. 8; all limb defects, 31 vs. 28; club feet only, 25 vs. 18; limb reduction, 6 vs. 10; orofacial anomalies, 18 vs. 11; mental retardation, 26 vs. 26; other defects, 15 vs. 14 (all n.s.). Misoprostol was used in 47 cases of Mbius syndrome and 3 cases of NTD (odds ratio 29.7, 95% confidence interval [CI] 11.676.0). Among the 47 cases of misoprostol use, 20 took the drug orally, 20 took it both orally and vaginally, 3 took it vaginally only, and 4 could not recall how they took the drug. The authors concluded that attempted abortion with misoprostol was associated with an increased risk of Mbius syndrome (18,19).

A 1994 abstract reported a case of a woman who took misoprostol 600 g/day for 2 days at 7 weeks’ gestation in an unsuccessful attempt to induce abortion (20). An elective abortion at 17 weeks’ gestation revealed a male fetus with an omphalocele, left leg below-the-knee amputation, absence of the middle and distal phalanges of four fingers of the right hand with distal fusion by amniotic band, and evidence of early amniotic rupture. Although the mother had had chicken pox at 12 weeks, there was no evidence in the placenta or fetus of viral infection.

The Latin-America Collaborative Study of Congenital Malformations found 12 misoprostol-exposed newborns among 5,708 malformed and 5,708 nonmalformed matched controls (21). Each of the exposures involved unsuccessful attempts by the women to induce abortion. Four of the infants were in the control group, but the maternal dose (1000 g) was known in only one case. Of the eight exposed infants, two had Down syndrome (doses 1400 g and 4000 g) and two had minor anomalies (caf-au-lait spot on right leg, dose 600 g; extranumerary nipple on left, dose 400 g). These cases do not appear to be related to misoprostol. In the remaining four infants, the authors characterized the defects as suggestive of misoprostol-induced in utero vascular disruption (maternal dose shown in parenthesis) (21): Missing metacarpals and phalanges; hypoplasia of thumbs and two fingers; partial syndactyly of two fingers; peculiar face with prominent nasal bridge and ocular hypertelorism; weak cry (400 g) Complete bilateral cleft lip and palate; ocular hypertelorism; short limbs; absence of thumbs and 5th fingers; skin tags on one finger; stiff knees; bilateral talipes equinovarus (dose unknown) Skin scar over T2T3; no evidence of spina bifida by x-ray (dose unknown) Gastroschisis (1400 g) In a second report from the above group, they found 57 newborn infants exposed to misoprostol among 9,653 newborns; 34 in 4,673 malformed infants and 23 in 4,980 control infants (n.s.) (22). In comparing exposed vs. nonexposed malformed infants, significant differences were measured for four vascular disruption malformations that had been reported by others: arthrogryposis (5.88% vs. 0.73%), hydrocephalus (11.76% vs. 3.04%), terminal transverse limb reduction (8.82% vs. 0.67%), and limb constriction ring or skin scars (8.82% vs. 0.24%). No cases of cranial nerve palsies (e.g., Mbius sequence) were in the registry because these types of defects would not be obvious at birth. Significant associations with two other malformations that had not been reported previously were holoprosencephaly (5.88% vs. 0.34%) and bladder exstrophy (2.94% vs. 0.06%). However, the authors recommended caution in interpreting these latter defects as causal associations. They concluded that there was a causal association between the four vascular disruption defects and the use of misoprostol as an abortifacient (22).

Of note, a 1996 report provided detailed descriptions of three cases of arthrogryposis (i.e., arthrogryposis multiplex congenita; the use of the shorter term, arthrogryposis, implies multiple, nonprogressive congenital joint contractures) after failed mechanical attempts at pregnancy termination (23). The cause of the defect was thought to be vascular disruption resulting in nerve damage that led to fetal akinesia and subsequent contractures (23).

A relative risk of >7.0 for congenital malformations, particularly Mbius sequence, was found among 732 children born after 1990 who were attending five outpatient genetic clinics in Brazil (24). About 10% of the children had been exposed in utero to misoprostol. There were 25 cases of Mbius syndrome, 24 cases of reduction of phalanges, and 227 cases with isolated malformations. Associations with misoprostol occurred in 17 (68%), 7 (29%), and 15 (6.6%), respectively, of the cases (24).

A below-the-knee amputation was observed in a female newborn delivered at 29 weeks’ gestation because of fetal distress (25). An abortion had been attempted at about 13 weeks’ under medical supervision. A single misoprostol tablet (strength not specified) had been inserted vaginally for 4 days, but only some vaginal bleeding had occurred on day 4. Spontaneous rupture of the membranes was documented at about 26 weeks’ gestation (25).

A 1998 study proposed that the abnormalities observed in children exposed in utero during the 1st trimester to misoprostol were induced by uterine contractions that caused vascular disruption in the fetuses, including ischemia of the brain-stem (26). Of the 42 infants with congenital malformations, 17 had equinovarus with cranial nerve defects (usually of nerves 5, 6, and 7), 10 had equinovarus as part of a more extensive arthrogryposis, and 9 had terminal transverse-limb defects. Five children had a distinctive arthrogryposis, without cranial nerve injury, that was confined to the legs. Severe amyoplasia of the legs was confirmed in five children by electromyography, and two of the cases had deficient anterior horn cell activity. Eight had hydrocephalus associated with increased pressure that required shunt placement to relieve. One child had an omphalocele, but no evidence of cranial nerve defects of arthrogryposis (26).

A 1997 abstract and 1999 full report described a prospective, observational cohort study of 86 misoprostol-exposed pregnancies compared with 86 pair-matched controls (27,28). All of the women had called a teratogen information service regarding pregnancy exposure to either misoprostol or nonteratogenic agents. There were no statistical differences between the groups in the rates of major (2/67 vs. 2/81) or minor (7/67 vs. 3/81) malformations, gestational age at birth, prematurity, birth weight, low birth weight, sex ratio, or rates of cesarean section. However, there were more abortions in the exposed group, 17.1% vs. 5.8%, relative risk 2.97, 95% CI 1.127.88. The sample size had limited power as it was only able to detect an eight-fold increase in the risk of major malformations (28).

A study published in 2000 reported the clinical evaluations of 15 children (8 males, 7 females; average age 2 years) from Salvador and Brazil with misoprostol-induced arthrogryposis (29). Their mothers had taken 4004800 g of misoprostol, orally or vaginally, from 8 to 12 weeks’ gestation for attempted abortions. Common pathologic features in the children were growth retardation, underdeveloped bones, short feet with equinovarus, rigidity of joints with skin dimples and webs, neurologic impaired leg movement, bilateral symmetrical hypoplasia or atrophy of limb muscles, and absent tendon reflexes. Twelve had normal intelligence (information not available for the other three). Other abnormalities included neurogenic bladder/bowel (N=9), hip dislocation (N=6), upper and lower limb deformity (N=5), cryptorchidism (N=2), inguinal hernia (N=2), and single cases of medullar stenosis/syringomyelia, spina bifida, abdominal muscle hypoplasia, and nail hypoplasia. Neurogenic patterns suggestive of anterior horn cell defects were observed on electromyogram in five children (29).

In another 2000 report, a multicenter, case-control study compared the frequency of misoprostol exposure in 93 children with vascular disruption anomalies (subjects) and 279 children with other types of defects (controls) (30). All of the children were born after 1992. Congenital malformations classified as vascular disruptions in the subject cases were Mbius syndrome (N=29), transverse limb reduction (N=27), hemifacial microsomia (N=16), arthrogryposis (N=9), microtia (N=9), porencephalic cyst (N=2), and hypoglossia hypodactyly (N=1). Misoprostol exposure (all for attempted abortion) occurred in 32 subject cases (34.4%) compared to 12 controls (4.3%), p
A case of maternal misoprostol overdosage resulting in fetal death was reported in 1994 (31). In a suicide attempt, a 19-year-old woman at 31 weeks’ gestation ingested 6000 g (thirty 200-g tablets) and 8 mg of trifluoperazine. She was seen 2 hours later at a hospital complaining of feeling hot, chills, shortness of breath, restlessness, and discomfort. A tetanic uterus was observed, and physical examination revealed her cervix to be dilated to 5 cm with 80% effacement. Fetal movements and heart motion (by sonogram) were absent 1 hour after admission (3 hours after ingestion), and 1 hour later she delivered a stillborn 1800-g fetus that was diffusely ecchymotic. Postmortem examination was remarkable only for diffuse head and upper body bruising (31).

Misoprostol has been used for the induction of labor in cases involving intrauterine fetal death (IUFD) or when medical or genetic reasons existed for pregnancy termination (32,33 and 34). In 20 cases of IUFD, pregnancy termination occurred a mean 9.2 hours after the start of oral misoprostol, 400 g every 4 hours (mean total dose 1000 g) (32). Maternal adverse effects were common. A second study, involving 72 women with IUFD at 1840 weeks’ gestation, used a lower dose (100 g; one-half of an oral 200-g tablet) introduced into the vaginal posterior fornix every 12 hours (up to 48 hours) until effective contractions and cervical dilatation were obtained (33). Only 6 women (8%) required treatment between 24 and 48 hours and all had delivered within 48 hours (mean 12.6 hours; range 248 hours). None of the women required surgical intervention. Other than one case of abruptio placentae, no complications were observed. A dose of 200 g, also administered vaginally, was used in a third study, with a comparison group receiving a 20-mg prostaglandin E2 (PGE2) vaginal suppository every 3 hours (34). Successful abortions were obtained within 24 hours in 89% (25 of 28) of women treated with misoprostol and in 81% (22 of 27) of women administered PGE2 (n.s.). The remaining three misoprostol-treated women had successful abortions within 38 hours (similar data for PGE2 were not given). Complete abortions (passage of the fetus and the placenta simultaneously) occurred in 43% and 32% of the misoprostol- and PGE2-treated groups, respectively. Significantly more women experienced adverse effects (pyrexia, uterine pain, vomiting, and diarrhea) with PGE2 than with misoprostol, and the difference in average cost between the treatments was large ($315.30 for PGE2 versus $0.97 for misoprostol). Two other studies have described the use of intravaginal misoprostol (200800 g) to successfully induce legal abortion at gestational ages ranging from 11 to 23 weeks (35,36).

Several reports and communications have described the use of misoprostol for cervical ripening and labor induction in the 3rd trimester (37,38,39,40,41,42 and 43). The doses used were 50100 g administered either as a single dose or at 4-hour intervals, but one group of investigators was studying a 25-g dose (42). Tachysystole was observed in some cases, but the uterine hyperstimulation was not associated with an increased incidence of fetal distress or a higher rate of operative deliveries. The American College of Obstetricians and Gynecologists considers low-dose (e.g., 25 g) intravaginal misoprostol to be effective for inducing labor in pregnant women who have unfavorable cervices (44,45).

In summary, the prostaglandin E1 analogue misoprostol is a potent uterine stimulant that induces abortion after either oral or vaginal administration early in pregnancy. The drug has been used as an illicit abortifacient, and most cases of birth defects have been associated with abortion attempts. However, congenital malformations have also been associated with the therapeutic use of the drug. The teratogenic mechanism appears to be related to the induction of uterine contractions that deform the embryo, resulting in vascular disruption, hemorrhage, and cell death. Some authors consider the potential teratogenicity of misoprostol following an unsuccessful abortion attempt a reason to proceed cautiously with the use of the drug for this purpose, particularly in countries with limited medical services (46). Investigational and clinical use during the 2nd and 3rd trimesters have demonstrated the utility of misoprostol for labor induction and cervical ripening. Misoprostol appears to be superior, in terms of maternal morbidity and cost, to PGE2 when used for 2nd-trimester pregnancy terminations and for cervical ripening.

Breast Feeding Summary

No studies evaluating the passage of misoprostol or its active metabolite, misoprostol acid, into milk have been located. The manufacturer considers the drug to be contraindicated during nursing because of the potential for severe, drug-induced diarrhea in the nursing infant (1). Natural occurring PGE1, however, is excreted into milk in concentrations similar to that in maternal plasma and may have an important function (e.g., cytoprotection) in the gastrointestinal tract of the nursing infant (47).



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