Congenital abnormalities in Brazilian children associated with misoprostol misuse in first trimester of pregnancy

doi:10.1016/S0140-6736(97)12363-7

The Lancet

Volume 351, Issue 9116, 30 May 1998, Pages 1624-1627

https://doi.org/10.1016/S0140-6736(97)12363-7 Get rights and content

Summary

Background

Misoprostol is commonly used to induce abortion in Brazil, and in other countries in South and Central America where abortions are illegal. However, misoprostol is not very effective in inducing abortions, and exposure to the drug in utero can cause abnormalities in the fetus. We aimed to define the common phenotypical effects of exposure to the drug.

Methods

We studied 42 infants from São Paulo, Brazil, who were exposed to misoprostol during the first 3 months of gestation, and then born with congenital abnormalities. We interviewed each of the infants' mothers to find out about misoprostol exposure and dosage. Each infant was physically examined by a geneticist or a neuropaediatrician.

Findings

17 of the infants had equinovarus with cranial-nerve defects. Ten children had equinovarus as part of more extensive arthrogryposis. The most distinctive phenotypes were arthrogryposis confined to the legs (five cases) and terminal transverse-limb defects (nine cases) with or without Möbius sequence. The most common dose of misoprostol taken was 800 μg (range 200–16000 μg).

Interpretation

Deformities attributed to vascular disruption were found in these children. We suggest that the uterine contractions induced by misoprostol cause vascular disruption in the fetus, including brain-stem ischaemia. Information on the effects of taking misoprostol during pregnancy should be made more widely available, to dissuade women from misusing the drug.

Introduction

In Brazil, and in other countries in South and Central America, misoprostol, a synthetic analogue of prostaglandin E, is commonly used to induce abortion.1, 2, 3, 4, 5 Abortion is illegal in Brazil, except in cases of rape or incest, or when the mother's life is in danger. The demand for illegal abortions is high, and misoprostol can be bought from pharmacies and on the black market. However, misoprostol is not very effective at inducing abortion, and exposure to misoprostol in utero can cause abnormalities in the fetus. Thus, exposure to this teratogen is common in Brazil.

Misoprostol (Cytotec, Searle do Brasil) is marketed for treatment of upper-gastrointestinal damage caused by non-steroidal anti-inflammatory drugs. The manufacturer's label states that misoprostol is contraindicated for use in pregnant women, since it has uterotonic effects.⁶ Publicity about the illegal use of misoprostol contrary to the manufacturers' instructions has led to the imposition of restrictions, and an 80% decrease in sales of the drug.⁴ However, misoprostol is still available through illegal sources.

The first report of fetal damage from the unsuccessful use of misoprostol to induce abortion described unusually large lateral defects of the scalp and cranium in five infants.³ Gonzalez and colleagues⁷ reported seven children with terminal transverse-limb defects. These defects were commonly associated with cranial-nerve defects, also known as Möbius syndrome. Since case reports cannot prove a causal link between in-utero exposure to misoprostol and birth defects, systematic studies are needed to identify the phenotypic effects of misoprostol and to define the period of greatest sensitivity to the drug during pregnancy. Unfortunately, use of misoprostol to induce abortion is illegal and difficult to confirm, and therefore systematic studies are not easy to do.

We report on a consecutive series of infants and children with birth defects, at one large referral hospital, in whom exposure to misoprostol was confirmed by the mother's reports.

Section snippets

Methods

We studied a consecutive sample of 42 misoprostol-exposed infants with any type of birth defect who were assessed by a geneticist or a neuropaediatrician at the Instituto da Crianca do Hospital das Clinicas, Faculty of Medicine, University of São Paulo, between May, 1992, and April, 1997. Assessment included a family history and a pregnancy history, which noted exposures, to known teratogens and abortifacients, including misoprostol. Case-histories were taken more than once during the

Results

The most common misoprostol phenotype (table), equinovarus with cranial-nerve deficiencies (most commonly of nerves V, VI, and VII), was seen in 17 of the children studied. Ten children had equinovarus as part of a more extensive arthrogryposis, in some with amyoplasia. The most distinctive type of arthrogryposis, without associated cranial-nerve defects, was confined to the legs in five of the children (figure 1).

Terminal transverse-limb defects included shortness or absence of one or more

Discussion

Abnormalities observed in children exposed to misoprostol in utero have previously been associated with vascular anomalies, and have been attributed to vascular disruption. For example, Sodre and colleagues⁹ found by angiography and doppler flow analysis of 30 children that equinovarus was associated with hypoplasia or premature termination of the anterior tibial artery and the middle plantar arteries. Bouwess-Bavinck and Weaver¹⁰ suggested that vascular disruption was the potential basis for

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Cited by (213)

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Teratogenicity and Reactive Oxygen Species after transient embryonic hypoxia: Experimental and clinical evidence with focus on drugs with human abortive potential.
Reactive Oxygen Species (ROS) can be harmful to embryonic tissues. The adverse embryonic effects are dependent on the severity and duration of the hypoxic event and when during organongenesis hypoxia occurs. The vascular endothelium of recently formed arteries in the embryo is highly susceptible to ROS damage. Endothelial damage results in vascular disruption, hemorrhage and maldevelopment of organs, which normally should have been supplied by the artery. ROS can also induce irregular heart rhythm in the embryo resulting in alterations in blood flow and pressure from when the tubular heart starts beating. Such alterations in blood flow and pressure during cardiogenesis can result in a variety of cardiovascular defects, for example transpositions and ventricular septal defects. One aim of this article is to review and compare the pattern of malformations produced by transient embryonic hypoxia of various origins in animal studies with malformations associated with transient embryonic hypoxia in human pregnancy due to a failed abortion process. The results show that transient hypoxia and compounds with potential to cause failed abortion in humans, such as misoprostol and hormone pregnancy tests (HPTs) like Primodos, have been associated with a similar spectrum of teratogenicity. The spectrum includes limb reduction-, cardiovascular- and central nervous system defects. The hypoxia-ROS related teratogenicity of misoprostol and HPTs, is likely to be secondary to uterine contractions and compression of uterinoplacental/embryonic vessels during organogenesis.
How Risky Are Risk Factors? An Analysis of Prenatal Risk Factors in Patients Participating in the Congenital Upper Limb Differences Registry
2022, Journal of Hand Surgery Global Online
Risk factors for congenital upper limb differences (CoULDs) are often studied at the general population level. The CoULD registry provides a unique opportunity to study prenatal risk factors within a large patient sample.
All patients enrolled between June 2014 and March 2020 in the prospective CoULD registry, a national multicenter database of patients diagnosed with a CoULD, were included in the analysis. We analyzed self-reported, prenatal risk factors, including maternal smoking, alcohol use, recreational drug use, prescription drug use, gestational diabetes mellitus (GDM), and gestational hypertension. The outcome measures included comorbid medical conditions, proximal involvement of limb difference, bilateral involvement, and additional orthopedic conditions. Multivariable logistic regression was used to analyze the effect of the risk factors, controlling for sex and the presence of a named syndrome.
In total, 2,410 patients were analyzed, of whom 72% (1,734) did not have a self-reported risk factor. Among the 29% (676) who did have at least 1 risk factor, prenatal maternal prescription drug use was the most frequent (376/2,410; 16%). Maternal prescription drug use was associated with increased odds of patient medical comorbidities (odds ratio [OR] = 1.43, P = .02). Gestational diabetes mellitus was associated with increased odds of comorbid medical conditions (OR = 1.58, P = .04), additional orthopedic conditions (OR = 1.51, P = .04), and proximal involvement (OR = 1.52, P = .04). Overall, reporting 1 or more risk factors increased the odds of patient comorbid medical conditions (OR = 1.42, P < .001) and additional orthopedic conditions (OR = 1.25, P = .03).
Most caregivers (72%) did not report a risk factor during enrollment. However, reporting a risk factor was associated with patient medical and orthopedic comorbidities. Of note, GDM alone significantly increased the odds of both these outcome measures along with proximal limb differences. These findings highlight the ill-defined etiology of CoULDs but suggest that prenatal risk factors, especially GDM, are associated with a higher degree of morbidity.
Prognostic III.
Pregnant women, prescription, and fetal risk
2020, Handbook of Clinical Neurology
Since the historical scandal of thalidomide in the 1960s, practitioners and future mothers are fearful of drugs during pregnancy. In-uterine exposure to drugs can induce major malformation of the fetus or even intrauterine fetal death. Prescribing drugs to a pregnant woman requires particular attention, and it is necessary to consider both the maternal needs and the proven and potential fetal risks. In this chapter, we review the mechanisms for medication transfer from mother to fetus, fetal risk according to pregnancy timeline, and the main dangerous drugs during pregnancy. We also focus on three prescription debates, which are relevant for neurodevelopmental disorder, because they each point to a paradigmatic situation—diethylstilbestrol, which shows transgenerational adversary effects; valproate, which impacts neurodevelopment as a whole; and antidepressants for which the adverse impact on neurodevelopment is still controversial given the impact of depression itself. Finally, we consider the implications for practice and toxicologic research to promote risk prevention.
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To investigate the distinguishing morphological characteristics of the upper extremities in children with Möbius syndrome.
Twenty-seven involved extremities in 14 patients with a diagnosis of Möbius syndrome were identified at 2 institutions. Medical records, radiographs, and clinical photographs were evaluated. Congenital hand differences were classified according to the Oberg, Manske, and Tonkin classification, and hands with symbrachydactyly were classified by the Blauth and Gekeler classification. The presence of other congenital anomalies was catalogued.
There was bilateral involvement in 93% of patients with congenital hand anomalies. Twelve patients demonstrated congenital hand anomalies and 2 patients had been diagnosed with arthrogryposis. Among the 12 patients with congenital hand anomalies, 21 hands were classifiable as symbrachydactyly by the Oberg, Manske, and Tonkin classification and could be categorized by the Blauth and Gekeler classification. Short finger type was the most common subtype of symbrachydactyly, present in 13 hands. Eleven of these 13 patients (85%) were primarily affected on the radial side of the hand. Proximal arm involvement was identified in 2 patients with symbrachydactyly, both of whom had Poland syndrome and an absent pectoralis major.
Symbrachydactyly in Möbius syndrome differs from the typical presentation of symbrachydactyly. Characteristically, there is a bilateral presentation with a strong predilection for radially based brachydactyly. These described characteristics may help the hand surgeon appropriately assess patients, especially those with radial-sided symbrachydactyly.
Diagnostic III.
Isolated Antenatal Hydrocephalus After Fetal Exposure to Misoprostol: Teratogenic Effect of the Cytotec?
2019, World Neurosurgery
Misoprostol is often used for termination of pregnancy in France and other countries. However, some pregnancies are continued after taking the drug and congenital malformations are known to be the consequence of fetal exposure to misoprostol, among them hydrocephalus. The type of hydrocephalus in case of misoprostol exposure is not known.
We report the first case in the literature of an obstructive hydrocephalus due to an aqueduct of Sylvius stenosis diagnosed during pregnancy after misoprostol intake.
The possible physiopathologic implications of the drug regarding the genesis of this malformation are discussed.
Teratology
2019, Fetal Medicine: Basic Science and Clinical Practice

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Early ReportCongenital abnormalities in Brazilian children associated with misoprostol misuse in first trimester of pregnancy

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Results

Discussion

Lancet

Lancet

Lancet

Lancet

Contraception

J Pediatr

Lancet

Lancet

J Pediatr

Misuse of misoprostol

Lancet

Limb deficiency with or without Mobius sequence in seven Brazilian children associated with misoprostol use in the first trimester of pregnancy

Am J Med Genet

Early Report
Congenital abnormalities in Brazilian children associated with misoprostol misuse in first trimester of pregnancy