Misoprostol exposure during the first trimester of pregnancy: Is the malformation risk varying depending on the indication?

OBJECTIVE: To report the prospective follow-up of pregnancies exposed to misoprostol during the first trimester and analyse the teratogenic risk depending on the indication for use. STUDY DESIGN: Prospective observational study of 265 women exposed to misoprostol during the first 12 weeks of pregnancy and followed until the delivery. Women were included if they or their physician had contacted a French pharmacovigilance centre before 22 weeks of gestation (WG) to obtain information on the risk of misoprostol exposure, and if there had been misoprostol exposure before 13 WG. Data were collected at the time of the first contact, and the pregnancy outcome was recorded at follow-up. Women were prospectively enrolled from January 1988 to December 2013. RESULTS: The main indication for misoprostol was voluntary abortion (60.9%). Ten major malformations (5.5%) (95% CI 2.65-9.82%) were reported and five of them were consistent with the pattern of malformations attributed to misoprostol: Möbius sequence, hydrocephalus, terminal transverse limb reduction associated with a clubfoot, syndactyly, and complete posterior encephalocele. The rate of malformations was higher, but not significantly, in women exposed to misoprostol for voluntary abortion (7.9%) compared with women exposed to misoprostol for other or unknown indications (3.2%). CONCLUSIONS: Our results confirmed a specific pattern of malformations due to misoprostol use in early pregnancy, even with low dose of misoprostol. Despite the small number of cases, we observed a higher proportion of major malformations in fetuses born to women who continued their pregnancy after a failed voluntary abortion with misoprostol. Further studies should be conducted to evaluate other potential factors, such as combination treatment with mifepristone and the socio-environmental characteristics in this group of women.

Síndrome de Moebius, comunicación interventricular asociado a exposición prenatal a misoprostol / Moebius Syndrome, ventricular septal defect due to prenatal exposure to misoprostol

Introducción: El síndrome o secuencia de Moebius se caracteriza por la afectación del nervio facial y nervio abducens y puede estar asociado a defectos congênitos orofaciales y de las extremidades. Adicionalmente en las dos últimas décadas se han reortada una posible asociación con exposición prenatal a misoprostol. Objetivo: Presentar un caso de síndrome de Moebius con cardiopatía compleja (comunicación interventricular y pseudocoartación de aorta) asociado a exposición prenatal a misoprostol. Caso clínico: Paciente de 5 años quien consulta por antecedente de retardo en el desarrollo psicomotor, anomalías craneofaciales, cardiacas y de las extremidades, con antecedente de exposición prenatal a misoprostol, a quien se le diagnóstica síndrome de Moebius. Conclusiones: Aunque la etiología de este síndrome no es clara, un mecanismo fisiopatológico involucrado es el de la hipoxia que puede ser secundario a la exposición prenatal a misoprostol.

Introduction: Moebius syndrome/sequence is characterized by facial and abducens nerve damage and may be associated with congenital orofacial and limb defects. Additionally, in the last two decades, a possible association with prenatal exposure to misoprostol has been reported. Objective: To present a case of Moebius Syndrome with complex heart disease (ventricular septal defect and pseudocoarctation of the aorta) associated with prenatal exposure to misoprostol. Case report: A 5 year old patient diagnosed with Moebius Syndrome who consulted specialists due to psychomotor retardation, craniofacial, heart and limb defects, and with a history of prenatal exposure to misoprostol is presented. Conclusions: Although the etiology of this syndrome is not clear, hypoxia is a pathophysiological mechanism involved, which can be secondary to prenatal exposure to misoprostol.

Birth defects after exposure to misoprostol in the first trimester of pregnancy: prospective follow-up study.

Misoprostol during the first trimester of pregnancy is associated with a specific malformative pattern (Moebius sequence and limb defects) whose incidence remains unknown. Data originate mostly from illegal use for abortion and are mainly retrospective. The present prospective controlled study analyses outcomes of first trimester misoprostol exposures after medical prescriptions. Malformation rate was higher among 236 pregnancies exposed before 12 gestational weeks (4%) than in 255 controls (1.8%), although not statistically significant (OR=2.2 [95% CI=0.6-7.7]). Three malformations (2%) in the exposed group were consistent with the misoprostol malformative pattern. This is the largest prospective study on first trimester misoprostol exposure and the first one relying on prescriptions. A trend toward a doubling of the overall rate of malformations was observed and for the first time an estimation of the incidence of misoprostol specific spectrum is proposed (2%). Brainstem injuries including severe trismus might be added to this specific pattern.

[Abortion and misoprostol: health practices and scientific controversy]. / Aborto e misoprostol: usos médicos, práticas de saúde e controvérsia científica.

This article puts into perspective the controversy between the association of the use of misoprostol for abortion and teratogenicity studies of the type found in a case report. The use of herbal medicinal drugs and the medical-obstetric and national and international norms governing the registration and circulation of pharmaceutical products were examined. Official documents of ANVISA, the Ministry of Health and the World Health Organization on the use of misoprostol, as well as 68 articles such as case reports published in national journals, linking abortion, misoprostol and teratogenicity were reviewed, systematically filed and analyzed using the monographic method. The legal prohibition of abortion prevents the proper prescription and use of a drug such as misoprostol that is both safe and effective. Thus, the danger for the health of women is linked not to the intrinsic characteristics of the drug, but to the moral arguments that constitute negligence and disregard for the fundamental rights of women.

Aborto e misoprostol: usos médicos, práticas de saúde e controvérsia científica / Abortion and misoprostol: health practices and scientific controversy

Este artigo coloca em perspectiva a controvérsia entre a associação do uso de misoprostol para aborto e teratogenicidade, encontrada em estudos do tipo relato de caso, e a consagração do uso de medicamentos à base do fármaco na área médico-obstétrica e em documentos normativos nacionais e internacionais que regulam o registro e a circulação de produtos farmacêuticos. Através do método monográfico, foram revisados, sistematizados e analisados documentos oficiais da Anvisa, Ministério da Saúde e Organização Mundial da Saúde sobre o uso do misoprostol, bem como 68 artigos do tipo relato de casos clínicos, publicados em periódicos científicos nacionais, que associam aborto, misoprostol e teratogenicidade. A interdição legal do aborto impede a prescrição e o uso adequados de uma droga que produz efeitos eficazes e seguros como o misoprostol. Assim, o grande malefício à saúde de mulheres está ligado não a características intrínsecas ao fármaco, mas a argumentos morais que representam descaso e desrespeito aos direitos fundamentais de mulheres.

This article puts into perspective the controversy between the association of the use of misoprostol for abortion and teratogenicity studies of the type found in a case report. The use of herbal medicinal drugs and the medical-obstetric and national and international norms governing the registration and circulation of pharmaceutical products were examined. Official documents of ANVISA, the Ministry of Health and the World Health Organization on the use of misoprostol, as well as 68 articles such as case reports published in national journals, linking abortion, misoprostol and teratogenicity were reviewed, systematically filed and analyzed using the monographic method. The legal prohibition of abortion prevents the proper prescription and use of a drug such as misoprostol that is both safe and effective. Thus, the danger for the health of women is linked not to the intrinsic characteristics of the drug, but to the moral arguments that constitute negligence and disregard for the fundamental rights of women.

What can we learn from the thalidomide experience: an ophthalmologic perspective.

PURPOSE OF REVIEW: The thalidomide tragedy of the early 1960s resulted in a great number of studies and reports involving many specialties of medicine. Because of the estimated large number of affected children (5000+) worldwide exposed to this potent teratogen, and the many informative cases in which the exposure time was known, a teratogenic timetable was constructed relating affected structures to the time of exposure. This demonstrated that thalidomide had a teratogenic effect between approximately 20 to 36 days after fertilization. RECENT FINDINGS: We found that Duane syndrome and its variants were prominent in individuals who were exposed to thalidomide early in the sensitive period (days 20 to 26±). Other anomalies associated with this early effect were aberrant tearing, facial nerve palsy, ear malformations, and autism. Structural eye malformations were less frequent in this early phase, appearing slightly later in the sensitive period. SUMMARY: This study summarizes the ophthalmologic findings from a number of studies and compares them with respect to the implications of time of exposure. Because the timing of anomalies such as external ear and limb malformations are well established in the thalidomide literature, correlation with associated eye anomalies gives insight into the approximate timing of the causative teratogen exposure.

Moebius syndrome and holoprosencephaly following exposure to misoprostol.

Moebius syndrome is a rare disease characterized by congenital facial paralysis and abducens palsy. Involvement of other cranial nerves, orofacial dysmorphism, and limb abnormalities are frequently associated. Reported here is the case of a 10-month-old child born with Moebius syndrome and presenting with holoprosencephaly, following exposure in utero to misoprostol. To our knowledge, this is the first published case report describing this association. The etiologic hypotheses of Moebius syndrome are also discussed.

Thalidomide and misoprostol: Ophthalmologic manifestations and associations both expected and unexpected.

Thalidomide is a very potent teratogen capable of causing severe systemic malformations if the fetus is exposed during the sensitive period. Although structural anomalies of the eye can occur from thalidomide exposure, the most frequent eye complication is secondary to damage to the cranial nuclei in the brain stem, resulting in aberrant neurologic connections causing a condition of abnormal ocular movement, Duane syndrome. A less frequent anomalous neurologic complication is tearing when eating (paradoxical gustolacrimal tearing or "crocodile tears") or lack of emotional tearing. The involvement of the 6th and 7th cranial nerves, often seen together in the thalidomide-affected individual, is also characteristic of Möbius syndrome/sequence. This syndrome usually occurs sporadically, but characteristic findings of this condition have also been observed in South American children who were born after an unsuccessful attempt to induce abortion with the prostaglandin drug misoprostol (Cytotec). Aberrant tearing also occurs in some individuals with Möbius syndrome. Autism spectrum disorder (ASD), an unexpected associated finding in a Swedish thalidomide study, is now also noted in Möbius studies, in patients both with and without exposure to misoprostol.

Misoprostol and pregnancy: risk of malformations.

(1) Misoprostol, a synthetic prostaglandin E1 analogue, is used to treat gastric and duodenal ulcers, and, in combination with mifepristone, for medical abortion. (2) The French and American summaries of product characteristics, based on data submitted to the relevant regulatory agencies, mention no teratogenicity in animals. However, some studies showed malformations in rats and rabbits. (3) Severe malformations have been reported in countries where misoprostol is frequently used for abortion without medical supervision despite its poor efficacy when used alone. The malformations included cranial nerve defects (especially pairs 6 and 7, characteristic of the Möbius syndrome) and various limb abnormalities. (4) Malformations, including one case of Möbius syndrome, have been reported in France after medically supervised use of misoprostol. (5) In practice, when a patient wishes to continue a pregnancy after a failed attempt at drug-induced abortion, she needs to be informed of the risk to her unborn child. Cranial nerve defects are rarely detectable by sonography, however thorough. In addition, misoprostol has a negative risk-benefit balance in the prevention or treatment of gastro-duodenal ulcers in young women.

Möbius syndrome in a neonate after mifepristone and misoprostol elective abortion failure.

OBJECTIVE: To report a case of a child born with Möbius syndrome following exposure in utero to mifepristone and misoprostol for elective abortion. CASE SUMMARY: In the seventh week of pregnancy, a woman was administered mifepristone 600 mg and, 2 days later, misoprostol 400 mug for abortion. One month later, despite significant metrorrhagia, an ultrasound examination showed ongoing gestation. At 33 weeks and 3 days of gestation, the woman gave birth to a male with left facial palsy, microretrognathia, and axial hypotonia related to Möbius syndrome. DISCUSSION: Möbius syndrome is characterized by unilateral or bilateral palsy of the abducens (VI) and facial (VII) cranial nerves. Other cranial nerves (eg, the hypoglossal [XII]), craniofacial or orofacial anomalies, and limb malformations are often associated. The etiology of the Möbius syndrome remains largely unknown and probably involves multiple factors. The most likely etiological hypothesis is disruption of the developing vascular system, with transient ischemia (particularly in the vertebral arteries) and fetal hypoxia. A teratogenic cause of Möbius syndrome has been suggested. The critical period for the development of Möbius syndrome following teratogen exposure appears to be 5-8 weeks of gestation. To date, mifepristone alone does not appear to have induced Möbius syndrome. In contrast, oral or vaginal misoprostol administration can lead to a significant increase in Doppler-measured uterine artery resistance and may induce uterine contractions. If these occur during the critical embryonic period, they may cause flexion in the areas of the sixth and seventh cranial nerves and decreased blood flow. CONCLUSIONS: Ineffective use of mifepristone and misoprostol in the first trimester of pregnancy may be associated with a risk of Möbius syndrome, primarily due to misoprostol activity. Women with ongoing pregnancy after failed abortion with misoprostol administration should be informed of this risk.

A incidência de anomalias ortopédicas em portadores da seqüência de Mõbius e sua associação com o uso do misoprostol / Prevalence of orthopedic abnormalities in patients with Mõbius: sequence and its association to the use of misoprostol

Objetivo: Descrever as anomalias ortopédicas em portadores de SM, investigando possível associação de tais alterações entre casos em que as mães não usaram misoprostol com outras em que a droga foi usada durante o primeiro trimestre de gravidez. Métodos: Foram analisados 42 portadores da SM, atendidos na Associação de Assistência à Criança Deficiente – Pernambuco, no período de 1999 a 2005. Entre os pacientes, 25 eram do sexo feminino e 17 do masculino. A idade no momento da pesquisa variou de oito meses a 15 anos e 11 meses, média de seis anos e um mês de idade. O diagnóstico da doença foi feito por equipe multidisciplinar formada por neuropediatra, oftalmologista, ortopedista e psicólogo. As mães dos investigados foram interrogadas quanto ao uso do misoprostol durante a gravidez. O estudo foi observacional, sendo descritos os achados ortopédicos de uma série de casos. Foi introduzido componente analítico para investigar se a freqüência de anomalias do aparelho locomotor estava ou não associada ao uso de misoprostol. Resultados: Das 42 mães desses pacientes, 25 (59,5%) utilizaram o misoprostol como abortivo durante o primeiro trimestre de gestação e 17 (40,5%) negaram ter usado abortivos durante a gestação. Houve acometimento do VI e do VII pares cranianos em todos os pacientes e do IX e do X pares, em 17 (40,5%). A associação com síndrome de Poland foi vista em um paciente e, com paralisia cerebral, em quatro. Entre os pacientes, 34 (80,9%) apresentaram alguma deformidade ortopédica, sendo o pé torto a mais comum. Conclusão: Anomalias ortopédicas foram observadas na grande maioria dos pacientes incluídos no estudo, sendo o pé torto congênito a mais encontrada. Não houve diferença estatisticamente significante entre a freqüência de anomalias ortopédicas em portadores da seqüência de Mõbius, filhos de mães que usaram misoprostol, quando comparadas com os casos em que a droga não foi usada

A case of Moebius syndrome presenting with congenital bilateral vocal cord paralysis.

We describe a female infant with bilateral facial paralysis and abducens palsy. To the best of our knowledge, this is the first report of Moebius syndrome presenting with congenital bilateral vocal cord paralysis (CBVCP). Although CBVCP can be part of a recognizable syndrome, i.e. Down syndrome, 22q deletion syndrome, Robinow's syndrome and cerebro-oculo-facio-skeletal syndrome, no reports of Moebius syndrome with CBVCP were found in the literature. CBVCP is often associated with central nervous system abnormalities. However, our patient had no detectable brain abnormalities. The etiology of Moebius syndrome remains unknown. It is interesting that the clinical manifestations of Moebius syndrome can include CBVCP. However, the pathophysiology of CBVCP is unknown and further investigations into the etiology of Moebius syndrome are required.

Embriopatías asociadas al uso de misoprostol / Moebius syndrome and arthrogriposis associated to the use of misoprostol

Se presenta un caso clínico de síndrome de Moebius y artrogriposis asociado al uso de misoprostol durante el primer trimestre de gestación.

We present a case of Moebius syndrome and arthrogriposis associated to the use of misoprostol during the first trimester of gestation.

Early dental management of patients with Mobius syndrome.

OBJECTIVE(S): The aim of this study was to evaluate the orofacial manifestations in patients with Mobius syndrome (MS), establish an early adequate dental treatment and discuss the possible etiology of all cases examined based on information about the gestational intercurrences. DESIGN: Prospective study. SETTING: Special Care Dentistry Center, School of Dentistry, University of Sao Paulo, Brazil. Subject(s) and methods: Twenty-nine patients with MS aged 0 to 4 underwent prospective dental examination as well as early orthodontic treatment. RESULTS: All patients presented micrognathia, lack of lip seal, high arched palate and weak soft palate. The use of orthopedic appliances was recommended to all 29 patients, but only 13 adhered to treatment and were monitored for at least 24 months. We observed that, after 24 months of treatment, the palate was expanded and micrognathia became less severe in the majority of the cases. Pregnancy-related complications were reported by 27 (97%) of the 29 mothers. CONCLUSION(S): The early use of orthopedic appliances was important to prevent malocclusion and glossoptosis. Attempted abortion with misoprostol is associated with an increased risk of MS in infants.

Ergotamine as a possible cause of Möbius sequence: additional clinical observation.

A case of Möbius sequence after exposure to ergotamine during early development is reported. Vascular disruption is one of the theories explaining the pathogenesis of Möbius sequence. Ergotamine can cause vasospasm and a prolonged and marked increase in uterine tone. This is the second report suggesting a relation between maternal ingestion of ergotamine in early pregnancy and subsequent Möbius sequence in a child.

Autism with ophthalmologic malformations: the plot thickens.

PURPOSE: To review the association of autism spectrum disorder (ASD) in individuals manifesting thalidomide embryopathy and Möbius sequence and compare them with three new studies in which ASD was also associated with ocular and systemic malformations: (1) a Swedish study of individuals with CHARGE association (Coloboma, Heart, choanal Atresia, developmental or growth Retardation, Genital anomaly, and Ear involvement); (2) a Swedish study of Goldenhar syndrome; and (3) Brazilian Möbius syndrome (sequence) study. METHODS: In the Swedish CHARGE study, 31 patients met the inclusion criteria (3+ or 4 of the common characteristics of the CHARGE syndrome). The same team of investigators also evaluated 20 Swedish patients with Goldenhar syndrome. In the Brazilian Möbius study, 28 children with a diagnosis of Möbius sequence were studied; some children had a history of exposure during their mother's pregnancy to the abortifacient drug misoprostol in an unsuccessful abortion attempt. RESULTS: In the CHARGE study, five patients had the more severe autism disorder and five had autistic-like condition. In the Goldenhar study, two had autism disorder and one had autistic-like condition. In the Brazilian Möbius study, the systemic findings of the misoprostol-exposed and misoprostol-unexposed patients were almost undistinguishable, and ASD was present in both groups (autism disorder in five and autistic-like condition in three). CONCLUSION: Autism spectrum disorder has been reported in two conditions with known early pregnancy exposure to the teratogenic agents thalidomide and misoprostol. In the Brazilian Möbius study, autism also occurred in both the misoprostol-exposed and misoprostol-unexposed groups. Autism also was present in patients with both CHARGE association and Goldenhar syndrome.

Autism and Möbius sequence: an exploratory study of children in northeastern Brazil.

The psychiatric examination was performed with diagnostic instruments for autism (DSM-IV and Childhood Autism Rating Scale-CARS) in 23 children with Möbius sequence. From the 23 patients studied with Möbius sequence, five (26.1%) met the diagnostic criteria for infantile autism according DSM-IV and two (8.6%), under two years old, showed autistic-like behavior. The scores for six children were compatible to severe autism symptoms according CARS and one child met the criteria for moderate autism symptoms. Among five children with autism, three (60%) had positive history of misoprostol exposure during the first trimester of pregnancy and from two cases autistic-like, one (50%) had positive history of misoprostol exposure during pregnancy. According to our data, this is the first report of Möbius sequence with autism and positive history of misoprostol use during pregnancy.

[Moebius syndrome due to the use of misoprostol. Case report]. / Sindrome de Moebius: fetopatía por misoprostol. Reporte de un paciente.

We report a patient affected with Moebius Syndrome (OMIM 157900) due to the use of misoprostol during the first trimester of the pregnancy, when abortion was intended twice using this drug, vias vaginal (600 mg) and oral (900 mg), with failure to induce abortion on both occasions. Since the use of misoprostol for abortion, without any medical indication or supervision, appears to be rather frequent in our population and since there are reports of severe malformations in children born after failed intents of abortion with this medication, it is necessary to alert the medical community and the population in general about the teratogenic risks of this drug.