Maria Teresa Vieira Sanseverino

Pregnancy outcome after exposure to misoprostol in Brazil: a prospective, controlled study.

BACKGROUND Misoprostol, a synthetic prostaglandin E1 analog is labeled for the treatment of gastric and duodenal ulcers. In Brazil, where abortion is not a legal procedure, there is a widespread popular misuse of this drug in abortion attempts. This misuse and the fact that, in many cases the desired pregnancy termination does not occur, raise concerns about fetal safety. Case reports of congenital anomalies after maternal use of misoprostol have been published. The objective of this work was to compare pregnancy outcome following misoprostol exposure with a matched control group. This is the first prospective controlled study on fetal safety after misoprostol use. METHODS A prospective, observational cohort study with 86 exposed and 86 pair-matched, non-exposed controls. RESULTS There was no significant difference in the rates of major or minor birth between exposed compared to non-exposed infants (2/67 vs 2/81, major defects; 7/67 vs. 3/81, minor anomalies) There were significantly more miscarriages in the exposed group (17.1% vs. 5.8%; relative risk, 2.97; 95% confidence interval, 1.12 to 7.88). There was no statistical difference in gestational age at delivery, birth weight, sex ratio, rate of prematurity, low birth weight, or rates of cesarean section between groups. CONCLUSIONS Our study, despite its limited statistical power, does not suggest a potent teratogenic action of misoprostol exposure during pregnancy.

Avaliação de teratógenos potenciais na população brasileira

O fato de agentes ambientais, nomeadamente farmacos, infeccoes maternas, e agentes quimicos ou fisicos poderem causar danos ao embriao ou feto em desenvolvimento e um problema reconhecido principalmente a partir do seculo 20. Nos paises em desenvolvimento, existem caracteristicas especiais que podem tornar esse problema mais agudo. Essas caracteristicas incluem niveis educacionais e economicos baixos da populacao, alta incidencia de doencas infecciosas e carenciais, escassos recursos para saude e pesquisa, pratica frequente e sem controle de automedicacao, facilidade de obtencao de medicacoes que deveriam estar submetidas a prescricao medica e, finalmente, proibicao legal de interrupcao da gestacao. Alem disso, pode somar-se uma qualidade ambiental precaria ou mesmo condicoes de trabalho insalubres durante a gravidez. No presente trabalho apresentamos as principais metodologias para deteccao e monitorizacao de potenciais teratogenos, com enfase especial nos programas desenvolvidos no Brasil e America Latina.

Reproductive outcomes in an area adjacent to a petrochemical plant in southern Brazil

OBJECTIVE To evaluate possible adverse reproductive outcomes in an area adjacent to a petrochemical plant in southern Brazil. METHODS A review of 17,113 birth records of the main hospital of the municipality of Montenegro, southern Brazil, from 1983 to 1998 was carried out. Three groups of cases were selected: (1) newborns with major congenital malformations; (2) newborns with low birth weight (<2,500 g); and (3) stillborns (>500 g). A control was assigned to each case. Controls were the first newborns weighing </= 12,500 g without malformations and of case-matching sex. Mothers residence during pregnancy was used as an exposure parameter. Statistical analyses were performed using Chi-square test or Fisher test, odds ratio, 0.05 significance level, and 95% confidence interval. RESULTS For unadjusted analysis, it was found a correlation between low birth weight and geographical proximity of mothers residence to the petrochemical plant (OR = 1.66; 95% CI = 1.01 - 2.72) or residence on the way of preferential wind direction (OR = 1.62; 95% CI = 1.03 - 2.56). When other covariates were added in the conditional logistic regression (maternal smoking habits, chronic disease and age), there was no association. CONCLUSIONS Despite final results were negative, low birth weight could be a good parameter of environmental contamination and should be closely monitored in the studied area.

Epidemiological surveillance of birth defects compatible with thalidomide embryopathy in Brazil.

The thalidomide tragedy of the 1960s resulted in thousands of children being born with severe limb reduction defects (LRD), among other malformations. In Brazil, there are still babies born with thalidomide embryopathy (TE) because of leprosy prevalence, availability of thalidomide, and deficiencies in the control of drug dispensation. Our objective was to implement a system of proactive surveillance to identify birth defects compatible with TE. Along one year, newborns with LRD were assessed in the Brazilian hospitals participating in the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). A phenotype of LRD called thalidomide embryopathy phenotype (TEP) was established for surveillance. Children with TEP born between the years 2000–2008 were monitored, and during the 2007–2008 period we clinically investigated in greater detail all cases with TEP (proactive period). The period from 1982 to 1999 was defined as the baseline period for the cumulative sum statistics. The frequency of TEP during the surveillance period, at 3.10/10,000 births (CI 95%: 2.50–3.70), was significantly higher than that observed in the baseline period (1.92/10,000 births; CI 95%: 1.60–2.20), and not uniformly distributed across different Brazilian regions. During the proactive surveillance (2007–2008), two cases of suspected TE were identified, although the two mothers had denied the use of the drug during pregnancy. Our results suggest that TEP has probably increased in recent years, which coincides with the period of greater thalidomide availability. Our proactive surveillance identified two newborns with suspected TE, proving to be a sensitive tool to detect TE. The high frequency of leprosy and the large use of thalidomide reinforce the need for a continuous monitoring of TEP across Brazil.

Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings.

Thalidomide is the best-known teratogen worldwide. It was first marketed as a sedative in the late 1950s, but the birth of ∼10 000 children with birth defects resulted in the withdrawal of thalidomide from the market in 1962. Thalidomide embryopathy affects almost all organs but the main defects are concentrated in the limbs, eyes, ears, and heart. Shortly after the withdrawal of thalidomide from the market, its effectiveness in the treatment of erythema nodosum leprosum, an inflammatory condition resulting from leprosy, was reported and since the mid-1990s, the drug has been used widely in the treatment of cancers and autoimmune diseases, among other conditions. 40 000 new cases of leprosy are diagnosed every year in Brazil. Although there is a strict legislation for the prescription and use of thalidomide in Brazil, cases of thalidomide embryopathy have continued to be reported. Here, we present two new cases of thalidomide embryopathy identified in 2011 and review the major clinical findings in the literature that can aid the identification of the embryopathy.

Exposure to misoprostol and hormones during pregnancy and risk of congenital anomalies

This study evaluated the association between use of misoprostol and other drugs to induce menstruation, and congenital anomalies. A sample of 4,856 pregnant women 20 years and older were enrolled consecutively in prenatal services in the Unified National Health System, in six Brazilian State capitals. Data on socio-demographics and use of medicines were obtained using an interview from the 21st to 28th week of pregnancy. Other data, including information on delivery and diagnosis of congenital anomalies by the attending neonatal physician were obtained from patient charts. Potential confounders were adjusted by logistic regression. Use of drugs to induce menstruation was reported by 707 women (14.6%), of whom 120 (17%) reported use of misoprostol. After adjusting for the study center, a positive association was observed between misoprostol and congenital anomalies (OR = 2.64; 95% CI: 1.03-6.75); a positive association was also observed for sex hormones (OR = 2.24; 95% CI: 1.06-4.74). The results suggest that the use of misoprostol or sex hormones during pregnancy increases the risk of congenital anomalies.

Prenatal alcohol exposure as a risk factor for dysfunctional behaviors: the role of the pediatrician

OBJECTIVE Although the classic features of fetal alcohol syndrome have been recognized since 1968, research on alcohol teratogenesis has only recently demonstrated that the brain is the organ in the body most vulnerable to the effects of prenatal alcohol exposure. In this present article, we reviewed the literature focusing mainly on behavioral disturbances related to prenatal ethanol exposure. SOURCES We performed a PubMed search on the literature published between 1968 and 2006 using the terms ethanol, pregnancy and behavior. We limited our search to studies on humans. SUMMARY OF THE FINDINGS The data presented in this review suggested that youths with fetal alcohol spectrum disorder are at risk of disruptive social behavior, among other neurobehavioral abnormalities. CONCLUSIONS Although it is still impossible to completely separate brain teratogenesis secondary to alcohol exposure from environmental postnatal influences as the definite cause for these outcomes, the pediatrician should be encouraged to early diagnose children affected by fetal alcohol syndrome and fetal alcohol spectrum disorder. This provides proper management and care and avoids long-term consequences on their behavior, besides ensuring better and productive school and social adaptation.

Detection of organic acidemias in Brazil.

BACKGROUND Organic acidurias or organic acidemias are inherited metabolic disorders in which organic acids (carboxylic acids) accumulate in tissues and physiologic fluids of affected individuals. They are considered the most frequent metabolic disorders among severely ill children. Patients frequently present acute symptoms in early life. Metabolic acidosis and neurologic symptoms are the most common signs. METHODS Urine specimens obtained from 1,926 children from January 1994 to July 2001 were used in analyses. Venous blood specimens were also collected from some patients. Samples were initially submitted to screening tests for detection of inborn errors of metabolism. Identification and semi-quantitation of organic acids in urine were performed by gas chromatography or gas chromatography coupled to mass spectrometry using capillary column (DB-5) and flame ionization detection. RESULTS Ninety three (4.8%) cases of organic acidemias were diagnosed among 1,926 patients investigated from January 1994 to July 2001. Prompt therapy was instituted after diagnosis in a considerable number of patients and resulted in rapid improvement in their symptomatology, distinct from our previous cases diagnosed abroad where patients representing index cases died before any measure could be taken. CONCLUSIONS Results demonstrate the importance of diagnosing organic acidurias in loco in developing countries despite implied extra costs.

Prenatal diagnosis of fetal chromosomal abnormalities: Report of an 18-year experience in a Brazilian public hospital

The study of the fetal karyotype became an important tool for the fetal diagnosis of genetic diseases in the 1970s. Although application of this test has remained very restricted in Brazil, we had 905 referrals for prenatal fetal karyotyping between 1989 and 2007. In 879 cases, a fetal karyotype was obtained. We detected 74 abnormal karyotypes (8.4%), the majority being found when the prior indication was fetal malformation. When obtaining amniotic fluid or chorionic villus samples was difficult, alternative fetal materials (urine, cystic hygroma, cystic lung, intreperitoneal and cerebrospinal fluids) were collected and we had success in obtaining karyotypes in all 13 cases. Although, the option of terminating abnormal pregnancies does not legally exist in Brazil, the information gained in assessing the prognosis of on-going pregnancies or estimating recurrence risks justifies prenatal diagnosis of chromosome abnormalities. We conclude that, in keeping with the policy in most other countries, prenatal cytogenetic analysis is strongly recommended in high-risk pregnancies for fetal abnormalities. However, the unique aspect of this type of study is not its rarity in world terms, but its rarity in Brazil. This argues that Brazilian health policy on prenatal diagnosis requires reforming to make it much more widely available within the public health care sector.

Reproductive results associated with misoprostol and other substances utilized for interruption of pregnancy

Sir, In Brazil, the main use of misoprostol is to induce abortion, even though this practice is illegal. There are only two situations in which abortion is not a criminal act: when the pregnant woman’s life is at risk and when pregnancy has resulted from rape or incest. The use of misoprostol as an abortion-inducing substance may lead to a situation in which the pregnancy is not lost [1], thereby generating anxiety regarding the risk to the fetus and the pregnant woman. Case and case-control studies have suggested that the use of misoprostol in unsuccessful abortions may be associated with congenital malformations, for example in children with limb reduction defects and/or Mobius Sequence [2, 3] and anomalies of the central nervous system [4]. However, in one cohort study correlating the use of misoprostol with teratogenic effects, no difference was found in the rates of congenital malformations between 86 cases of exposure to misoprostol during pregnancy and 86 cases without exposure to this drug [5]. In this letter, we report an association observed between the use of misoprostol during the first trimester of pregnancy and congenital malformation of the child or fetal death, from the Brazilian Study of Gestational Diabetes, a cohort of women attending prenatal services at public hospitals in six Brazilian cities, between February 1991 and June 1995. Data relating to the use of misoprostol and other substances with the potential to induce abortion during the pregnancy (obtained during the first phase of the cohort) and data relating to the neonate’s state of health (obtained during the third phase of the cohort) were analyzed. Interviews were held with 5,564 women aged 20 years or over who were between their 21st week and 28th week of pregnancy (Table 1). Information on the use of substances with the potential to induce abortion was obtained from the interviews with the pregnant women. The diagnosis of congenital malformation was made by the attending doctor and entered in the pregnant woman’s records. The present analysis included the pregnant women who were followed through to the third phase of the cohort, thus resulting in a sample of 4,862 women (87.4% of the initial sample). Use of substances with the potential to induce abortion was reported by 707 pregnant women (14.6%); of these, 120 declared that they had used misoprostol during the first trimester of pregnancy. More cases of congenital malformation were found in the group exposed to misoprostol than in the unexposed group (RR=2.39), with threshold significance (95% CI 0.99–5.80) (Table 2). Using a logistic regression model that included the variables of skin color, marital situation and research center, the risk increased slightly (RR=2.61; 95% CI 1.01–6.75). The malformations that occurred in the sample of pregnant women who made use of misoprostol were: syndactyly, twisted foot, meningomyelocele, microcephaly and fingernail defects. A significant difference was also observed between the women with and without exposure to misoprostol, in relation to fetal death (RR=2.63; 95% CI 1.17–5.88 (Table 3). After adjustment using the regression model, the relative risk increased to 3.21 (95% CI 1.34–7.68). The data available in the literature on the effects on the fetus and child mostly come from case reports and case-control studies of limited sample size. Moreover, they do not include adverse events other than the congenital malformations that are important for the outcome of the pregnancy. The prospective populationbased study that included a cohort of 86 cases and 86 externally selected controls did not have sufficient T. da Silva Dal Pizzol (&) University of Passo Fundo, Rua Paissandu, 1973, apto 604, Passo Fundo, Rio Grande do Sul, 99010-102, Brasil E-mail: tatiane@saude.upf.tche.br