Antiobesity drugs in early pregnancy and congenital malformations in the offspring.

Little information exists on the possible teratogenic effect of modern antiobesity drugs. The present study refers to orlistat, sibutramine, and rimonabant. Data in the Swedish Medical Birth Register were utilised. During the years 1998-2011, among 392,126 infants born, 509 had been exposed to antiobesity drugs in early pregnancy: 248 to orlistat, 242 to sibutramine, 12 to rimonabant, 13 to unspecified antiobesity drugs. Simultaneous use of orlistat and sibutramine occurred in six cases. No increase in major malformation risk was seen after orlistat (relative risk=0.42, 95% confidence interval 0.11-1.07) but a significantly high risk was seen after sibutramine (relative risk=1.81, 95% confidence interval 1.02-2.99). The latter effect, which seemed to be mainly due to an increased risk for a cardiovascular defects, may be related to the capacity of the drug to prolong QT-time. Sibutramine has been withdrawn in Europe but is still available on the Internet and is a component in some slimming preparations. Among the 12 infants exposed to rimonabant, two which were in a twin pair were malformed.

Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations.

BACKGROUND: Maternal use of selective serotonin re-uptake inhibitors (SSRIs) has recently been associated with an increased risk for certain malformations. METHODS: Using the Swedish Medical Birth Register, we identified women who had reported the use of SSRIs in early pregnancy and studied their infants, born between July 1, 1995 and the end of 2004. Congenital malformations were identified from that register, from the Register of Congenital Malformations, and from the Hospital Discharge Register. The effect of drug exposure was studied after adjustment for a number of identified maternal characteristics that could act as confounders. RESULTS: We identified 6,481 women who reported the use of SSRIs in early pregnancy and their 6,555 infants. There was no general increase in malformation risk. An increased risk for cystic kidneys was seen, but this was based on only nine malformed infants, and the pathology varied between these cases. An in-depth study of cardiovascular defects identified an association between such defects and notably ventricular and atrial septum defects and maternal use of paroxetine but not other SSRIs. No support for a postulated association between SSRI use and infant craniostenosis or omphalocele was found. CONCLUSIONS: Use of SSRIs in early pregnancy does not seem to be a major risk factor for infant malformations. The association between paroxetine use and infant cardiovascular defects may be a result of multiple testing, but is supported by other studies.

Use of oral decongestants during pregnancy and delivery outcome.

OBJECTIVE: The purpose of this study was to evaluate delivery outcome after maternal use of oral decongestants. STUDY DESIGN: We identified 2474 women who had reported the use of oral decongestants (mainly phenylpropanolamine) during early pregnancy and 1771 women who used prescription oral decongestants later in pregnancy. With Mantel-Haenszel analysis, comparisons were made with all women who gave birth in Sweden. RESULTS: The risk ratio for any congenital malformation after the use of oral decongestants was 0.96 (95% CI, 0.80-1.16). Women who were prescribed decongestants after the first antenatal visit less often than expected had infants who were born preterm (odds ratio, 0.68; 95% CI, 0.52-0.88), of low birth weight (odds ratio, 0.53; 95% CI, 0.37-0.77), small-for-date (odds ratio, 0.71; 95% CI, 0.47-1.08), or perinatally dead (odds ratio, 0.53; 95% CI, 0.22-12.5). CONCLUSION: No teratogenic effect of oral decongestants was found. An association found between the late pregnancy use of such drugs and a favorable neonatal outcome can be explained hypothetically by the postulated association between pregnancy rhinitis and placental hormones.

Obstetric outcome of 6346 pregnancies with infants affected by congenital heart defects.

OBJECTIVE: To evaluate whether pregnancies with infants affected by congenital heart defects are associated with adverse obstetric and perinatal outcome. STUDY DESIGN: In a prospective population-based cohort study from Sweden (1992-2001), 6346 singleton pregnancies with infants affected by congenital heart defects were, after suitable adjustments, compared to all delivered women. RESULTS: The prevalence of cardiovascular defects was 9.1 per 1000 births. Among them, mothers of 6346 infants (71%) had information on maternal smoking habits and maternal height and weight in early pregnancy that enabled the calculation of BMI. All cases with known chromosomal abnormalities and/or maternal pre-existing diabetes were excluded. Eighty-four percent (n=5338) had an isolated cardiovascular defect. Severe types occurred in 21.7% (n=1378). In the group of pregnancies with infants affected by congenital heart defects as compared to all delivered women, there was an increased risk of the following outcomes (adjusted OR (95%CI)): pre-eclampsia (1.21 (1.06-1.37)), cesarean section (1.91 (1.79-2.03)), instrumental delivery (1.21 (1.10-1.34)), pre-term delivery (2.58 (2.39-2.79)), small-for gestational age (1.96 (1.77-2.16)), meconium aspiration (1.51 (1.28-1.77)), and fetal distress (1.38 (1.17-1.63)). CONCLUSIONS: Pregnancies with infants affected by congenital heart defects are associated with several obstetric and neonatal complications.

Methodological issues in the epidemiological study of the teratogenicity of drugs.

The review presented here discusses and exemplifies problems in epidemiological studies of drug teratogenesis according to methodology: case-control studies, cohort studies, or total population studies. Sources of errors and the possibility of confounding are underlined. The review stresses the caution with which conclusions have to be drawn when exposure data are retrospective or other possible bias exists. It also stresses the problem with the multiple testing situation that is usually present in the studies. It is therefore difficult to draw any firm conclusion from single studies and still more difficult to draw conclusions on causality. As randomized studies are in most cases out of the question, one has to rely on the type of studies which can be made, but the interpretation of the results should be cautious. The ideal study, next to a randomized one, is a large prospective study with detailed exposure information and detailed and unbiased outcome data. Even so, such a study can mainly be used for identifying possible associations which have to be verified or rejected in new studies. Nearly every finding of a risk increase, if not extremely strong, should only be regarded as a tentative signal to be tested in independent studies.

Is erythromycin therapy teratogenic in humans?

The possible teratogenic effect of erythromycin therapy, noted previously, was studied. Women who had taken erythromycin or penicillin V in early pregnancy and their infants were studied, using the Swedish Medical Birth Register where information on drug use during pregnancy was recorded based on interviews in early pregnancy. The risk for any congenital malformation after erythromycin therapy (but not after penicillin V therapy) was increased (odds ratio 1.24, 95% confidence interval: 1.01-1.51) and this was due to an effect on cardiovascular malformations (odds ratio 1.92, 95% CI: 1.37-2.68). There was also an indicated increased risk for pyloric stenosis (risk ratio 3.0, 95% CI: 1.1-8.5 after exposure in early pregnancy). Various explanations to the finding are discussed, one of them linked to the fact that erythromycin inhibits a specific cardiac potassium channel (IKr) which seems to play a major role in cardiac rhythm regulation in the early embryo. Potent blocking drugs cause as a class effect cardiac defects in animal experiments.

Maternal obesity and infant heart defects.

OBJECTIVE: This study determined whether obese women have an increased risk of cardiovascular defects in their offspring compared with average weight women. RESEARCH METHODS AND PROCEDURES: In a case-control study, prospectively collected information was obtained from Swedish medical health registers. The study included 6,801 women who had infants with a cardiovascular defect and, as controls, all delivered women (N = 812,457) during the study period (1992 to 2001). Infants with chromosomal anomalies or whose mothers had pre-existing diabetes were excluded. Obesity was defined as BMI >29 kg/m(2), and morbid obesity was defined as BMI >35 kg/m(2). Comparisons were made with average weight women (BMI = 19.8 to 26 kg/m(2)). RESULTS: In the group of obese mothers, there was an increased risk for cardiovascular defects compared with the average weight mothers [adjusted odds ratio (OR) = 1.18; 95% CI, 1.09 to 1.27], which was slightly more pronounced for the severe types of cardiovascular defects (adjusted OR = 1.23; 95% CI, 1.05 to 1.44). With morbid obesity, the OR for cardiovascular defects was 1.40 (95% CI, 1.22 to 1.64), and for severe cardiovascular defects, the OR was 1.69 (95% CI, 1.27 to 2.26). There was an increased risk for all specific defects studied among the obese women, but only ventricular septal defects and atrial septal defects reached statistical significance. DISCUSSION: In this sample, a positive association was found between maternal obesity in early pregnancy and congenital heart defects in the offspring. A suggested explanation is undetected type 2 diabetes in early pregnancy, but other explanations may exist.

Maternal drug use in early pregnancy and infant cardiovascular defect.

The purpose of the paper is to identify maternal drug use that may be associated with an increased risk for cardiac defects in the offspring. A case-control study was performed with cases (cardiovascular defects without known chromosome anomalies) being identified from three Swedish health registers (n=5015) and controls being all infants born in Sweden during the period 1 July 1995-2001 (n=577,730). Information on drug exposure was obtained by interview in early pregnancy. Associations between maternal drug use and infant cardiovascular defect were identified for insulin, antihypertensives, fertility drugs, erythromycin, naproxen, anticonvulsants, nitrofurantoin, clomipramine, and budesonide in nasal preparations. Some of these associations are probably due to confounding from underlying disease or complaint, some may be due to multiple testing, some may be true drug effects. Further studies are needed to verify or reject these associations.

Use of folic acid and delivery outcome: a prospective registry study.

Periconceptional use of folic acid is thought to reduce the risk for both neural tube defects and other congenital malformations. Most published data were obtained retrospectively. We used the Swedish Medical Birth Registry to study congenital malformations in infants born of women who reported the use of folic acid in early pregnancy (of which 70% probably used it also preconceptionally) and compared them with population rates. We divided the material according to two major confounders: subfertility problems and use of antiepileptic drugs. We found no protective effect of folic acid tablet use on the rate of congenital malformations but data on neural tube defects were scarce. Our results support the scepticism recently expressed in the literature on the beneficial effect of folic acid in preventing congenital malformations, especially of a non-neural tube defect type.

Chlorination byproducts and nitrate in drinking water and risk for congenital cardiac defects.

Drinking water disinfection byproducts have been associated with an increased risk for congenital defects including cardiac defects. Using Swedish health registers linked to information on municipal drinking water composition, individual data on drinking water characteristics were obtained for 58,669 women. Among the infants born, 753 had a cardiac defect. The risk for a cardiac defect was determined for ground water versus surface water, for different chlorination procedures, and for trihalomethane and nitrate concentrations. Ground water was associated with an increased risk for cardiac defect when crude rates were analyzed but after suitable adjustments this excess rate was found to be determined by chlorination procedures including chlorine dioxide. Chlorine dioxide appears itself as an independent risk factor for cardiac defects (adjusted odds ratio 1.61 (95%CI 1.00-2.59)). The risk for cardiac defects increased with increasing trihalomethane concentrations (P=0.0005). There was an indicated but statistically nonsignificant excess risk associated with nitrate concentration. The individual risk for congenital cardiac defect caused by chlorine dioxide and trihalomethanes is small but as a large population is exposed to public drinking water, the attributable risk for cardiac defects may not be negligible.

Risk factors for cardiovascular malformation--a study based on prospectively collected data.

OBJECTIVES: The aim of this study was to identify risk factors for cardiovascular malformation. METHODS: In a case-referent study prospectively collected data were obtained from original medical records. The study included 277 woman who had infants with a severe cardiac defect, and for each case two referents (medical records study) were included. Data on parental age, maternal reproductive history, disease in early pregnancy, reported maternal use of drugs and alcohol, smoking habits, parental occupation, and maternal body mass index (BMI) were extracted. When data were available from Swedish medical health registers, a comparison was made (register study) between all infants with cardiovascular defects (2208) and all infants born (175 768). RESULTS: Maternal diabetes mellitus was associated with an increased risk for cardiovascular malformation [odds ratio (OR) 2.38, 95% confidence interval (95% CI) 1.36-4.15], as was a high BMI (> 29) (OR 1.46, 95%CI 1.12-1.90). A tendency towards an increased risk was found for involuntary childlessness, spontaneous abortion, thyroid drugs, and nonsteroid anti-inflammatory drugs. CONCLUSIONS: Some known risk factors for cardiac defects (eg, maternal diabetes mellitus and the use of antiepileptics) could be identified. Other postulated risk factors could not be verified, for example, paternal age and parental occupation. The use of medicinal drugs seems not to be a major factor in the etiology of cardiac defects. It is possible, however, that there is an association with the use of nonsteroid anti-inflammatory drugs or drugs for thyroid disease. The relationship between a high BMI and cardiovascular malformation observed in this study may be explained by impaired maternal glucose tolerance.