Are hypnotic benzodiazepine receptor agonists teratogenic in humans?

BACKGROUND: Hypnotic benzodiazepine receptor agonists (HBRAs; zolpidem, zopiclone, and zaleplon) are used in the treatment of insomnia. Little is known about the safety of HBRAs during pregnancy. METHODS: Data from the Swedish Medical Birth Registry from July 1, 1995, up to 2007 were used to identify 1318 women who reported the use of HBRAs in early pregnancy. They gave birth to 1341 infants. Maternal characteristics and the presence of congenital malformations were compared with all other women who gave birth (n = 1,106,001) and all other infants (n = 1,125,734) born during the study period. RESULTS: Use and/or reporting of HBRAs increased with maternal age and were higher at first than higher parity. Maternal smoking was strongly associated with reported use of HBRAs. The probability of using HBRAs increased in women who had had 3 or more earlier miscarriages or 5 or more years of involuntary childlessness. An excess use of other drugs and above all psychoactive drugs were seen in women reporting use of HBRAs.Hypnotic benzodiazepine receptor agonists were not associated with an increased risk for congenital malformations. A statistically significant high risk for other intestinal malformations than atresias/stenosis was based on only 4 infants. CONCLUSIONS: Maternal use of HBRAs does not seem to increase malformation risk. The tentative association with some intestinal malformations may be due to chance because of multiple testing and needs confirmation.

Opioid maintenance treatment of pregnant women in the Scandinavian countries.

Background: WHO guidelines emphasise the need for descriptions of clinical practice and observational studies on risk and benefits of pharmacotherapies in pregnancy. The aims of the present study were to: (1) Describe opioid maintenance treatment (OMT) in the Scandinavian countries in general, and specifically for pregnant women, (2) Describe a project which utilises a new approach using registry-linkage data to examine associations between prenatal exposure to OMT and child outcomes: a Scandinavian cohort study of pregnant women in OMT during pregnancy (ScopeOMT). Data: Guidelines describing the treatment of persons with opioid use disorders in general, and specifically for pregnant women. Scandinavian registry-linkage data from ScopeOMT. Results: Registry data show that approximately 800 pregnant women received OMT during pregnancy in the period of the ScopeOMT study. Similarities across the Scandinavian countries include access to free healthcare and treatment; multidisciplinary teams trained to support pregnant women in OMT; buprenorphine as the recommended drug when initiating therapy; and a holistic focus on the patients' lives. An important difference is that Norwegian women who use illegal substances that may harm the foetus may be admitted - voluntarily, or against their will - for parts of, or the remainder of the pregnancy to inpatient treatment at specialised clinics. Conclusion: Many similarities in the treatment provided to opioid-dependent persons in the Scandinavian countries place this area in an excellent position to combine the efforts and carry out observational studies concerning the safety of OMT during pregnancy.

Maternal use of thyroid hormones in pregnancy and neonatal outcome.

OBJECTIVE: To describe neonatal outcome including the presence of congenital malformations in infants born to women substituted with thyroid hormones, and the maternal characteristics of these women. DESIGN: Register study based on prospectively collected data in relation to delivery. SETTING: Swedish Health Registers. POPULATION: All pregnant women (n=848,468) and all infants born (n=861,989) in Sweden from 1 July 1995 to 31 December 2004. METHODS: Women who reported the use of thyroid hormones in early pregnancy or obtained a prescription for thyroid hormones later in pregnancy (n=9,866), as well as their infants (n=10,055) were identified from the Swedish Medical Birth Register. The reference population consisted of all women giving birth and their offspring during the same time interval. MAIN OUTCOME MEASURES: Neonatal outcome, malformations and maternal characteristics. Data were analyzed with adjustments for identified confounders. RESULTS: Women using thyroxine had an increased rate of pre-eclampsia, diabetes (pre-existing or gestational), cesarean sections and inductions of labour compared to women in the reference population. The risk for preterm birth was marginally increased (OR 1.13, 95% CI 1.03-1.25). Neonatal thyroid disease was found in eight infants (seven with thyreotoxicosis and one unspecified), the expected number was 0.2. No further anomalies in neonatal diagnoses were found. A small but statistically significant risk for congenital malformations (OR =1.14, 95% CI 1.05-1.26) was found. CONCLUSION: Women on thyroid substitution during pregnancy had an increased risk for some pregnancy complications, but their infants were only slightly affected.

Narcolepsy Treated with Racemic Amphetamine during Pregnancy and Breastfeeding.

This case report describes a woman with narcolepsy treated with racemic amphetamine (rac-amphetamine) during pregnancy and breastfeeding with follow-up on the infant's development up to 10 months of age. The pregnancy outcome and the pharmacokinetics of rac-amphetamine were studied during breastfeeding. The pregnancy and the delivery were uneventful. Concentrations of rac-amphetamine were determined in the plasma of the mother and infant, and in the breast milk with a liquid chromatography-mass spectrometry method. Samples were obtained at 2, 5, and 9 weeks postpartum. The transfer of rac-amphetamine to the breast milk was extensive (mean milk/maternal plasma concentration ratio approximately 3). The breastfed infant had a low plasma concentration of rac-amphetamine (about 9% of the maternal plasma level) and the calculated relative infant dose was low (2%). No adverse effects were observed in the breastfed infant. The infant's somatic and psychomotor development up to 10 months of age was normal. Further studies of amphetamine prescribed for medical reasons during pregnancy and lactation are needed.

Use of ondansetron during pregnancy and congenital malformations in the infant.

The study investigates teratogenic risks with ondansetron (Zofran(®)). Data from the Swedish Medical Birth Register combined with the Swedish Register of Prescribed Drugs were used to identify 1349 infants born of women who had taken ondansetron in early pregnancy, 1998-2012. Presence of congenital malformations in the offspring was identified with three national health registers. In a Mantel-Haenszel analysis adjustment was made for year of delivery, maternal age, parity, smoking in early pregnancy and pre-pregnancy body mass index. Risks were expressed as odds or risk ratios with 95% confidence intervals. No statistically significantly increased risk for a major malformation was found. The risks for a cardiovascular defect and notably a cardiac septum defect were increased and statistically significant (OR=1.62, 95% CI 1.04-2.14, and RR 2.05, 95% CI 1.19-3.28, respective). The teratogenic risk with ondansetron is low but an increased risk for a cardiac septum defect is likely.

Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: maternal characteristics.

BACKGROUND: Use of benzodiazepine (BZD) drugs or hypnotic benzodiazepine receptor agonists (HBRAs) during pregnancy may represent a hazard for the foetus. In order to analyse this in an adequate way, knowledge of maternal characteristics as putative confounders is needed. METHODS: In the Swedish Medical Birth Register, 2149 pregnant women using BZDs or HBRAs were identified, 1944 of them in early pregnancy. These women were compared with other women (n = 859 455) giving births during the same period (1 July 1995-31 December 2004). The following maternal characteristics were studied: age, parity, smoking habits, education, previous miscarriages, years of involuntary childlessness as an estimate of subfertility, concomitant drug use and some pregnancy complications. RESULTS: Use and/or reporting of BZDs or HBRAs increased with maternal age. It was higher at first and 4+ parity and increased markedly with maternal smoking. Women with low education reported a higher use than women with high education. Previous miscarriage or subfertility had little impact on the use of these drugs. Preterm birth and caesarean section (also at term birth) were more common than expected. In women using BZDs or HBRAs, other types of psychoactive drugs were used in excess. CONCLUSIONS: Women using BZDs or HBRAs differ in many aspects from women not using those drugs. These differences may act as confounders in the analysis of pregnancy outcome.

Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations.

BACKGROUND: Exposure to Benzodiazepines (BZD) during foetal life has been suggested to contribute to neonatal morbidity and some congenital malformations, for example, orofacial clefts. Here we aimed to study the neonatal outcome and congenital malformations in neonates whose mothers reported use of BZD and/or hypnotic benzodiazepine receptor agonists (HBRA) during pregnancy. METHODS: In the Swedish Medical Birth Register we identified 1979 infants whose mothers (n = 1944) reported use of BZD and/or HBRA in early pregnancy. An additional 401 infants were studied, born to 390 mothers who were prescribed such drugs during late pregnancy. Neonatal outcome including congenital malformations after exposure was compared with that of all births (n = 873 879). RESULTS: An increased risk for preterm birth and low birth weight was detected in the exposed population. The rate of relatively major congenital malformations was moderately increased among infants exposed in early pregnancy (adjusted OR = 1.24, 95%CI 1.00-1.55), not explained by known teratogenic maternal co-medication. A higher than expected number of infants with pylorostenosis or alimentary tract atresia (especially small gut) was found. This was, however, based on only seven infants for each group of malformation without association to any specific BZD or HBRA. The earlier proposed increased risk for orofacial clefts was not confirmed in our study. CONCLUSIONS: Maternal use of BZD and/or HBRA may increase the risk for preterm birth and low birth weight and cause neonatal symptoms, but does not appear to have a strong teratogenic potential. The tentative association with pylorostenosis and alimentary tract atresia needs confirmation.