Myla E. Moretti

Maternal Hyperthermia and the Risk for Neural Tube Defects in Offspring: Systematic Review and Meta-Analysis

Background: In animals, excessive core body temperatures have been documented to cause malformations; neural tube defects (NTDs) are among the most frequently reported. In humans, data are inconclusive and often conflicting. The objective of our report is to determine the risk for neural tube defects associated with maternal hyperthermia in early pregnancy Methods: We conducted a systematic review and meta-analysis to evaluate available evidence on this topic in humans. MEDLINE, EMBASE, references from published reports, and biologic abstracts from meetings were searched for relevant studies. Reviewers evaluated all the retrieved articles and extracted the relevant data. Individual and summary odds ratios and relative risks were calculated using the Mantel–Haenszel method. Results: Fifteen studies, reporting on 1,719 cases and 37,898 noncases, were included in the meta-analysis. The overall odds ratio for neural tube defects associated with maternal hyperthermia was 1.92 (95% confidence interval = 1.61–2.29). When analyzed separately, the 9 case-control studies had an odds ratio of 1.93 (1.53–2.42). The summary relative risk for the 6 cohort studies was 1.95 (1.30–2.92). Conclusions: Maternal hyperthermia in early pregnancy is associated with increased risk for neural tube defects and may be a human teratogen.

Fetal effects of cocaine: an updated meta-analysis.

BACKGROUND A very large number of women in the reproductive age group consume cocaine, leading to grave concerns regarding the long term health of millions of children after in utero exposure. The results of controlled studies have been contradictory, leading to confusion, and, possible, misinformation and misperception of teratogenic risk. OBJECTIVE To systematically review available data on pregnancy outcome when the mother consumed cocaine. METHODS A meta-analysis of all epidemiologic studies based on a priori criteria was conducted. Comparisons of adverse events in subgroups of exposed vs. unexposed children were performed. Analyses were based on several exposure groups: mainly cocaine, cocaine plus polydrug, polydrug but no cocaine, and drug free. RESULTS Thirty three studies met our inclusion criteria. For all end points of interest (rates of major malformations, low birth weight, prematurity, placental abruption, premature rupture of membrane [PROM], and mean birth weight, length and head circumference), cocaine-exposed infants had higher risks than children of women not exposed to any drug. However, most of these adverse effects were nullified when cocaine exposed children were compared to children exposed to polydrug but no cocaine. Only the risk of placental abruption and premature rupture of membranes were statistically associated with cocaine use itself. CONCLUSIONS Many of the perinatal adverse effects commonly attributed to cocaine may be caused by the multiple confounders that can occur in a cocaine using mother. Only the risk for placental abruption and PROM could be statistically related to cocaine. For other adverse effects, additional studies will be needed to ensure adequate statistical power.

Cyclosporine excretion into breast milk.

Although many female patients of childbearing age who are receiving cyclosporine have successful pregnancies, these women may be advised not to breast-feed. During recent years, cases of uneventful pregnancies and subsequent successful breast-feeding have been reported in the literature. The infants blood cyclosporine concentration was usually very low. Based on these findings and the lack of detectable adverse effects, some investigators have suggested that women on cyclosporine may breast-feed, challenging the conventional view that cyclosporine is contraindicated during breast-feeding. Here, we report our experience with cyclosporine use during breast-feeding in five mother-infant pairs. We show a wide range of infant exposures to the drug in milk, noting that one of the infants had therapeutic blood concentrations of cyclosporine despite relatively low concentrations of the drug in milk.

Pregnancy outcome following in utero exposure to bisphosphonates

BACKGROUND AND AIM The safety of bisphosphonates in human pregnancy has not been well established. To characterize pregnancy outcome in women receiving bisphosphonates, we conducted a multi-centre, prospective cohort study with a comparison group. METHODS Patients were recruited through 3 teratogen information centres in Canada and South Korea. We followed 21 women exposed to bisphosphonates during or <3 months before pregnancy, and 21 matched-comparison group women without exposure to known teratogens. Pregnancy/neonatal outcome data were collected by interview. The primary endpoint was neonatal outcome including major birth defects. The secondary endpoints included other pregnancy outcomes such as spontaneous abortions. RESULTS Indication of the therapy was osteoporosis in all patients. There was no difference in the maternal demographics between the 2 groups. In the bisphosphonate group, there were 18 live births, 2 spontaneous abortions and 1 therapeutic abortion, which were not significantly different from the comparison group. The mean gestational age (mean+/-SD) of the bisphosphonate group was 38.7+/-1.9 weeks (comparison group: 39.3+/-1.9 weeks; P=0.42), and the mean birth weight was 3.1+/-0.3 kg (comparison group: 3.3+/-0.5 kg; P=0.11). In the bisphosphonate group, there was a child diagnosed with Apert syndrome, an autosomal dominant acrocephalosyndactyly, with a fibroblast growth factor 2 mutation. CONCLUSION Coupled with existing data in the literature, our findings suggest that preconceptional and first-trimester use of bisphosphonates may not pose substantial fetal risks.

Nonsteroidal Antiinflammatory Drugs During Third Trimester and the Risk of Premature Closure of the Ductus Arteriosus: A Meta-Analysis:

Background: Nonsteroidal antiinflammatory drugs (NSAIDs) are increasingly being used during pregnancy to treat a variety of conditions. An evaluation of the risk of premature closure of the ductus arteriosus is useful in determining the safety of NSAIDs at different stages of pregnancy. Objective: To determine whether NSAID use during the third trimester of pregnancy is associated with an increased risk of premature constriction of the ductus arteriosus. Methods: A systematic review was conducted of MEDLINE (1966–2004), Embase (1980–2004), and the Cochrane Database of Systematic Reviews (1991–2004). Summary estimates of the odds ratios, comparing ductal outcomes in exposed and unexposed fetuses, and their 95% confidence intervals were calculated assuming a random effects model. Results: Based on 217 patients exposed to indomethacin and 221 to placebo, the risk of ductal closure was 15-fold higher in the group of women exposed to NSAIDs compared with those receiving either placebo or other NSAIDs (8 studies; OR = 15.04, 95% CI 3.29 to 68.68). There was no significant increased risk of ductal closure in the infants of women treated with indomethacin compared with those receiving other drugs (4 studies; OR = 2.12, 95% CI 0.48 to 9.25). Similar results were found when calculating rate differences. Conclusions: Short-term use of NSAIDs in late pregnancy is associated with a significant increase in the risk of premature ductal closure.

Medication use in pregnancy: a cross-sectional, multinational web-based study

Objectives Intercountry comparability between studies on medication use in pregnancy is difficult due to dissimilarities in study design and methodology. This study aimed to examine patterns and factors associated with medications use in pregnancy from a multinational perspective, with emphasis on type of medication utilised and indication for use. Design Cross-sectional, web-based study performed within the period from 1 October 2011 to 29 February 2012. Uniform collection of drug utilisation data was performed via an anonymous online questionnaire. Setting Multinational study in Europe (Western, Northern and Eastern), North and South America and Australia. Participants Pregnant women and new mothers with children less than 1 year of age. Primary and secondary outcome measures Prevalence of and factors associated with medication use for acute/short-term illnesses, chronic/long-term disorders and over-the-counter (OTC) medication use. Results The study population included 9459 women, of which 81.2% reported use of at least one medication (prescribed or OTC) during pregnancy. Overall, OTC medication use occurred in 66.9% of the pregnancies, whereas 68.4% and 17% of women reported use of at least one medication for treatment of acute/short-term illnesses and chronic/long-term disorders, respectively. The extent of self-reported medicated illnesses and types of medication used by indication varied across regions, especially in relation to urinary tract infections, depression or OTC nasal sprays. Women with higher age or lower educational level, housewives or women with an unplanned pregnancy were those most often reporting use of medication for chronic/long-term disorders. Immigrant women in Western (adjusted OR (aOR): 0.55, 95% CI 0.34 to 0.87) and Northern Europe (aOR: 0.50, 95% CI 0.31 to 0.83) were less likely to report use of medication for chronic/long-term disorders during pregnancy than non-immigrants. Conclusions In this study, the majority of women in Europe, North America, South America and Australia used at least one medication during pregnancy. There was a substantial inter-region variability in the types of medication used.

Polymorphism of the MDR1/ABCB1 C3435T drug-transporter and resistance to anticonvulsant drugs: a meta-analysis.

Background:  Approximately one‐third of patients with epilepsy patients have recurrent seizures despite therapy. It has been suggested that therapeutic failure is associated with high expression of the multidrug efflux ABCB1 (MDR1) drug‐transporter; specifically, that patients with the 3435CC genotype have higher efflux of anticonvulsants out of brain tissue, with correspondingly lower concentrations in the central nervous system.

Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.

BACKGROUND Use of HMG-CoA reductase inhibitors (statins) is becoming increasingly common. However, a recent study based on a series of cases reported to FDA suggests possible teratogenic effects of statins on embryogenesis, such as limb defects and severe central nervous system anomalies. METHODS In a prospective, observational cohort study with a comparison group to examine a fetal toxicity risk of statins, we followed 64 pregnant women taking statins, and 64 comparison group women without exposure to known teratogens. The statin group women were exposed to atorvastatin (n=46), simvastatin (n=9), pravastatin (n=6), or rosuvastatin (n=3) during the first trimester. RESULTS There was no difference in the rate of major malformations between the statin group (1/46 live birth: 2.2%) and the comparison group (1/52 live birth: 1.9%, p=0.93). Similarly, there were no statistical differences between the statin and comparison groups in live births (71.9% vs 81.2%), spontaneous abortions (14: 21.9% vs 11: 17.2%), therapeutic abortions (3: 4.7% vs 0: 0%) and stillbirths (1: 1.5% vs 1: 1.6%). Gestational age at birth (38.4+/-2.8 weeks vs 39.3+/-1.3 weeks: M+/-S.D., p=0.04) and birth weight (3.14+/-0.68kg vs 3.45+/-0.42kg, p=0.01) were lower in the statin group. CONCLUSIONS The absolute risk of teratogenicity of statins, if any, appears relatively small. A large-scale study is needed to further characterize the teratogenic potential.

Safety of Glyburide for Gestational Diabetes: A Meta-Analysis of Pregnancy Outcomes

BACKGROUND: Gestational diabetes mellitus affects approximately 4% of all pregnancies. As with other oral hypoglycemics, the use of glyburide in pregnancy has been limited by fears of neonatal hypoglycemia following fetal exposure. Recent experimental and clinical studies have suggested, however, that the drug is not detectable in umbilical blood. OBJECTIVE: To determine the safety of glyburide use in pregnancy in the treatment of gestational diabetes compared with insulin therapy by analyzing all available human studies. METHODS: We conducted a systematic review and meta-analysis of all randomized and cohort studies that reported on the perinatal complications among women with gestational diabetes who received glyburide versus insulin. MEDLINE, EMBASE, and biological abstracts using BIOSIS previews were searched from inception of these databases through October 2006. The following outcomes were included: macrosomia, birthweight, gestational age, neonatal hypoglycemia, and intensive care unit (ICU) admissions. Odds ratios were calculated by the random effects method using Cochranes Review Manager version 4.3. RESULTS: Nine studies met the inclusion criteria, including a total of 745 glyburide-exposed pregnancies and 637 insulin-exposed pregnancies, with each adverse perinatal outcome reported by 4–7 studies. The use of glyburide was not associated with risk of macrosomia (OR 1.07; 95% CI 0.78 to 1.47), differences in birth weight (weighted mean difference [WMD] OR 20.46 g; 95% CI −34.90 to 75.82), rate of large for gestational age (OR 1.04; 95% CI 0.75 to 1.43), differences in gestational age at birth (WMD 0.02 wk; 95% CI −0.23 to 0.26), ICU admission (OR 0.95; 95% CI 0.43 to 2.09), or increased risk of neonatal hypoglycemia (OR 1.24; 95% CI 0.91 to 1.69). CONCLUSIONS: The data shown here do not suggest increased perinatal risks with glyburide. The effectiveness and safety of glyburide require further evaluation, as most studies to date were not randomized.

Pregnancy outcome following rubella vaccination: a prospective controlled study.

The rubella virus is a potent human teratogen. Because the rubella vaccine is prepared with live virus, a high level of anxiety surrounds exposure in pregnancy. There is relatively scarce data on fetal risk following vaccination in pregnancy, and all of the available data were collected retrospectively. Our objective was to examine whether periconceptional exposure to rubella vaccine can cause the congenital rubella syndrome, and to compare the rate of major malformations and developmental milestones among offspring of women who received rubella vaccine 3 months pre‐ or post‐conception to an unexposed comparison group. We collected prospectively and followed up 94 women who received rubella vaccination 3 months pre‐ or post‐conception and a comparison group that consisted of 94 women who were counseled during pregnancy in a similar manner but were not exposed to known teratogens. The controls were matched for age, smoking, alcohol, and drug use. Not any of the women exposed to the vaccine gave birth to a child with congenital rubella syndrome. Rates of major malformations were similar in both groups as were birth weights and developmental milestones. In contrast, the rate of therapeutic abortions was higher in the exposed group (7.4% vs. 0%) (P < 0.05), due to fears of teratogenicity. We conclude that rubella vaccination in pregnancy does not appear to affect pregnancy outcome in general or cause congenital rubella syndrome in particular.