Teratogenic Signal Research Articles

Bayesian hierarchical methods in the detection of potentially teratogenic first-trimester medications.

Bayesian hierarchical models (BHMs) have been used to identify adverse drug reactions, allowing information sharing amongst adverse reactions and drugs expected to have similar properties. This study evaluated the use of BHMs in the routine signal detection analyses of potential first-trimester teratogens, where these models have not previously been applied. Data on 15 058 malformed foetuses exposed to first trimester medications (1995-2011) from 13 European congenital anomaly (CA) registries were analysed. The proportion of each CA in women taking a specific medication was compared with the proportion of that CA in all other women in the dataset (55 CAs × 523 medications). BHMs were grouped by either medications or CAs or by both simultaneously, and the results compared with analysing each medication-CA combination separately and adjusting for multiplicity using a double false discovery rate (FDR) procedure. The proportions of "high-risk" medications (medications which have been shown to carry a moderate to high risk of foetal malformations) identified as potential signals were compared, as well as the total number of potential signals requiring follow up (the effective workload). BHMs identified more high-risk medications than the double FDR method, but the effective workload was larger. A BHM grouping both medications and CAs, for example, identified 23% of high-risk medications compared with 14% by the double FDR; however, there was an increase from 16 to 71 potential signals requiring follow up. For comparable effective workloads, BHMs did not outperform the double FDR, which is comparatively straightforward to implement and is therefore recommended for continued use in teratogenic signal detection analyses.

Pregnancy outcomes in patients with multiple sclerosis treated with teriflunomide: Clinical study data and 5 years of post-marketing experience

Background: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception. Objectives: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting. Methods: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017). Results: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports. Conclusions: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies.

PREGNANCY OUTCOMES FROM TERIFLUNOMIDE CLINICAL STUDIES

Introduction Teriflunomide is a once-daily oral immunomodulator approved for treatment of relapsing–remitting multiple sclerosis. Teriflunomide is the active metabolite of leflunomide, approved for treatment of rheumatoid arthritis since 1998. Evidence from animal models suggests a potential for fetal risk from teriflunomide. Methods Reliable contraception was mandated during teriflunomide trials. Pregnant patients were to discontinue treatment and undergo an accelerated elimination procedure (cholestyramine or activated charcoal). Pregnancies were reported in the teriflunomide clinical database (cut-off October 2013). Results Eighty-three pregnancies were reported in female patients and 22 in partners of male patients; 26 live births occurred in teriflunomide-treated women and 16 occurred in partners of male patients receiving teriflunomide. Newborns whose parents received teriflunomide had no structural defects or functional deficits at birth. The spontaneous abortion rate for female patients was 18.6%–within the range reported in the general population. Conclusions Data from the clinical programme have shown no teratogenic signal for teriflunomide, consistent with findings of the Organization of Teratology Information Services (OTIS) registry, and >2.5 million patient-years of post-marketing data for leflunomide. Current pregnancy numbers are too small to draw firm conclusions. Additional data will be provided by teriflunomide pregnancy registries.

Final results from the 16-year sumatriptan, naratriptan, and treximet pregnancy registry.

To monitor for a signal of major teratogenicity by determining the risk of all birth major defects following in utero exposure to sumatriptan, naratriptan, and the sumatriptan/naproxen sodium combination product (tablets marketed in the United States as Treximet [GlaxoSmithKline, Research Triangle Park, NC, USA]), and to monitor for unusual patterns of defects that might suggest teratogenicity. The prevalence of migraine is highest in women of childbearing age. Coupled with the recurrent nature of migraine attacks and the high proportion of unplanned pregnancies, intentional and inadvertent exposure to anti-migraine drugs in pregnancy is likely. The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry captured data on women exposed to those drugs during pregnancy to monitor for evidence of major teratogenicity. In this primarily prospective, observational study, health care professionals from anywhere in the world enrolled, on a voluntary basis, women exposed to sumatriptan, naratriptan, or the sumatriptan/naproxen sodium combination product during their pregnancies. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The proportion of infants or fetuses with major birth defects was calculated as the total number of infants/fetuses with major birth defects divided by the sum of the number of infants/fetuses with major birth defects + the number of live births without defects. The risk of major birth defects was further stratified by earliest trimester of pregnancy exposure. The registry enrolled 680 evaluable exposed pregnant women, which resulted in 689 infants and fetuses (outcomes). Of these outcomes, 626 were exposed to sumatriptan, 57 were exposed to naratriptan (seven were exposed to both sumatriptan and naratriptan), and six were exposed to the sumatriptan/naproxen sodium combination product. Twenty outcomes with major birth defects were reported among 528 outcomes exposed in the first trimester to sumatriptan. The estimated risk of major birth defects following first-trimester sumatriptan exposure is 4.2% (20/478 [95% confidence interval [CI] 2.6%-6.5%]). Among 52 first-trimester exposures to naratriptan, major birth defects were reported in one outcome, an infant with exposure to both sumatriptan and naratriptan [birth defect risk of 2.2% (1/46 [95% CI 0.1%-13.0%]). No major defects were reported among the five outcomes with first-trimester exposure to the sumatriptan/naproxen sodium combination products. The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry detected no signal of teratogenicity associated with major birth defects for sumatriptan. This finding is consistent with results from other observational studies using a variety of control groups. Enrollment in the registry was insufficient to permit definitive conclusions of the risks associated with naratriptan or sumatriptan/naproxen sodium tablets, or to assess the risk of individual birth defects in any of the products studied. Low enrollment and high rates of loss to follow up within the registry over an extended period of time led the registry's scientific advisory committee to conclude that continuation of the registry beyond its 16 years would offer little additional power to rule out more moderate increases in the risk of birth defects. Data from the other ongoing surveillance sources constitute an important element of post-marketing surveillance of these medications. The lack of a signal of major teratogenicity with sumatriptan across these several sources of data is encouraging.

Antidepressants and the developing nervous system

Antidepressants and the developing nervous system

Safety of sumatriptan in pregnancy: a review of the data so far.

The high prevalence of migraine in women during their reproductive years means that new drug treatments for migraine, such as the serotonin 5-HT(1B/1D) receptor agonists (the 'triptans'), are likely to be widely used by women of childbearing potential. Scrutiny of these agents in an effort to detect any signal of teratogenicity is thus important. A systematic review of the medical literature was conducted to identify information regarding the safety of sumatriptan during pregnancy. This agent was chosen to be investigated because it has been available for the longest and is the most widely used of the triptan class. Information was obtained regarding the impact of migraine on pregnancy outcome, and data on sumatriptan use in pregnancy were obtained from animal studies, preclinical drug trials, postmarketing surveillance efforts, prospective pregnancy registries, national birth registries and teratogen information services. Synthesis of information from these sources is sufficient to rule out a large increase in birth defects from sumatriptan use during pregnancy and is reassuring for cases where inadvertent exposure to sumatriptan during pregnancy has occurred. However, current information is not sufficient to rule out small increases in the risk for birth defects. For this reason, caution should be exercised in making a positive recommendation for the use of sumatriptan during pregnancy.

Birth defect classification by organ system: a novel approach to heighten teratogenic signalling in a pregnancy registry.

The Antiretroviral Pregnancy Registry (APR) is an ongoing international prospective exposure-registration cohort study that monitors outcomes of pregnancies exposed to marketed antiretroviral medications. The population of women exposed to antiretrovirals remains relatively small, which limits the power of the registry. In order to maximize identification of a teratogenic signal, a special birth defect classification system was devised. Birth defects were organized based upon organ system and embryology, using the Metropolitan Atlanta Congenital Defects Program as a model. Grouping defects that share embryology and pathogenesis increases the likelihood that a teratogenic effect will be apparent. The result is a three-tiered system: organ system, preferred defect term, and reported defect term. This system is text based, which eliminates the need to memorize codes and allows use by anyone familiar with medical terminology. Once established, the new APR Organ System Classification retains enough flexibility that categories may be collapsed or expanded as experience grows. Standardized nomenclature also minimizes variation introduced by collecting defect reports from many different sources.

Retinoids and Mammalian Development

All vertebrate embryos require retinoic acid (RA) for fulfilment of the developmental program encoded in the genome. In mammals, maternal homeostatic mechanisms minimize variation of retinoid levels reaching the embryo. Retinol is transported as a complex with retinol-binding protein (RBP): transplacental transfer of retinol and its uptake by the embryonic tissues involves binding to an RBP receptor at the cell surface. Embryonic tissues in which this receptor is present also contain the retinol-binding protein CRBP I and the enzymes involved in RA synthesis; the same tissues are particularly vulnerable to vitamin A deficiency. In the nucleus, the RA signal is transduced by binding to a heterodimeric pair of retinoid receptors (RAR/RXR). In general, the receptors show functional plasticity, disruption of one RAR or RXR gene having minor or no effects on embryogenesis. However, genetic studies indicate that RXR alpha is essential for normal development of the heart and eye. Excess RA causes abnormalities of many systems; altered susceptibility to RA excess in mice lacking RAR gamma or RXR alpha suggests that the teratogenic signal is transduced through different receptors compared with physiological RA function in the same tissue.