Association between reported venlafaxine use in early pregnancy and birth defects,national birth defects prevention study, 1997–2007

BACKGROUND

Few epidemiologic studies have investigated the use of venlafaxine (Effexor XR capsules, Product Monograph, Wyeth, Montreal, Canada), an antidepressant used to treat major depression and anxiety disorders in adults, during pregnancy. Our objective was to determine whether use of venlafaxine during pregnancy is associated with specific birth defects.

METHODS

We used data from the National Birth Defects Prevention Study (NBDPS), a population‐based, case‐control study in the United States. Our analysis included mothers with pregnancies affected by one of 30 selected birth defects (cases) and babies without birth defects (controls) with estimated dates of delivery between 1997 and 2007. Exposure was any reported use of venlafaxine from 1 month preconception through the third month of pregnancy. We calculated adjusted odds ratios (aORs) and 95% Fisher Exact confidence intervals (CIs) for 24 birth defect groups for which at least 400 case mothers were interviewed. Our adjusted analyses controlled for maternal age and race/ethnicity.

RESULTS

Among the 27,045 NBDPS participants who met inclusion criteria, 0.17% (14/8002) of control mothers and 0.40% (77/19,043) of case mothers reported any use of venlafaxine from 1 month preconception through the third month of pregnancy. Statistically significant associations were found for anencephaly, atrial septal defect (ASD) secundum, or ASD not otherwise specified, coarctation of the aorta, cleft palate, and gastroschisis.

CONCLUSIONS

Our data suggest associations between periconceptional use of venlafaxine and some birth defects. However, sample sizes were small, CIs were wide, and additional studies are needed to confirm these results. Birth Defects Research (Part A), 2013. © 2012 Wiley Periodicals, Inc.     

The developmental bases of limb reduction and body elongation in squamates

Employing an integrative approach to investigate the evolution of morphology can yield novel perspectives not attainable from a single field of study. Studies of limb loss and body elongation in squamates (snakes and lizards) present a good example in which integrating studies of systematics and ecology with genetics and development can provide considerable new insight. In this comment we address several misunderstandings of the developmental genetic literature presented in a paper by Wiens and Slingluff (2001) to counter their criticism of previous work in these disciplines and to clarify the apparently contradictory data from different fields of study. Specifically, we comment on (1) the developmental mechanisms underlying axial regionalization, body elongation, and limb loss; (2) the utility of presacral vertebral counts versus more specific partitioning of the primary body axis; (3) the independent, modular nature of limbs and limb girdles and their utility in diagnosing genetic changes in development; and (4) the causal bases of hind limb reduction in ophidian and nonophidian squamates.     

Preconceptional folic acid‐containing supplement use in the national birth defects prevention study

Background: Despite public health campaigns encouraging women to take a daily folic acid supplement, the proportion of reproductive age women, in the United States, who comply with this recommendation is less than optimal. The objective of this analysis was to identify predictors of preconceptional folic acid‐containing supplement use to define subgroups of women who may benefit from targeted folic acid campaigns. Methods: This study included 6570 mothers of live born infants from the control population of National Birth Defects Prevention Study (1997–2005). Logistic regression analyses were used to identify predictors of preconceptional folic acid supplementation. A classification and regression tree (CART) analysis was used to define subgroups of women with different patterns of preconceptional folic acid supplementation. Results: Race/ethnicity, education, age at delivery, nativity, employment, income, number of dependents, smoking, and birth control use were significantly associated with preconceptional folic acid‐containing supplement use. Based on a CART analysis, education, race/ethnicity, and age were the most distinguishing factors between women with different preconceptional supplementation patterns. Non‐white women with <4 years of a college education were the least likely to use folic acid‐containing supplements (11%). However, even in the most compliant subgroup (women with ≥4 years of college), only 60% of women supplemented with folic acid. Conclusion: These results demonstrate the need for continued efforts to increase folic acid supplementation among all reproductive aged women. However, the success of such efforts may be improved if maternal characteristics such as education, race/ethnicity, and age, are considered in the development of future interventions. Birth Defects Research (Part A) 100:472–482, 2014. © 2014 Wiley Periodicals, Inc.     

The power of zebrafish models for understanding the co‐occurrence of craniofacial and limb disorders

Craniofacial and limb defects are two of the most common congenital anomalies in the general population. Interestingly, these defects are not mutually exclusive. Many patients with craniofacial phenotypes, such as orofacial clefting and craniosynostosis, also present with limb defects, including polydactyly, syndactyly, brachydactyly, or ectrodactyly. The gene regulatory networks governing craniofacial and limb development initially seem distinct from one another, and yet these birth defects frequently occur together. Both developmental processes are highly conserved among vertebrates, and zebrafish have emerged as an advantageous model due to their high fecundity, relative ease of genetic manipulation, and transparency during development. Here we summarize studies that have used zebrafish models to study human syndromes that present with both craniofacial and limb phenotypes. We discuss the highly conserved processes of craniofacial and limb/fin development and describe recent zebrafish studies that have explored the function of genes associated with human syndromes with phenotypes in both structures. We attempt to identify commonalities between the two to help explain why craniofacial and limb anomalies often occur together.     

Lack of concordance between heat shock proteins and the development of tolerance to teratogen-induced neural tube defects

The present study was undertaken to examine the role of heat shock response in the development of tolerance and cross-tolerance in an in vivo murine model of teratogen-induced neural tube defects. The experimental paradigm designed to address this question was to utilize inbred mouse strains that differed in their sensitivity to hyperthermia and valproic acid induced neural tube defects, subjecting the dams to subteratogenic pretreatments with either heat or valproic acid at two different timepoints during development prior to the administration of the teratogenic insult. A statistically significant reduction in the frequency of neural tube defects and/or embryolethality following a pretreatment in dams subsequently exposed to a teratogenic treatment was considered evidence for the induction of tolerance. This was observed in the SWV embryos exposed to the 38°C pretreatment at 8:06 and to embryos exposed to either pretreatment temperature at 8:10 priorto a teratogenic heat shock at 8:12. In the LM/Bc embryos, only the 41°C pretreatment at 8:06 induced thermotolerance. There was no evidence of tolerance induced in either mouse strain using valproic acid. On the other hand, cross-tolerance was clearly demonstrated in this study, with a low temperature (41°C) pretreatment successfully protecting SWV fetuses from a subsequent teratogenic treatment with valproic acid, while valproic acid (200 mg/kg) was effective in reducing the risk of hyperthermia-induced neural tube defects in the LM/Bc fetuses. In all instances, tolerance was induced in the absence of significant induction of hsp synthesis. The lack ofconcordance between hsps and thermotolerance suggests that some other factor(s) is involved in conferring thermotolerance on developing murine embryos. © 1993 Wiley-Liss, Inc.     

Functional analysis of chick heparan sulfate 6‐O‐sulfotransferases in limb bud development

Heparan sulfate (HS) interacts with numerous growth factors, morphogens, receptors, and extracellular matrix proteins. Disruption of HS synthetic enzymes causes perturbation of growth factor signaling and malformation in vertebrate and invertebrate development. Our previous studies show that the O‐sulfation patterns of HS are essential for the specific binding of growth factors to HS chains, and that depletion of O‐sulfotransferases results in remarkable developmental defects in Drosophila, zebrafish, chick, and mouse. Here, we show that inhibition of chick HS‐6‐O‐sulfotransferases (HS6ST‐1 and HS6ST‐2) in the prospective limb region by RNA interference (RNAi) resulted in the truncation of limb buds and reduced Fgf‐8 and Fgf‐10 expressions in the apical ectodermal ridge and in the underlying mesenchyme, respectively. HS6ST‐2 RNAi resulted in a higher frequency of limb truncation and a more marked change in both Fgf‐8 and Fgf‐10 expressions than that achieved with HS6ST‐1 RNAi. HS6ST‐1 RNAi and HS6ST‐2 RNAi caused a significant but distinct reduction in the levels of different 6‐O‐sulfation in HS, possibly as a result of their different substrate specificities. Our data support a model where proper levels and patterns of 6‐O‐sulfation of HS play essential roles in chick limb bud development.