The case classification schema developed for the NBDPS may be of value to other clinicians working on epidemiologic studies of birth defects etiology. Consideration of these guidelines will lead to more comparable case groups, an important element of careful studies aimed at identifying risk factors for birth defects.

AEDs such as valproate and phenobarbital were associated with a higher risk of major malformations than newer AEDs such as lamotrigine and levetiracetam. Topiramate was associated with an increased risk of cleft lip compared with that of a reference population.

Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

Background There is controversy regarding whether the use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants in pregnancy is associated with increased risks for congenital cardiac defects. In particular, concerns exist about a possible association between paroxetine and right ventricular outflow tract obstruction (RVOTO), and between sertraline and ventricular septal defects (VSD). Methods We performed a cohort study nested in the 2000–2007 nationwide Medicaid Analytic eXtract. The study included 949,504 pregnant women enrolled in Medicaid from three months before conception through one month post delivery, and their live-born infants. We compared the risk of major cardiac defects in women with antidepressant medication use during the first trimester versus no use, restricting the cohort to women with depression and using propensity score adjustment to control for depression severity and other potential confounders. Results 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6,403 infants not exposed to antidepressants were born with a cardiac defect (72.3 per 10,000), compared with 580 infants exposed (90.1 per 10,000). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. For SSRIs, relative risks for any cardiac defect were 1.25 (95%CI, 1.13–1.38) unadjusted, 1.12 (1.00–1.26) depression-restricted, and 1.06 (0.93–1.22) depression-restricted and fully-adjusted. We found no significant associations between the use of paroxetine and RVOTO (1.07, 0.59–1.93), or the use of sertraline and VSD (1.04, 0.76–1.41). Conclusions Results of this large population-based cohort study suggest no substantial increased risk of cardiac malformations attributable to SSRIs.