Angela E. Scheuerle

Background: The primary objective of this study was to assess associations between maternal reports of diarrhea during early pregnancy and a range of different birth defects, most of which have not been assessed in previous studies. The secondary objective was to determine whether associations were modified by maternal use of multivitamins.Methods: We analyzed data on 16,675 mothers who participated in the National Birth Defects Prevention Study (NBDPS) and delivered between 2006 and 2011. Logistic regression was used to evaluate associations between maternal report of diarrhea during the periconceptional period and 32 categories of birth defects. Odds ratios were adjusted for nine covariates.Results: Eleven percent of women reported having diarrhea during the periconceptional period. We observed elevated associations (p < 0.10) between maternal report of diarrhea lasting 1–5 days and 9 of 32 independent categories of birth defects (hypoplastic left heart, muscular ventricular septal defect, single ventricle complex, secundum atrial septal defect, esophageal atresia, diaphragmatic hernia, omphalocele, gastroschisis, and amniotic band syndrome). The elevated adjusted odds ratios (aORs) ranged from 1.45 to 2.62. There were no decreased associations between maternal report of diarrhea lasting 1–5 days and any of the 32 birth defects. There was no evidence for a significant linear trend of stronger associations between maternal diarrhea and birth defects among mothers who had inadequate or suboptimal use of multivitamins.Conclusion: Our results are consistent with modest associations between shorter, but not longer, bouts of maternal diarrhea and specific categories of birth defects. These results add to existing evidence, suggesting maternal diarrhea and gastrointestinal infections during early pregnancy are associated with a higher frequency of some birth defects.

Epidemiologic studies of birth defects often conduct separate analyses for cases that have isolated defects (e.g., spina bifida only) and cases that have multiple defects (e.g., spina bifida and a congenital heart defect). However, in some instances, cases with additional defects (e.g., spina bifida and clubfoot) may be more appropriately considered as isolated because the co‐occurring defect (clubfoot) is believed to be developmentally related to the defect of interest. Determining which combinations should be considered isolated can be challenging and potentially resource intensive for registries. Thus, we developed automated classification procedures for differentiating between isolated versus multiple defects, while accounting for developmentally related defects, and applied the approach to data from the Texas Birth Defects Registry (1999–2018 deliveries). Among 235,544 nonsyndromic cases in Texas, 89% of cases were classified as having isolated defects, with proportions ranging from 25% to 92% across 43 specific defects analyzed. A large proportion of isolated cases with spina bifida (44%), lower limb reduction defects (44%), and holoprosencephaly (32%) had developmentally related defects. Overall, our findings strongly support the need to account for isolated versus multiple defects in risk factor association analyses and to account for developmentally related defects when doing so, which has implications for interpreting prior studies.

Choanal atresia and stenosis are common causes of congenital nasal obstruction, but their epidemiology is poorly understood. Compared to bilateral choanal atresia/stenosis, unilateral choanal atresia/stenosis is generally diagnosed later and might be under‐ascertained in birth defect registries. Data from the population‐based Texas Birth Defects Registry and Texas vital records, 1999–2018, were used to assess the prevalence of choanal atresia/stenosis. Poisson regression models were used to evaluate associations with infant and maternal characteristics in two analytic groups: isolated choanal atresia/stenosis (n = 286) and isolated, bilateral choanal atresia/stenosis (n = 105). The overall prevalence of choanal atresia/stenosis was 0.92/10,000, and the prevalence of isolated choanal atresia/stenosis was 0.37/10,000 livebirths. Variables associated with choanal atresia/stenosis in one or both analytic groups included infant sex, pregnancy plurality, maternal race/ethnicity, maternal age, and maternal residence on the Texas–Mexico border. In general, adjusted prevalence ratios estimated from the two analytic groups were in the same direction but tended to be stronger in the analyses restricted to isolated, bilateral defects. Epidemiologic studies of isolated choanal atresia/stenosis should consider focusing on cases with bilateral defects, and prioritizing analyses of environmental, social, and structural factors that could account for the association with maternal residence on the Texas–Mexico border.

NudC-like protein 2 (NUDCD2) is a 4-exon protein-coding gene at 5q34. The protein appears to act in concert with other genes regulating cell migration and microtubule extension. Early studies in model organisms show associations with LIS1, HERC2, and cohesin subunits via a co-chaperone function with Heat shock protein 90 (Hsp90). It is a candidate gene for human pathology. We present two unrelated patients with biallelic variants in NUDCD2. Their phenotypes comprise similar dysmorphic facies, midline brain hypoplasia, hypothyroidism, pulmonary and aortic valve stenosis, severe dysfunction of the liver and kidneys, profound hypotonia, and early death. The cellular analysis demonstrates the absence of the NUDCD2 protein in fibroblasts of one patient with biallelic loss-of-function variants. The data suggest that NUDCD2 deficiency causes this recognizable syndrome that has features of a ciliopathy with additional complications.

Background: Building on findings that linked higher levels of sunspot (SS) activity with a range of health and adverse birth outcomes, we sought to understand how SS activity over a 17‐year time period may be correlated with the occurrence of birth defects.Methods: Data from the Texas Birth Defects Registry, vital events from the Texas Center for Health Statistics, and mean monthly numbers of sunspots from the National Oceanic and Atmospheric Administration were utilized. Poisson regression was used to calculate crude/adjusted prevalence ratios (cPRs/aPRs) and 95% confidence intervals for three quartiles (Q) of increasing SS activity (compared to a referent of low activity) and 44 birth defects (31 non‐cardiac; 13 cardiac) with estimated dates of conception from 1998 to 2016.Results: We found moderately protective aPRs (range: 0.60–0.89) in a little over half of the case groups examined in our quartiles of higher SS activity (19 non‐cardiac; 6 cardiac), after adjusting for maternal age, race/ethnicity, and education. Particularly protective aPRs in the highest SS quartiles (Q3–4) were noted for: anophthalmia, cataract, gastroschisis, trisomy 18, ventricular septal defects, atrial septal defects, and pulmonary valve atresia or stenosis. Conversely, modestly elevated aPRs were noted for two defect groups (agenesis, aplasia, and hypoplasia of the lung and microcephaly [Q2–3]). Following an additional adjustment of year of conception, results remained similar although many of the estimates were attenuated.Conclusion: The seemingly protective associations between increasing SS activity may be an artifact of increasing spontaneous abortions that occur following conception during these periods of heightened SS activity.

Many infants with anotia or microtia (A/M) have co‐occurring birth defects, although few receive syndromic diagnoses in the perinatal period. Evaluation of co‐occurring birth defects in children with A/M could identify patterns indicative of undiagnosed/unrecognized syndromes. We obtained information on co‐occurring birth defects among infants with A/M for delivery years 1999–2014 from the Texas Birth Defects Registry. We calculated observed‐to‐expected ratios (OER) to identify birth defect combinations that occurred more often than expected by chance. We excluded children diagnosed with genetic or chromosomal syndromes from analyses. Birth defects and syndromes/associations diagnosed ≤1 year of age were considered. We identified 1310 infants with non‐syndromic A/M, of whom 38% (N = 492) were diagnosed with co‐occurring major defects. Top combinations included: hydrocephalus, ventricular septal defect, and spinal anomalies (OER 58.4); microphthalmia and anomalies of the aorta (OER 55.4); and cleft lip with or without cleft palate and rib or sternum anomalies (OER 32.8). Some combinations observed in our study may represent undiagnosed/atypical presentations of known A/M associations or syndromes, or novel syndromes yet to be described in the literature. Careful evaluation of infants with multiple birth defects including A/M is warranted to identify individuals with potential genetic or chromosomal syndromes.

Structural birth defects that occur in infants with syndromes may be etiologically distinct from those that occur in infants in whom there is not a recognized pattern of malformations; however, population‐based registries often lack the resources to classify syndromic status via case reviews. We developed criteria to systematically identify infants with suspected syndromes, grouped by syndrome type and level of effort required for syndrome classification (e.g., text search). We applied this algorithm to the Texas Birth Defects Registry (TBDR) to describe the proportion of infants with syndromes delivered during 1999–2014. We also developed a bias analysis tool to estimate the potential percent bias resulting from including infants with syndromes in studies of risk factors. Among 207,880 cases with birth defects in the TBDR, 15% had suspected syndromes and 85% were assumed to be nonsyndromic, with a range across defect types from 28.5% (atrioventricular septal defects) to 98.9% (pyloric stenosis). Across hypothetical scenarios varying expected parameters (e.g., nonsyndromic proportion), the inclusion of syndromic cases in analyses resulted in up to 50.0% bias in prevalence ratios. In summary, we present a framework for identifying infants with syndromic conditions; implementation might harmonize syndromic classification across registries and reduce bias in association estimates.

Purpose: There is emerging evidence that children with multiple congenital anomalies have a higher risk of developing cancer compared to unaffected children. However, there have been few population-based estimates of cancer risk among children with well-described patterns of recurrent multiple congenital anomalies (MCAs). VACTERL association is one such pattern that is defined by the presence of ≥3 of the following in the absence of a genetic diagnosis: vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal, and limb anomalies. VACTERL occurs in approximately 5% of children with Fanconi anemia (FA), a known cancer predisposition syndrome. In spite of this, there are no population-based estimates of cancer risk in children with VACTERL. Therefore, we investigated if VACTERL confers an elevated risk of pediatric cancer by examining a birth cohort of >7 million children from three U.S. states (Texas, North Carolina, and Oklahoma) for the period 1997-2013. Methods: Demographic and diagnostic data from birth certificates, birth defects registries, and cancer registries were linked in each state and pooled for analysis. For this analysis, children with chromosomal anomalies were excluded. We used Cox proportional hazards models to evaluate the risk of cancer before 19 years of age in three birth defect groups: (1) VACTERL; (2) ≥3 major anomalies but not VACTERL; and (3) 1 to 2 major anomalies. A hazard ratio (HR) and 95% confidence interval (CI) was calculated in each group for: (1) overall cancer risk and (2) risk of embryonal tumors (e.g., neuroblastoma, medulloblastoma, hepatoblastoma) based on reported associations between birth defects and these pediatric cancers. Results: In our cohort of 7,767,786 births, we identified: 2,090 children (0.02%) with VACTERL; 32,558 children with ≥3 non-VACTERL defects; and 201,871 children with 1 to 2 defects. Respectively, these three groups had 10, 167, and 684 cases of cancer. Compared to children without birth defects, children with VACTERL (HR=3.9, 95% CI: 2.1 - 7.2), ≥3 non-VACTERL defects (4.2, 3.6 - 4.9), and 1 to 2 defects (2.7, 2.5 - 2.9), were all more likely to develop cancer. Risk was higher for embryonal tumors among children with VACTERL (10.4, 4.7 - 23.1) than for those with ≥3 non-VACTERL defects (5.6, 4.2 - 7.4) or 1 to 2 defects (3.9, 3.4 - 4.5). Conclusion: In this population-based assessment, we demonstrated that children with VACTERL were more likely than other groups to develop cancer, particularly embryonal tumors, although the absolute cancer risk was Citation Format: Alexander Renwick, Jeremy M. Schraw, Tania A. Desrosiers, Amanda E. Janitz, Michael E. Scheurer, Mark A. Canfield, Peter H. Langlois, Angela E. Scheuerle, Sharon E. Plon, Philip J. Lupo. A population-based assessment of cancer risk in children with recurrent multiple congenital anomalies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1998.

The APR is prospective exposure-registration cohort study, monitoring for early warning signals of major teratogenic effects of antiretrovirals (ARV) used during pregnancy. This analysis aimed to assess maternal demographics, pregnancy and neonatal outcomes including birth defects among infants with periconception and prenatal exposure to DTG using APR data. Descriptive analysis with frequency tabulation of pregnancy and neonatal outcomes is reported. Periconception is defined as any exposure within two weeks prior to or through 28 days after conception. There were 1010 prospectively reported pregnancies with exposure to DTG through 31January2021, with 526 periconception exposures, 105 exposed later during 1^st trimester, 260 during 2^nd trimester and 119 during 3^rd trimester. Maternal median age at conception was 30 years and 77.0% of pregnancies were reported from the United States. At the time of reporting, 46.6% had CD4 count ≥500 cells/µL, 31.8% had 200-499 cells/µL, 12.5% had < 200 cells/µL and 9.1% unknown. The 1010 DTG exposed pregnancies resulted in 1036 outcomes: 956 (92.3%) live births (26 twin pairs), 12 (1.2%) stillbirths, 28 (2.7%) induced abortions, and 38 (3.7%) spontaneous abortions. Among live births, 39 (4.1%) reported birth defects. For 1^st trimester exposures, overall defect prevalence was 3.3% (19/576, 95% CI:2.0-5.1) and for 2^nd/3^rd trimester exposures defect prevalence was 5.3% (20/380, 95% CI:3.2-8.0). One neural tube defect (NTD) case of anencephaly with periconception DTG exposure was reported. Among the 873 singleton, live births without birth defects, 92 (10.5%) were preterm (< 37 weeks of gestation); 103 (11.8%) had low birth weight (lbw) < 2500 grams including 22 (2.5%) < 1500 (very lbw) grams. APR data do not demonstrate an increased risk of overall birth defects with DTG use above the population expected rate of defects (2.72 to 4.17 per 100 live births from Metropolitan Atlanta Congenital Defects Program [MACDP] and Texas Birth Defects Registry [TBDR] respectively). The number of periconception exposure outcomes is not yet sufficient to evaluate potential association of DTG with NTD. The Registry continues to closely monitor birth defects, including NTDs in pregnancies exposed to DTG and other integrase inhibitors. Vani Vannappagari, MBBS, MPH, PhD, ViiV Healthcare Limited (Employee) Jessica Albano, PhD, MPH, Syneos Health (Employee, Shareholder) Leigh Ragone, MS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Taylor Cook, BS, Syneos Health (Employee) Angela Scheuerle, MD, ViiV (Independent Contractor) William R. Short, MD, Gilead Sciences (Individual(s) Involved: Self): Consultant; ViiV (Individual(s) Involved: Self): Consultant Claire Thorne, MSc, PhD, MSD (Grant/Research Support)ViiV Healthcare (Grant/Research Support, Other Financial or Material Support, Contributor to Think Tank)