RESUMO
BACKGROUND: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). CONCLUSION: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.
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Citocromo P-450 CYP1B1 , Sequenciamento do Exoma , Exoma , Glaucoma , Humanos , Glaucoma/genética , Glaucoma/congênito , Citocromo P-450 CYP1B1/genética , Feminino , Masculino , Sequenciamento do Exoma/métodos , Estados Unidos , Exoma/genética , Mutação/genética , Predisposição Genética para Doença , Lactente , Recém-NascidoRESUMO
BACKGROUND: Fungal infections are common among pregnant people. Recent studies suggest positive associations between oral antifungals used to treat fungal infections and congenital heart defects (CHDs). METHODS: We estimated associations between first trimester antifungal use and 20 major, specific CHDs using data from the National Birth Defects Prevention Study (NBDPS), a multi-site, case-control study that included pregnancies with estimated delivery dates from October 1997 through December 2011. Infants with CHDs ("cases") were ascertained from 10 birth defect surveillance programs. Live born infants without major birth defects ("controls") were randomly selected from birth records or hospital discharge lists. First trimester antifungal use was self-reported via maternal interview. We estimated adjusted odds ratios (AORs) and 95% confidence intervals (CIs) using logistic regression with Firth's penalized likelihood. RESULTS: First trimester antifungal use was reported by 148/11,653 (1.3%) case and 123/11,427 (1.1%) control participants. We estimated AORs for 12 CHDs; six had AORs >1.5 (tetralogy of Fallot, double outlet right ventricle with transposition of the great arteries [DORV-TGA], atrioventricular septal defect, hypoplastic left heart syndrome, pulmonary atresia, muscular ventricular septal defect), and one (pulmonary valve stenosis) had an AOR <0.7. All CIs included the null, except for DORV-TGA. CONCLUSIONS: First trimester antifungal use was rare. We observed some positive associations for several specific CHDs in our analysis, although the CIs largely included the null. Results do not support a large increase in risk, but smaller increases in risk for certain CHD cannot be ruled out.
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Cardiopatias Congênitas , Micoses , Transposição dos Grandes Vasos , Gravidez , Lactente , Feminino , Humanos , Antifúngicos/efeitos adversos , Estudos de Casos e Controles , Cardiopatias Congênitas/epidemiologiaRESUMO
OBJECTIVE: Previous studies of alcohol consumption during pregnancy and omphalocele have produced mixed results. We updated an earlier analysis of National Birth Defects Prevention Study (NBDPS) data, adding six years of participants, to examine associations between maternal alcohol consumption and omphalocele. METHODS: NBDPS was a multi-site, population-based case-control study in the United States. Cases were identified from birth defect surveillance programs in 10 states; controls were liveborn infants without a birth defect randomly selected from the same catchment areas. Mothers self-reported alcohol consumption during the periconceptional period (one month before through the third gestational month) via telephone interview. Our study included mothers of 410 omphalocele cases and 11,219 controls with estimated dates of delivery (EDDs) during 1997-2011. We used logistic regression to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for periconceptional alcohol consumption and omphalocele. We performed a probabilistic bias analysis to evaluate the impact of alcohol exposure misclassification on our results. RESULTS: Overall, 44% of case and 38% of control mothers reported periconceptional alcohol consumption; 22% and 17%, respectively, reported binge drinking. Any maternal periconceptional alcohol consumption was associated with modestly increased odds of omphalocele (AOR 1.35, 95% CI 1.09, 1.68), as was binge drinking (AOR 1.47, 95% CI 1.08, 2.01). Our bias analysis yielded estimates further from the null. CONCLUSIONS: We observed modest associations between maternal periconceptional alcohol consumption and omphalocele. Based on our bias analysis, studies of alcohol and birth defects not accounting for exposure misclassification may underestimate associations.
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Consumo Excessivo de Bebidas Alcoólicas , Hérnia Umbilical , Gravidez , Lactente , Feminino , Humanos , Estados Unidos/epidemiologia , Hérnia Umbilical/epidemiologia , Hérnia Umbilical/etiologia , Fatores de Risco , Estudos de Casos e Controles , Exposição Materna , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologiaRESUMO
BACKGROUND: Previous studies report an association between prenatal maternal urinary tract infections (UTI) and specific congenital heart defects (CHDs); however, the role of fever and antibiotic use on this association is poorly understood. Using data from the National Birth Defects Prevention Study, we examined whether the relationship between maternal UTIs during the periconceptional period and occurrence of CHDs is modified by the presence of fever due to UTI and corresponding antibiotic use among 11,704 CHD case infants and 11,636 live-born control infants. METHODS: Information on UTIs, fever associated with UTI and antibiotic use (sulfonamides, nitrofurantoin, cephalosporins, penicillin, macrolides, and quinolones) during pregnancy were obtained using a computer-assisted telephone interview. Using unconditional multivariable logistic regression, we calculated adjusted odds ratios (ORs) to determine the association between maternal UTIs and subtypes of CHDs. Analyses were stratified by the presence of fever and medication use associated with UTI. RESULTS: The prevalence of UTIs during the periconceptional period was 7.6% in control mothers, and 8.7% in case mothers. In the absence of fever, UTI was associated with secundum atrial septal defects (ASD) (OR 1.3; 95% confidence interval [CI] 1.1-1.5) and in the absence of antibiotics, UTI was associated with conotruncal defects as a group and for four specific CHDs. When fever and UTI occurred concomitantly, no significantly elevated odds ratios were noticed for any subtypes of CHD. Among women with UTIs who used antibiotics, an elevated but statistically non-significant estimate was observed for secundum ASD (OR 1.4; 95% CI 1.0-2.0). CONCLUSION: Findings in the present study suggest that fever due to UTI and corresponding maternal antibiotic use do not substantially modify the association between maternal UTIs and specific CHDs in offspring. Further studies with larger sample sizes are warranted to guide clinical management of UTIs during the periconceptional period.
Assuntos
Cardiopatias Congênitas , Infecções Urinárias , Gravidez , Lactente , Humanos , Feminino , Antibacterianos/efeitos adversos , Fatores de Risco , Estudos de Casos e Controles , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/epidemiologia , Infecções Urinárias/complicações , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/epidemiologiaRESUMO
Zolpidem is a non-benzodiazepine agent indicated for treatment of insomnia. While zolpidem crosses the placenta, little is known about its safety in pregnancy. We assessed associations between self-reported zolpidem use 1 month before pregnancy through to the end of the third month ("early pregnancy") and specific birth defects using data from two multi-site case-control studies: National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study. Analysis included 39,711 birth defect cases and 23,035 controls without a birth defect. For defects with ≥ 5 exposed cases, we used logistic regression with Firth's penalised likelihood to estimate adjusted odds ratios and 95% confidence intervals, considering age at delivery, race/ethnicity, education, body mass index, parity, early-pregnancy antipsychotic, anxiolytic, antidepressant use, early-pregnancy opioid use, early-pregnancy smoking, and study as potential covariates. For defects with three-four exposed cases, we estimated crude odds ratios and 95% confidence intervals. Additionally, we explored differences in odds ratios using propensity score-adjustment and conducted a probabilistic bias analysis of exposure misclassification. Overall, 84 (0.2%) cases and 46 (0.2%) controls reported early-pregnancy zolpidem use. Seven defects had sufficient sample size to calculate adjusted odds ratios, which ranged from 0.76 for cleft lip to 2.18 for gastroschisis. Four defects had odds ratios > 1.8. All confidence intervals included the null. Zolpidem use was rare. We could not calculate adjusted odds ratios for most defects and estimates are imprecise. Results do not support a large increase in risk, but smaller increases in risk for certain defects cannot be ruled out.
Assuntos
Gastrosquise , Exposição Materna , Gravidez , Feminino , Humanos , Zolpidem/efeitos adversos , Gastrosquise/epidemiologia , Modelos Logísticos , Estudos de Casos e Controles , Fatores de Risco , Razão de ChancesRESUMO
PURPOSE: Recent studies suggest increased birth defect risk associated with maternal use of specific oral antifungals. We estimated associations between first-trimester antifungal use and selected non-cardiac birth defects using National Birth Defects Prevention Study (NBDPS) data. METHODS: Participants with a pregnancy affected by a study-eligible birth defect ("cases") were ascertained from 10 birth defect surveillance programs; participants who delivered livebirths without a major birth defect ("controls") were randomly selected from birth records or hospital discharge lists. First-trimester antifungal use was self-reported via maternal interview. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for birth defects with ≥5 exposed cases using logistic regression. We estimated crude ORs and exact 95% CIs for birth defects with 3-4 exposed cases. Additionally, we conducted a probabilistic bias analysis of exposure misclassification. RESULTS: Our analysis included 19 624 cases and 11 427 controls; 257 (1.3%) cases and 123 (1.1%) controls reported first-trimester antifungal use. Of those who reported antifungals, 62.6% of cases and 64.2% of controls reported topical antifungals; 10.1% of cases and 4.9% of controls reported oral antifungals. We observed the strongest associations for encephalocele and Dandy-Walker malformation and modestly elevated estimates for several other defects. Bias-adjusted estimates were similar to the main analysis. CONCLUSION: First-trimester antifungal use was positively associated with several birth defects in our analysis, although CIs were imprecise. Further study is warranted to investigate associations between antifungal use and birth defects, including potential bias due to confounding by indication.
Assuntos
Antifúngicos , Gravidez , Feminino , Humanos , Antifúngicos/efeitos adversos , Estudos de Casos e Controles , Primeiro Trimestre da Gravidez , Modelos Logísticos , Fatores de RiscoRESUMO
BACKGROUND: Birth defects and preterm birth co-occur, with some overlapping risk factors. Many birth defects and preterm births tend to have a male preponderance. We explored potential risk factors impacting sex and preterm (<37 weeks of gestation) birth differences among infants with selected birth defects delivered from 1997 to 2011 using data from the National Birth Defects Prevention Study (NBDPS). METHODS: The NBDPS was a large multisite, population-based case-control study. Using random forests, we identified important predictors of male preterm, female preterm, and male term, each compared with female term births for each birth defect. Using logistic regression, we estimated odds ratios for associations between important predictors and sex-preterm birth status by birth defect. RESULTS: We examined 11,379 infants with nine specific birth defects. The top 10 most important predictors of sex-preterm birth status from the random forests varied greatly across the birth defects and sex-preterm comparisons within a given defect group, with several being novel factors. However, one consistency was that short interpregnancy interval was associated with sex-preterm birth status for many of the studied birth defects. Although obesity has been identified as a risk factor for preterm birth and birth defects in other research, it was not associated with sex-preterm birth status for any of the examined defects. CONCLUSIONS: We confirmed expected associations for sex-preterm birth status differences and found new potential risk factors for further exploration among the studied birth defects.
Assuntos
Nascimento Prematuro , Lactente , Humanos , Recém-Nascido , Masculino , Feminino , Nascimento Prematuro/epidemiologia , Estudos de Casos e Controles , Modelos LogísticosRESUMO
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only â¼4%-8% of all CHDs but accounts for â¼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10-5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.
Assuntos
Síndrome do Coração Esquerdo Hipoplásico , Animais , Humanos , Síndrome do Coração Esquerdo Hipoplásico/genética , Alelos , Aorta , Calpaína/genética , Ventrículos CerebraisRESUMO
The objective of this analysis was to describe patterns of prescription medication use during pregnancy, including secular trends, with consideration of indication, and distributions of use within demographic subgroups. We conducted a descriptive secondary analysis using data from 9,755 women whose infants served as controls in two large United States case-control studies from 1997-2011 and 2014-2018. After excluding vitamin, herbal, mineral, vaccine, i.v. fluid, and topical products and over-the-counter medications, the proportion of women that reported taking at least one prescription medication in the first trimester increased over the study years, from 37% to 50% of women. The corresponding proportions increased with increasing maternal age and years of education, were highest for non-Hispanic White women (47%) and lowest for Hispanic women (24%). The most common indication for first trimester use of a medication was infection (12-15%). Increases were observed across the years for medications used for indications related to nausea/vomiting, depression/anxiety, infertility, thyroid disease, diabetes, and epilepsy. The largest relative increase in use among women was observed for medications to treat nausea/vomiting, which increased from 3.8% in the earliest years of the study (1997-2001) to 14.8% in 2014-2018, driven in large part by ondansetron use. Prescription medication use in the first trimester of pregnancy is common and increasing. Many medical conditions require treatments among pregnant women, often involving pharmacotherapy, which necessitates consideration of the risk and safety profiles for both mother and fetus.
Assuntos
Medicamentos sob Prescrição , Gravidez , Feminino , Humanos , Estados Unidos , Primeiro Trimestre da Gravidez , Medicamentos sob Prescrição/efeitos adversos , Prescrições , Náusea/tratamento farmacológico , Vômito/tratamento farmacológicoRESUMO
BACKGROUND: Caffeine consumption is common during pregnancy, but published associations with birth defects are mixed. We updated estimates of associations between prepregnancy caffeine consumption and 48 specific birth defects from the National Birth Defects Prevention Study (NBDPS) for deliveries from 1997 to 2011. METHODS: NBDPS was a large population-based case-control study conducted in 10 U.S. states. We categorized self-reported total dietary caffeine consumption (mg/day) from coffee, tea, soda, and chocolate as: <10, 10 to <100, 100 to <200, 200 to <300, and ≥ 300. We used logistic regression to estimate adjusted odds ratios (aORs [95% confidence intervals]). Analyses for defects with ≥5 exposed case children were adjusted for maternal race/ethnicity, age at delivery, body mass index, early pregnancy cigarette smoking and alcohol use, and study site. RESULTS: Our analysis included 30,285 case and 11,502 control children, with mothers of 52% and 54%, respectively, reporting consuming <100 mg caffeine, and 11% of mothers of both cases and controls reported consuming ≥300 mg per day. Low (10 to <100 mg/day) levels of prepregnancy caffeine consumption were associated with statistically significant increases in aORs (1.2-1.7) for 10 defects. Associations with high (≥300 mg/day) levels of caffeine were generally weaker, except for craniosynostosis and aortic stenosis (aORs = 1.3 [1.1-1.6], 1.6 [1.1-2.3]). CONCLUSIONS: Given the large number of estimates generated, some of the statistically significant results may be due to chance and thus the weakly increased aORs should be interpreted cautiously. This study supports previous observations suggesting lack of evidence for meaningful associations between caffeine consumption and the studied birth defects.
Assuntos
Cafeína , Craniossinostoses , Gravidez , Feminino , Criança , Humanos , Cafeína/efeitos adversos , Estudos de Casos e Controles , Dieta , MãesRESUMO
The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.
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Atresia Biliar , Humanos , Atresia Biliar/epidemiologia , Atresia Biliar/genética , Atresia Biliar/diagnóstico , Exoma/genética , Homozigoto , Pais , Estudos de Casos e Controles , Proteínas de Membrana/genéticaRESUMO
PURPOSE: Cyclobenzaprine is a muscle relaxant indicated for acute pain. Little is known about cyclobenzaprine's safety during pregnancy. We explored the association between maternal cyclobenzaprine exposure and risk of birth defects among offspring. METHODS: We combined data from two large, multi-site, population-based case-control studies in the United States. Cases were identified from birth defects registries across 10 states; controls were liveborn infants without birth defects randomly selected from the same catchment areas. Participants reported cyclobenzaprine use during the month before conception through the third month of pregnancy ("periconception") via computer-assisted telephone interview. We used logistic regression to assess associations between periconceptional cyclobenzaprine exposure and selected structural birth defects. We calculated crude odds ratios (OR) with corresponding 95% confidence intervals (CI). RESULTS: Our study included 33 615 cases and 13 110 controls. Overall, 51 case (0.15%) and 9 control (0.07%) participants reported periconceptional cyclobenzaprine use. We observed increased risk for all seven defects with ≥3 exposed cases: cleft palate (OR = 4.79, 95% CI 1.71-13.44), cleft lip (OR = 2.50, 95% CI 0.89-7.02), anorectal atresia/stenosis (OR = 6.91, 95% CI 1.67, 28.65), d-transposition of the great arteries (OR = 6.97, 95% CI 2.17-22.36), coarctation of the aorta (OR = 5.58, 95% CI 1.88-16.58), pulmonary valve stenosis (OR = 4.55, 95% CI 1.10-18.87), and secundum atrial septal defect (OR = 3.08, 95% CI 0.83-11.45). CONCLUSIONS: Even in our large sample, cyclobenzaprine use was rare. Our estimates are unadjusted and imprecise so should be interpreted cautiously. These hypothesis-generating results warrant confirmation and further research to explore possible mechanisms.
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Transposição dos Grandes Vasos , Gravidez , Feminino , Lactente , Humanos , Estados Unidos/epidemiologia , Exposição Materna/efeitos adversos , Modelos Logísticos , Estudos de Casos e Controles , Fatores de RiscoRESUMO
BACKGROUND: Studies evaluating associations between medication use in pregnancy and birth outcomes rely on various sources of exposure information. We sought to assess agreement between self-reported use of medications during early pregnancy and medication information in prenatal medical records to understand the reliability of each of these information sources. METHODS: We compared self-reported prescription medication use in early pregnancy to medical records from 184 New York women with deliveries in 2018 who participated in the Birth Defects Study To Evaluate Pregnancy exposureS. We assessed medications used chronically and episodically, and medications within 12 therapeutic groups. We calculated agreement using kappa (κ) coefficients, sensitivity, and specificity. We assessed differences by case/control status, maternal age, education, time to interview, and interview language. RESULTS: Medications used chronically showed substantial agreement between self-report and medical records (κ = 0.75, 0.61-0.88), with agreement for therapeutic groups used chronically ranging from κ = 0.61 for antidiabetics to κ = 1.00 for antihypertensives. Prescription medications used episodically showed worse agreement (κ = 0.40, 0.25-0.54), with the lowest agreement for opioid analgesics (κ = 0.20) and anti-infectives (κ = 0.33). Agreement did not differ by the characteristics examined, although we observed potential differences by interview language. CONCLUSIONS: Among our sample, we observed good agreement between self-report and medical records for medications used chronically and substantially less agreement for medications used episodically. Differences by source may be due to poor recall in self-reports, non-adherence with prescribed medications and lack of complete prescription information within medical records. Limitations should be considered when assessing prescription medication exposures during early pregnancy in epidemiologic studies.
Assuntos
Prontuários Médicos , Medicamentos sob Prescrição , Gravidez , Humanos , Feminino , New York , Reprodutibilidade dos Testes , AutorrelatoRESUMO
BACKGROUND: Heparin and low-molecular-weight heparin are the preferred anticoagulants during pregnancy as they do not cross the placenta. Although research on the safety of heparin products has been reassuring, previous studies have considered birth defects as a single outcome or by larger organ system and have not examined associations with specific birth defects. METHODS: We analyzed data from the National Birth Defects Prevention Study, a multisite, population-based case-control study from 1997 to 2011. We used unconditional logistic regression with Firth's penalized likelihood to calculate adjusted odds ratios (ORs) and profile likelihood 95% confidence intervals (CIs) for defects with at least five exposed cases. For defects with 3-4 exposed cases, we estimated crude ORs and exact 95% CIs. RESULTS: Of the 42,743 women in our analysis, 117 (0.4%) case and 44 (0.4%) control mothers reported using a heparin product in early pregnancy. The adjusted ORs ranged from 0.9 to 3.9 and were elevated for anorectal atresia (OR = 2.0, 95% CI = 0.8-4.3), longitudinal limb deficiency (3.5, 1.3-7.8), transverse limb deficiency (1.8, 0.6-4.3), atrioventricular septal defect (3.9, 1.4-9.0), and secundum atrial septal defect (2.2, 1.2-3.8). CONCLUSIONS: We observed elevated associations for some birth defects, although heparin is a rare exposure, which limited our ability to evaluate many associations. Future studies that can explore specific birth defects and adequately control for confounding by indication are needed. Given that women with an indication for heparin products during pregnancy often need to take medication, one must remain mindful of the underlying risk of a birth defect that exists regardless of medication use.
Assuntos
Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Feminino , Humanos , Heparina , Estudos de Casos e Controles , MãesRESUMO
BACKGROUND: Previous studies found consistent associations between pregestational diabetes and birth defects. Given the different biological mechanisms for type 1 (PGD1) and type 2 (PGD2) diabetes, we used National Birth Defects Prevention Study (NBDPS) data to estimate associations by diabetes type. METHODS: The NBDPS was a study of major birth defects that included pregnancies with estimated delivery dates from October 1997 to December 2011. We compared self-reported PGD1 and PGD2 for 29,024 birth defect cases and 10,898 live-born controls. For case groups with ≥5 exposed cases, we estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the association between specific defects and each diabetes type. We calculated crude ORs (cORs) and 95% CIs with Firth's penalized likelihood for case groups with 3-4 exposed cases. RESULTS: Overall, 252 (0.9%) cases and 24 (0.2%) control mothers reported PGD1, and 357 (1.2%) cases and 34 (0.3%) control mothers reported PGD2. PGD1 was associated with 22/26 defects examined and PGD2 was associated with 29/39 defects examined. Adjusted ORs ranged from 1.6 to 70.4 for PGD1 and from 1.6 to 59.9 for PGD2. We observed the strongest aORs for sacral agenesis (PGD1: 70.4, 32.3-147; PGD2: 59.9, 25.4-135). For both PGD1 and PGD2, we observed elevated aORs in every body system we evaluated, including central nervous system, orofacial, eye, genitourinary, gastrointestinal, musculoskeletal, and cardiac defects. CONCLUSIONS: We observed positive associations between both PGD1 and PGD2 and birth defects across multiple body systems. Future studies should focus on the role of glycemic control in birth defect risk to inform prevention efforts.
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Anormalidades Múltiplas , Diabetes Mellitus Tipo 2 , Malformações do Sistema Nervoso , Gravidez , Feminino , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Prostaglandina D2 , Fatores de RiscoRESUMO
BACKGROUND: About 20%-30% of children with birth defects have multiple major birth defects in more than one organ system, often referred to as multiple congenital anomalies (MCAs). Evaluating the patterns of MCAs can provide clues to the underlying causes, pathogenic mechanisms, and developmental pathways. We sought to explore selected patterns of MCAs within the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study that excluded cases attributed to known chromosomal or single-gene abnormalities. METHODS: We defined MCAs as having two or more NBDPS-eligible birth defects and calculated the adjusted observed-to-expected ratio for all observed MCA patterns using co-occurring defect analysis. RESULTS: Of the 50,186 case infants eligible for NBDPS, 2,734 (3.7%) had at least two eligible birth defects. We observed 209 distinct 2-way combinations of birth defects, 297 distinct 3-way combinations, 179 distinct 4-way combinations, and 69 distinct 5-way combinations. Sacral agenesis had the largest proportion of cases with MCAs (70%), whereas gastroschisis had the lowest (3%). Among the cases with MCAs, 63% had a heart defect, 23% had an oral cleft, and 21% had anorectal atresia/stenosis. Of the patterns with adjusted observed-to-expected ratios in the top 20%, most were consistent with the known associations or syndromes, including VATER/VACTERL association and CHARGE syndrome. CONCLUSIONS: Most but not all patterns that had the highest adjusted observed-to-expected ratios were instances of known syndromes or associations. These findings highlight the importance of considering birth defect combinations that suggest syndromic patterns in the absence of a formal syndromic diagnosis. New approaches for screening for sequences and associations, and VATER/VACTERL in particular, in surveillance systems with limited resources for manual review may be valuable for improving surveillance system quality. The observed MCA patterns within NBDPS may help focus future genetic studies by generating case groups of higher yield.
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Anormalidades Múltiplas , Gastrosquise , Cardiopatias Congênitas , Malformações do Sistema Nervoso , Lactente , Criança , Humanos , Estudos de Casos e Controles , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/etiologia , Malformações do Sistema Nervoso/epidemiologia , Gastrosquise/complicações , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/complicaçõesRESUMO
STUDY QUESTION: Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer? SUMMARY ANSWER: The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects. WHAT IS KNOWN ALREADY: The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2017 that resulted in live births in 2004-2018 in Massachusetts and North Carolina and live births in 2004-2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother's information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population included 165â125 ART children, 31â524 non-ART siblings, 12â451 children born to OI/IUI-treated women and 1â353â440 naturally conceived children. All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 29â571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated with cancer risk (HR 8.70 for all cancers and HR 21.90 for leukemia), further elevated in the presence of both chromosomal and nonchromosomal defects (HR 21.29 for all cancers, HR 64.83 for leukemia and HR 4.71 for embryonal tumors). Among the 83â946 children born from ART in the USA in 2019 compared to their naturally conceived counterparts, these risks translate into an estimated excess of 761 children with major birth defects, 31 children with cancer and 11 children with both major birth defects and cancer. LIMITATIONS, REASONS FOR CAUTION: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing versus vitrification), and data on ICSI were only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. Since OI/IUI is underreported on the birth certificate, some OI/IUI children were likely included among the naturally conceived children, which will decrease the difference between all the groups and the naturally conceived children. WIDER IMPLICATIONS OF THE FINDINGS: The use of ART is associated with increased risks of major nonchromosomal birth defects. The presence of birth defects is associated with greater risks for cancer, which adds to the baseline risk in the ART group. Although this study does not show causality, these findings indicate that children conceived with ART, non-ART siblings, and all children with birth defects should be monitored more closely for the subsequent development of cancer. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. M.L.E. reports consultancy for Ro, Hannah, Dadi, Sandstone and Underdog; presidency of SSMR; and SMRU board member. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
Assuntos
Infertilidade , Leucemia , Neoplasias , Gravidez , Lactente , Masculino , Criança , Humanos , Feminino , Estudos de Coortes , Neoplasias/etiologia , Técnicas de Reprodução Assistida/efeitos adversos , Infertilidade/etiologiaRESUMO
BACKGROUND: Maternal exposure to weather-related extreme heat events (EHEs) has been associated with congenital heart defects (CHDs) in offspring. Certain medications may affect an individual's physiologic responses to EHEs. We evaluated whether thermoregulation-related medications modified associations between maternal EHE exposure and CHDs. METHODS: We linked geocoded residence data from the U.S. National Birth Defects Prevention Study, a population-based case-control study, to summertime EHE exposures. An EHE was defined using the 90th percentile of daily maximum temperature (EHE90) for each of six climate regions during postconceptional weeks 3-8. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between EHE90 and the risk of CHDs were estimated by strata of maternal thermoregulation-related medication use and climate region. Interaction effects were evaluated on multiplicative and additive scales. RESULTS: Over 45% of participants reported thermoregulation-related medication use during the critical period of cardiogenesis. Overall, these medications did not significantly modify the association between EHEs and CHDs. Still, medications that alter central thermoregulation increased aORs (95% CI) of EHE90 from 0.73 (0.41, 1.30) among non-users to 5.09 (1.20, 21.67) among users in the Southwest region, U.S. This effect modification was statistically significant on the multiplicative (P = 0.03) and additive scales, with an interaction contrast ratio (95% CI) of 1.64 (0.26, 3.02). CONCLUSION: No significant interaction was found for the maternal use of thermoregulation-related medications with EHEs on CHDs in general, while medications altering central thermoregulation significantly modified the association between EHEs and CHDs in Southwest U.S. This finding deserves further research.
Assuntos
Cardiopatias Congênitas , Temperatura Alta , Estudos de Casos e Controles , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Exposição Materna , Fatores de RiscoRESUMO
Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.