Copy-number variants and candidate gene mutations in isolated split hand/foot malformation.

Split hand/foot malformation (SHFM) is a congenital limb deficiency with missing or shortened central digits. Some SHFM genes have been identified but the cause of many SHFM cases is unknown. We used single-nucleotide polymorphism (SNP) microarray analysis to detect copy-number variants (CNVs) in 25 SHFM cases without other birth defects from New York State (NYS), prioritized CNVs absent from population CNV databases, and validated these CNVs using quantitative real-time polymerase chain reaction (qPCR). We tested for the validated CNVs in seven cases from Iowa using qPCR, and also sequenced 36 SHFM candidate genes in all the subjects. Seven NYS cases had a potentially deleterious variant: two had a p.R225H or p.R225L mutation in TP63, one had a 17q25 microdeletion, one had a 10q24 microduplication and three had a 17p13.3 microduplication. In addition, one Iowa case had a de novo 10q24 microduplication. The 17q25 microdeletion has not been reported previously in SHFM and included two SHFM candidate genes (SUMO2 and GRB2), while the 10q24 and 17p13.3 CNVs had breakpoints within genomic regions that contained putative regulatory elements and a limb development gene. In SHFM pathogenesis, the microdeletion may cause haploinsufficiency of SHFM genes and/or deletion of their regulatory regions, and the microduplications could disrupt regulatory elements that control transcription of limb development genes.

Copy number variants in a population-based investigation of Klippel-Trenaunay syndrome.

Klippel-Trenaunay syndrome (KTS) is a rare congenital vascular disorder that is thought to occur sporadically; however, reports of familial occurrence suggest a genetic component. We examined KTS cases to identify novel, potentially causal copy number variants (CNVs). We identified 17 KTS cases from all live-births occurring in New York (1998-2010). Extracted DNA was genotyped using Illumina microarrays and CNVs were called using PennCNV software. CNVs selected for follow-up had ≥10 single nucleotide polymorphisms (SNPs) and minimal overlap with in-house controls or controls from the Database of Genomic Variants. We identified 15 candidate CNVs in seven cases; among them a deletion in two cases within transcripts of HDAC9, a histone deacetylase essential for angiogenic sprouting of endothelial cells. One of them also had a duplication upstream of SALL3, a transcription factor essential for embryonic development that inhibits DNMT3A, a DNA methyltransferase responsible for embryonic de novo DNA methylation. Another case had a duplication spanning ING5, a histone acetylation regulator active during embryogenesis. We identified rare genetic variants related to chromatin modification which may have a key role in regulating vascular development during embryogenesis. Further investigation of their implications in the pathogenesis of KTS is warranted. © 2016 Wiley Periodicals, Inc.

Rare copy number variants implicated in posterior urethral valves.

The cause of posterior urethral valves (PUV) is unknown, but genetic factors are suspected given their familial occurrence. We examined cases of isolated PUV to identify novel copy number variants (CNVs). We identified 56 cases of isolated PUV from all live-births in New York State (1998-2005). Samples were genotyped using Illumina HumanOmni2.5 microarrays. Autosomal and sex-linked CNVs were identified using PennCNV and cnvPartition software. CNVs were prioritized for follow-up if they were absent from in-house controls, contained ≥ 10 consecutive probes, were ≥ 20 Kb in size, had ≤ 20% overlap with variants detected in other birth defect phenotypes screened in our lab, and were rare in population reference controls. We identified 47 rare candidate PUV-associated CNVs in 32 cases; one case had a 3.9 Mb deletion encompassing BMP7. Mutations in BMP7 have been associated with severe anomalies in the mouse urethra. Other interesting CNVs, each detected in a single PUV case included: a deletion of PIK3R3 and TSPAN1, duplication/triplication in FGF12, duplication of FAT1--a gene essential for normal growth and development, a large deletion (>2 Mb) on chromosome 17q that involves TBX2 and TBX4, and large duplications (>1 Mb) on chromosomes 3q and 6q. Our finding of previously unreported novel CNVs in PUV suggests that genetic factors may play a larger role than previously understood. Our data show a potential role of CNVs in up to 57% of cases examined. Investigation of genes in these CNVs may provide further insights into genetic variants that contribute to PUV.

Fluconazole use and birth defects in the National Birth Defects Prevention Study.

BACKGROUND: Low-dose fluconazole is used commonly to treat vulvovaginal candidiasis, a condition occurring frequently during pregnancy. Conflicting information exists on the association between low-dose fluconazole use among pregnant women and the risk of major birth defects. OBJECTIVE: We used data from the National Birth Defects Prevention Study to examine this association. STUDY DESIGN: The National Birth Defects Prevention Study is a multisite, population-based, case-control study that includes pregnancies with estimated delivery dates from 1997 to 2011. Information on fluconazole use in early pregnancy was collected by self-report from 31,645 mothers of birth defect cases and 11,612 mothers of unaffected controls. Adjusted odds ratios and 95% confidence intervals were estimated for birth defects with 5 or more exposed cases; crude odds ratios and exact 95% confidence intervals were estimated for birth defects with 3-4 exposed cases. RESULTS: Of the 43,257 mothers analyzed, 44 case mothers and 6 control mothers reported using fluconazole. Six exposed infants had cleft lip with cleft palate, 4 had an atrial septal defect, and each of the following defects had 3 exposed cases: hypospadias, tetralogy of Fallot, d-transposition of the great arteries, and pulmonary valve stenosis. Fluconazole use was associated with cleft lip with cleft palate (odds ratio = 5.53; confidence interval = 1.68-18.24) and d-transposition of the great arteries (odds ratio = 7.56; confidence interval = 1.22-35.45). CONCLUSIONS: The associations between fluconazole and both cleft lip with cleft palate and d-transposition of the great arteries are consistent with earlier published case reports but not recent epidemiologic studies. Despite the larger sample size of the National Birth Defects Prevention Study, fluconazole use was rare. Further investigation is needed in large studies, with particular emphasis on oral clefts and conotruncal heart defects.

Maternal autoimmune disease and birth defects in the National Birth Defects Prevention Study.

BACKGROUND: Little is known about the association between maternal autoimmune disease or its treatment and the risk of birth defects. We examined these associations using data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. METHODS: Analyses included 25,116 case and 9897 unaffected control infants with estimated delivery dates between 1997 and 2009. Information on autoimmune disease, medication use, and other pregnancy exposures was collected by means of telephone interview. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for birth defects with five or more exposed cases; crude ORs and exact 95% CIs were estimated for birth defects with three to four exposed cases. RESULTS: Autoimmune disease was reported by 373 mothers (279 case and 94 control mothers). The majority of birth defects evaluated were not associated with autoimmune disease; however, a statistically significant association between maternal autoimmune disease and encephalocele was observed (OR, 4.64; 95% CI, 1.95-11.04). Eighty-two mothers with autoimmune disease used an immune modifying/suppressing medication during pregnancy; this was associated with encephalocele (OR, 7.26; 95% CI, 1.37-24.61) and atrial septal defects (OR, 3.01; 95% CI, 1.16-7.80). CONCLUSION: Our findings suggest maternal autoimmune disease and treatment are not associated with the majority of birth defects, but may be associated with some defects, particularly encephalocele. Given the low prevalence of individual autoimmune diseases and the rare use of specific medications, we were unable to examine associations of specific autoimmune diseases and medications with birth defects. Other studies are needed to confirm these findings. Birth Defects Research (Part A) 106:950-962, 2016. © 2016 Wiley Periodicals, Inc.

Novel copy-number variants in a population-based investigation of classic heterotaxy.

PURPOSE: Heterotaxy is a clinically and genetically heterogeneous disorder. We investigated whether screening cases restricted to a classic phenotype would result in the discovery of novel, potentially causal copy-number variants. METHODS: We identified 77 cases of classic heterotaxy from all live births in New York State during 1998-2005. DNA extracted from each infant's newborn dried blood spot was genotyped with a microarray containing 2.5 million single-nucleotide polymorphisms. Copy-number variants were identified with PennCNV and cnvPartition software. Candidates were selected for follow-up if they were absent in unaffected controls, contained 10 or more consecutive probes, and had minimal overlap with variants published in the Database of Genomic Variants. RESULTS: We identified 20 rare copy-number variants including a deletion of BMP2, which has been linked to laterality disorders in mice but not previously reported in humans. We also identified a large, terminal deletion of 10q and a microdeletion at 1q23.1 involving the MNDA gene; both are rare variants suspected to be associated with heterotaxy. CONCLUSION: Our findings implicate rare copy-number variants in classic heterotaxy and highlight several candidate gene regions for further investigation. We also demonstrate the efficacy of copy-number variant genotyping in blood spots using microarrays.

Sex ratios among infants with birth defects, National Birth Defects Prevention Study, 1997-2009.

A small number of population-based studies have examined sex differences among infants with birth defects. This study presents estimates of sex ratio for both isolated cases and those with multiple congenital anomalies, as well as by race/ethnicity. Male-female sex ratios and their 95% confidence intervals were calculated for 25,952 clinically reviewed case infants included in the National Birth Defects Prevention Study (1997-2009), a large population-based case-control study of birth defects. The highest elevations in sex ratios (i.e., male preponderance) among isolated non-cardiac defects were for craniosynostosis (2.12), cleft lip with cleft palate (2.01), and cleft lip without cleft palate (1.78); the lowest sex ratios (female preponderance) were for choanal atresia (0.45), cloacal exstrophy (0.46), and holoprosencephaly (0.64). Among isolated cardiac defects, the highest sex ratios were for aortic stenosis (2.88), coarctation of the aorta (2.51), and d-transposition of the great arteries (2.34); the lowest were multiple ventricular septal defects (0.52), truncus arteriosus (0.63), and heterotaxia with congenital heart defect (0.64). Differences were observed by race/ethnicity for some but not for most types of birth defects. The sex differences we observed for specific defects, between those with isolated versus multiple defects, as well as by race/ethnicity, demonstrate patterns that may suggest etiology and improve classification.

Fetal alcohol syndrome among children aged 7-9 years - Arizona, Colorado, and New York, 2010.

Fetal alcohol syndrome (FAS) is a serious birth defect and developmental disorder caused by in utero exposure to alcohol. Assessment of the public health burden of FAS through surveillance has proven difficult; there is wide variation in reported prevalence depending on the study population and surveillance method. Generally, records-based birth prevalence studies report estimates of 0.2-1.5 per 1,000 live births, whereas studies that use in-person, expert assessment of school-aged children in a community report estimates of 6-9 per 1,000 population. The Fetal Alcohol Syndrome Surveillance Network II addressed some of the challenges in records-based ascertainment by assessing a period prevalence of FAS among children aged 7‒9 years in Arizona, Colorado, and New York. The prevalence across sites ranged from 0.3 to 0.8 per 1,000 children. Prevalence of FAS was highest among American Indian/Alaska Native children and lowest among Hispanic children. These estimates continue to be much lower than those obtained from studies using in-person, expert assessment. Factors that might contribute to this discrepancy include 1) inadequate recognition of the physical and behavioral characteristics of FAS by clinical care providers; 2) insufficient documentation of those characteristics in the medical record; and 3) failure to consider prenatal alcohol exposure with diagnoses of behavioral and learning problems. Addressing these factors through training of medical and allied health providers can lead to practice changes, ultimately increasing recognition and documentation of the characteristics of FAS.

Maternal asthma medication use during pregnancy and risk of congenital heart defects.

BACKGROUND: Asthma affects 4% to 8% of pregnant women and studies suggest maternal asthma, particularly when uncontrolled, may be associated with adverse reproductive outcomes. METHODS: We examined self-reported asthma medication use and the risk of congenital heart defects (CHD) in the National Birth Defects Prevention Study, a multi-center, population-based case-control study of selected major structural defects. We evaluated maternal use of bronchodilators and anti-inflammatories during the periconceptional period (1 month before conception through the first 3 pregnancy months) among 7638 infants with CHDs and 8106 nonmalformed controls with estimated delivery dates from 1997 to 2007. We used logistic regression to estimate odds ratios and 95% confidence intervals for 20 types of CHDs. RESULTS: Among asthma medications reported during the periconceptional period among controls, albuterol accounted for 85.1% of all bronchodilator use, and fluticasone, prednisone, and montelukast accounted for 46.1%, 15.6%, and 14.9% of anti-inflammatory use, respectively. Of the women who reported bronchodilators during the periconceptional period, 71.1% reported use throughout pregnancy and only 29.4% reported concurrent use of an anti-inflammatory. We observed one statistically significant association between maternal bronchodilator use only and anomalous pulmonary venous return (odds ratio 2.3, 95% confidence interval 1.1-4.8) among numerous comparisons. CONCLUSION: We did not observe statistically significant associations between the reported use of asthma medications during pregnancy and most specific types of CHDs. Despite limitations in our inability to evaluate asthma status and severity, our study suggests that maternal asthma medication use does not substantially, if at all, increase the risk of CHDs.

Maternal periconceptional alcohol consumption and congenital heart defects.

BACKGROUND: Congenital heart defects (CHDs) are the leading cause of infant death from birth defects. Animal studies suggest in utero alcohol exposure is a teratogen for cardiogenesis; however, results from epidemiologic studies are mixed. METHODS: Data from the National Birth Defects Prevention Study were used to estimate associations between CHDs and case (n = 7076) and control (n = 7972) mother reports of periconceptional (1 month before pregnancy through the first trimester) alcohol consumption with expected delivery dates during 1997 to 2007. CHDs were examined by category (conotruncal, septal, left ventricular outflow tract obstruction, and right ventricular outflow tract obstruction, heterotaxy with CHD) and subtype (e.g., tetralogy of Fallot [TOF]). Alcohol measures examined were any consumption, maximum average drinks per month, binge drinking, and alcohol type. Adjusted odds ratios and 95% confidence intervals were estimated using unconditional logistic regression analysis. RESULTS: Increased risks, albeit marginally statistically significant, were observed for TOF and each maternal alcohol measure examined and for right ventricular outflow tract obstruction and heterotaxy with CHD and consumption of distilled spirits. Significantly reduced risks were observed for several CHD categories (septal defects, left ventricular outflow tract obstruction, and right ventricular outflow tract obstruction) and some corresponding subtypes with different alcohol measures. Significant risks were not observed for the other CHDs examined. CONCLUSION: Analysis of this large, well-defined study sample did not show statistically significant increased risks between measures of maternal alcohol consumption and most CHDs examined. These findings may reflect, in part, limitations with retrospective exposure assessment or unmeasured confounders. Additional studies with continued improvement in measurement of alcohol consumption are recommended.

Maternal cigarette, alcohol, and coffee consumption in relation to risk of clubfoot.

BACKGROUND: Clubfoot is associated with maternal cigarette smoking in several studies, but it is not clear if this association is confined to women who smoke throughout the at-risk period. Maternal alcohol and coffee drinking have not been well studied in relation to clubfoot. METHODS: The present study used data from a population-based case-control study of clubfoot conducted in Massachusetts, New York, and North Carolina from 2007 to 2011. Mothers of 646 isolated clubfoot cases and 2037 controls were interviewed about pregnancy events and exposures, including the timing and frequency of cigarette smoking, alcohol intake, and coffee drinking. RESULTS: More mothers of cases than controls reported smoking during early pregnancy (28.9% vs. 19.1%). Of women who smoked when they became pregnant, those who quit in the month after a first missed period had a 40% increase in clubfoot risk and those who continued to smoke during the next 3 months had more than a doubling in risk, after controlling for demographic factors, parity, obesity, and specific medication exposures. Adjusted odds ratios for women who drank >3 servings of alcohol or coffee per day throughout early pregnancy were 2.38 and 1.77, respectively, but the numbers of exposed women were small and odds ratios were unstable. CONCLUSIONS: Clubfoot risk appears to be increased for offspring of women who smoke cigarettes, particularly those who continue smoking after pregnancy is recognisable, regardless of amount. For alcohol and coffee drinkers, suggested increased risks were only observed in higher levels of intake.

Medication use in pregnancy in relation to the risk of isolated clubfoot in offspring.

Clubfoot, a common major structural malformation, develops early in gestation. Epidemiologic studies have identified higher risks among boys, first-born children, and babies with a family history of clubfoot, but studies of risks associated with maternal exposures are lacking. We conducted the first large-scale, population-based, case-control study of clubfoot with detailed information on maternal medication use in pregnancy. Study subjects were ascertained from birth defect registries in Massachusetts, New York, and North Carolina during 2007-2011. Cases were 646 mothers of children with clubfoot without other major structural malformations (i.e., isolated clubfoot); controls were mothers of 2,037 children born without major malformations. Mothers were interviewed within 12 months of delivery about medication use, including product, timing, and frequency. Odds ratios were estimated for exposure to 27 medications in pregnancy months 2-4 after adjustment for study site, infant sex, first-born status, body mass index (weight (kg)/height (m)(2)), and smoking. Odds ratios were less than 1.20 for 14 of the medications; of the remainder, most odds ratios were only slightly elevated (range, 1.21-1.66), with wide confidence intervals. The use of antiviral drugs was more common in clubfoot cases than in controls (odds ratio = 4.22, 95% confidence interval: 1.52, 11.73). Most of these results are new findings and require confirmation in other studies.

Population-based study to determine mortality in spina bifida: New York State Congenital Malformations Registry, 1983 to 2006.

BACKGROUND: The lifetime risk of death among individuals with spina bifida is 10-times higher compared with the general population. A population-based analysis on cause-specific mortality among individuals spina bifida is lacking. METHODS: Using statewide, population-based New York Congenital Malformations Registry, we examined all births between years 1983 and 2006, and identified 1988 births with spina bifida and 10,951 births with congenital hypertrophic pyloric stenosis (CHPS). We linked registry records to birth and death files from vital records, and determined age- and cause-specific mortality for isolated and multiple spina bifida, and compared the findings with the less fatal CHPS. RESULTS: Mortality in spina bifida is significantly high compared with CHPS (16.9% vs. 0.96%, respectively). The probability of survival in spina bifida was lower compared with CHPS. A majority of the deaths in spina bifida occurred in infants within the first year of birth; however, an increased risk of death persisted in young adulthood for both isolated and multiple cases of spina bifida. The common causes of death in children with spina bifida were hydrocephalus, infections, cardiac anomalies, pneumonia, and pulmonary embolism; while infections, heart or kidney failure, injuries and neoplasms contributed to deaths in adults. CONCLUSION: We conclude that mortality in spina bifida is a large concern, and individuals living with the defect require improved clinical care for lethal medical complications. Primary prevention of spina bifida through mandatory folic acid fortification remains as the best strategy to reduce both disability and mortality associated with this defect across the world.

Methodology for establishing a population-based birth cohort focusing on couple fertility and children's development, the Upstate KIDS Study.

BACKGROUND: Critical data gaps remain regarding infertility treatment and child development. We assessed the utility of a birth certificate registry for developing a population cohort aimed at answering such questions. METHODS: We utilised the Upstate New York livebirth registry (n = 201,063) to select births conceived with (n = 4024) infertility treatment or exposed infants, who were then frequency-matched by residence to a random sample of infants conceived without (n = 14,455) treatment or unexposed infants, 2008-10. Mothers were recruited at 2-4 months postpartum and queried about their reproductive histories, including infertility treatment for comparison with birth certificate data. Overall, 1297 (32%) mothers of exposed and 3692 of unexposed (26%) infants enrolled. RESULTS: Twins represented 22% of each infant group. The percentage of infants conceived with/without infertility treatment was similar whether derived from the birth registry or maternal report: 71% none, 16% drugs or intrauterine insemination, and 14% assisted reproductive technologies (ART). Concordant reporting between the two data sources was 93% for no treatment, 88% for ART, and 83% for fertility drugs, but differed by plurality. Exposed infants had slightly (P < 0.01) earlier gestations than unexposed infants (38.3 ± 2.8 and 38.7 ± 2.7 weeks, respectively) based upon birth certificates but not maternal report (38.7 ± 2.7 and 38.7 ± 2.9, respectively). Conversely, mean birthweight was comparable using birth certificates (3157 ± 704 and 3194 ± 679 g, respectively), but differed using maternal report (3167 ± 692 and 3224 ± 661, respectively P < 0.05). CONCLUSIONS: The birth certificate registry is a suitable sampling framework as measured by concordance with maternally reported infertility treatment. Future efforts should address the impact of factors associated with discordant reporting on research findings.

Maternal butalbital use and selected defects in the national birth defects prevention study.

BACKGROUND: Butalbital is a barbiturate contained in combination products with caffeine and an analgesic prescribed for the treatment of migraine and tension-type headaches. Controversy exists as to whether butalbital should continue to be prescribed in the United States because of the potential for abuse, overuse headache, and withdrawal syndromes. Butalbital crosses the placenta but there is limited information about potential teratogenicity. OBJECTIVE: To evaluate associations between butalbital and a wide range of specific birth defects. METHODS: The National Birth Defects Prevention Study is an ongoing, case-control study of nonsyndromic, major birth defects conducted in 10 states. The detailed case classification and large number of cases in the National Birth Defects Prevention Study allowed us to examine the association between maternal self-reported butalbital use and specific birth defects. We conducted an analysis of 8373 unaffected controls and 21,090 case infants with estimated dates of delivery between 1997 and 2007; included were birth defects with 250 or more cases. An exploratory analysis examined groups with 100 to 249 cases. RESULTS: Seventy-three case mothers and 15 control mothers reported periconceptional butalbital use. Of 30 specific defect groups evaluated, adjusted odds ratios for maternal periconceptional butalbital use were statistically significant for 3 congenital heart defects: tetralogy of Fallot (adjusted odds ratio = 3.04; 95% confidence interval = 1.07-8.62), pulmonary valve stenosis (adjusted odds ratio = 5.73; 95% confidence interval = 2.25-14.62), and secundum-type atrial septal defect (adjusted odds ratio = 3.06; 95% confidence interval = 1.07-8.79). In the exploratory analysis, an elevated odds ratio was detected for 1 congenital heart defect, single ventricle. CONCLUSIONS: We observed relationships between maternal periconceptional butalbital use and certain congenital heart defects. These associations have not been reported before, and some may be spurious. Butalbital use was rare and despite the large size of the National Birth Defects Prevention Study, the number of exposed case and control infants was small. However, if confirmed in additional studies, our findings will be useful in weighing the risks and benefits of butalbital for the treatment of migraine and tension-type headaches.

Analysis of polychlorinated biphenyls and organochlorine pesticides in archived dried blood spots and its application to track temporal trends of environmental chemicals in newborns.

Dried blood spots (DBS) collected from infants shortly after birth for the newborn screening program (NSP) in the United States are valuable resources for the assessment of exposure to environmental chemicals in newborns. The NSP was debuted as a public health program in the United States in the 1960s; and the DBS samples collected over a period of time can be used in tracking temporal trends in exposure to environmental chemicals by newborns. In this study, polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were measured in DBS samples collected from newborns in Upstate New York from 1997 to 2011 by gas chromatography-high resolution mass spectrometry (GC-HRMS). Twelve PCBs and two OCPs were found in DBS samples at a detection rate above 50% (n=51). The mean whole blood concentration of ΣPCBs (sum of 12 congeners) over the 15-year period was 1.06 ng/mL, followed by p,p'-DDE (0.421 ng/mL) and HCB (0.065 ng/mL). The measured concentrations of PCBs and p,p'-DDE in infants'blood were comparable to those reported in cord blood, suggesting maternal/trans-placental transfer of these compounds from mothers to fetuses. The concentrations of ΣPCBs and p,p'-DDE in blood samples of infants decreased significantly between 1997 and 2001, and no significant reduction was found thereafter. This observation is consistent with the trends reported for these chemicals in other human tissues in the United States.

Exploring maternal patterns of dietary caffeine consumption before conception and during pregnancy.

We describe patterns of dietary caffeine consumption before and after pregnancy recognition in a cohort of women who recently gave birth. This study included 8,347 mothers of non-malformed liveborn control infants who participated in the National Birth Defects Prevention Study during 1997-2007. Maternal self-reported consumption of beverages (caffeinated coffee, tea, and soda) and chocolate the year before pregnancy was used to estimate caffeine intake. The proportions of prepregnancy caffeine consumption stratified by maternal characteristics are reported. In addition, patterns of reported change in consumption before and after pregnancy were examined by maternal and pregnancy characteristics. Adjusted prevalence ratios were estimated to assess factors most associated with change in consumption. About 97 % of mothers reported any caffeine consumption (average intake of 129.9 mg/day the year before pregnancy) and soda was the primary source of caffeine. The proportion of mothers reporting dietary caffeine intake of more than 300 mg/day was significantly increased among those who smoked cigarettes or drank alcohol. Most mothers stopped or decreased their caffeinated beverage consumption during pregnancy. Young maternal age and unintended pregnancy were associated with increases in consumption during pregnancy. Dietary caffeine consumption during pregnancy is still common in the US. A high level of caffeine intake was associated with known risk factors for adverse reproductive outcomes. Future studies may improve the maternal caffeine exposure assessment by acquiring additional information regarding the timing and amount of change in caffeine consumption after pregnancy recognition.

Examination of mental health status and aggravation level among mothers of children with isolated oral clefts.

OBJECTIVE: To examine self-reported mental health status and aggravation level in mothers of children with isolated oral clefts. METHODS: Population-based sample of children (aged 4 to 9 years) with isolated oral clefts was enumerated from births from 1998 through 2003 in Arkansas, Iowa, and New York State. Mothers of 294 children completed the Mental Health Inventory 5-item questionnaire and Aggravation in Parenting Scale. The Mental Health Inventory and Aggravation in Parenting Scale scores, stratified by poor (Mental Health Inventory ≤ 67) and better (Mental Health Inventory > 67) mental health status or high (Aggravation in Parenting Scale ≤ 11), moderate (Aggravation in Parenting Scale = 12 to 15) and low (Aggravation in Parenting Scale = 16) aggravation, were compared by selected maternal and child characteristics. Mean scores for each instrument and proportion of mothers with poor mental health or high aggravation were compared with those reported in the National Survey of American Families. RESULTS: Mean scores for each instrument and proportion of mothers with poor mental health or high aggravation differed little from published data. Mothers with poor mental health tended to be less educated, to have lower household incomes, and to rate their health and their child's health lower than those in better mental health. Mothers with high aggravation tended to have lower household incomes, to have more children, and to rate their health and their child's health lower than those with moderate or low aggravation. CONCLUSIONS: Mothers of affected children were not more likely to experience poor mental health or high aggravation compared with published data; however, sociodemographic characteristics were associated with maternal psychosocial adaptation. Brief screeners for mental health and parenting administered during routine appointments may facilitate identifying at-risk caregivers.

Anorectal atresia and variants at predicted regulatory sites in candidate genes.

Anorectal atresia is a serious birth defect of largely unknown etiology but candidate genes have been identified in animal studies and human syndromes. Because alterations in the activity of these genes might lead to anorectal atresia, we selected 71 common variants predicted to be in transcription factor binding sites, CpG windows, splice sites, and miRNA target sites of 25 candidate genes, and tested for their association with anorectal atresia. The study population comprised 150 anorectal atresia cases and 623 control infants without major malformations. Variants predicted to affect transcription factor binding, splicing, and DNA methylation in WNT3A, PCSK5, TCF4, MKKS, GLI2, HOXD12, and BMP4 were associated with anorectal atresia based on a nominal P value < 0.05. The GLI2 and BMP4 variants are reported to be moderately associated with gene expression changes (Spearman's rank correlation coefficients between -0.260 and 0.226). We did not find evidence for interaction between maternal pre-pregnancy obesity and variants in MKKS, a gene previously associated with obesity, on the risk of anorectal atresia. Our results for MKKS support previously suggested associations with anorectal malformations. Our findings suggest that more research is needed to determine whether altered GLI2 and BMP4 expression is important in anorectal atresia in humans.

Maternal race/ethnicity and survival experience of children with congenital heart disease.

OBJECTIVE: To investigate the existence of racial/ethnic disparity in mortality risk among children with individual congenital heart defects and identify any other risk factors. STUDY DESIGN: The study cohort, comprising children born between 1983 and 2006 with a selected congenital heart defect, was matched to death records to ascertain vital status. The birth and maternal risk factors were obtained from birth certificates. RESULTS: After adjusting for covariates using a multivariate regression model, the risk of mortality was significantly higher in children of non-Hispanic black mothers with transposition of the great arteries (hazard ratio (HR), 1.31; 95% CI, 1.07-1.60), tetralogy of Fallot (HR, 1.34; 95% CI, 1.06-1.69), and coarctation of the aorta (HR, 1.40; 95% CI, 1.10-1.79), compared with children of non-Hispanic white mothers. Time trends analysis examining the mortality risk by survival age and birth period found a significant decrease in 5-year mortality risk from 1983 to 2003 births, with a nearly 50% reduction for hypoplastic left heart syndrome and coarctation of the aorta across 3 maternal racial/ethnic groups examined. CONCLUSION: Our findings may help identify at-risk populations and mortality risk factors and thereby contribute to improved survival and quality of life for these children across the lifespan.