Search

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 90 th 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background/objective: Research suggests gestational exposure to particulate matter ≤2.5 μm (PM 2.5 ) and extreme heat may independently increase risk of birth defects. We investigated whether duration of gestational extreme heat exposure modifies associations between PM 2.5 exposure and specific congenital heart defects (CHDs). We also explored nonlinear exposure-outcome relationships., Methods: We identified CHD case children (n = 2824) and non-malformed live-birth control children (n = 4033) from pregnancies ending between 1999 and 2007 in the National Birth Defects Prevention Study, a U.S. population-based multicenter case-control study. We assigned mothers 6-week averages of PM 2.5 exposure during the cardiac critical period (postconceptional weeks 3-8) using the closest monitor within 50 km of maternal residence. We assigned a count of extreme heat days (EHDs, days above the 90th percentile of daily maximum temperature for year, season, and weather station) during this period using the closest weather station. Using generalized additive models, we explored logit-nonlinear exposure-outcome relationships, concluding logistic models were reasonable. We estimated joint effects of PM 2.5 and EHDs on six CHDs using logistic regression models adjusted for mean dewpoint and maternal age, education, and race/ethnicity. We assessed multiplicative and additive effect modification., Results: Conditional on the highest observed EHD count (15) and at least one critical period day during spring/summer, each 5 μg/m 3 increase in average PM 2.5 exposure was significantly associated with perimembranous ventricular septal defects (VSDpm; OR: 1.54 [95% CI: 1.01, 2.41]). High EHD counts (8+) in the same population were positively, but non-significantly, associated with both overall septal defects and VSDpm. Null or inverse associations were observed for lower EHD counts. Multiplicative and additive effect modification estimates were consistently positive in all septal models., Conclusions: Results provide limited evidence that duration of extreme heat exposure modifies the PM 2.5 -septal defects relationship. Future research with enhanced exposure assessment and modeling techniques could clarify these relationships., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Unconventional natural gas developments (UNGD) may release air and water pollutants into the environment, potentially increasing the risk of birth defects. We conducted a case-control study evaluating 52,955 cases with birth defects and 642,399 controls born between 1999 and 2011 to investigate the relationship between UNGD exposure and the risk of gastroschisis, congenital heart defects (CHD), neural tube defects (NTDs), and orofacial clefts in Texas. We calculated UNGD densities (number of UNGDs per area) within 1, 3, and 7.5 km of maternal address at birth and categorized exposure by density tertiles. For CHD subtypes with large case numbers, we also performed time-stratified analyses to examine temporal trends. We calculated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the association with UNGD exposure, accounting for maternal characteristics and neighborhood factors. We also included a bivariable smooth of geocoded maternal location in an additive model to account for unmeasured spatially varying risk factors. Positive associations were observed between the highest tertile of UNGD density within 1 km of maternal address and risk of anencephaly (aOR: 2.44, 95% CI: 1.55, 3.86), spina bifida (aOR: 2.09, 95% CI: 1.47, 2.99), gastroschisis among older mothers (aOR: 3.19, 95% CI: 1.77, 5.73), aortic valve stenosis (aOR: 1.90, 95% CI: 1.33, 2.71), hypoplastic left heart syndrome (aOR: 2.00, 95% CI: 1.39, 2.86), and pulmonary valve atresia or stenosis (aOR: 1.36, 95% CI: 1.10, 1.66). For CHD subtypes, results did not differ substantially by distance from maternal address or when residual confounding was considered, except for atrial septal defects. We did not observe associations with orofacial clefts. Our results suggest that UNGDs were associated with some CHDs and possibly NTDs. In addition, we identified temporal trends and observed presence of spatial residual confounding for some CHDs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Hypospadias, one of the most common male genital birth defects, occurs in 1 out of every 200 male births in the United States and is increasing in prevalence globally., Objective: This study aimed to characterize the combinations of birth defects that co-occur with hypospadias more often than expected by chance, while accounting for the complex clustering patterns of congenital defects., Study Design: We analyzed cases with hypospadias and at least one additional co-occurring defect from the Texas Birth Defect Registry born between 1999 and 2014. For each combination, we calculated adjusted observed-to-expected (O/E) ratios, using Co-Occurring Defect Analysis (CODA)., Results: Among 16,442 cases with hypospadias and without known syndromes, 2,084 (12.7%) had at least one additional defect. Many of the birth defect combinations within the highest adjusted O/E ratios included cardiac, musculoskeletal, and additional urogenital defects. For example, a top combination with an adjusted O/E of 139.0 included renal agenesis and dysgenesis, reduction defects of the upper limb, and other anomalies of upper limb (including shoulder girdle). High adjusted O/E ratios were also observed in combinations that included defects outside of the urogenital developmental field. For instance, the combination with the highest O/E ratio included buphthalmos, and congenital cataract and lens anomalies (adjusted O/E ratio: 192.9). Similar results were obtained when we restricted our analyses to cases with second- or third-degree hypospadias., Discussion: Many combinations in the top results were expected (e.g., multiple urogenital defects); however, some combinations with seemingly unrelated patterns of defects may suggest the presence of some etiologic mechanisms yet to be identified., Conclusion: In summary, this study described patterns of co-occurring defect combinations with hypospadias that can inform further study and may provide insights for screening and diagnostic practices., Competing Interests: Conflict of interest None., (Copyright © 2020 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Purpose: Our objective was to comprehensively evaluate the risk of a broad range of birth defects among offspring of women with diabetes, overall and stratified by pregestational versus gestational diagnosis, using the phenome-wide association (PheWAS) methodology., Methods: We performed a registry linkage study of all live births (>6,500,000) and birth defects cases (>290,000) in Texas, 1999-2015. We ascertained diabetes from birth and fetal death certificates. We calculated prevalence rate ratios (PRR) for phenotypes with ≥10 cases among exposed offspring (n = 130)., Results: Diabetes was associated with the prevalence of any defect (PRR 1.40, 95% confidence interval [CI] 1.38-1.42), multiple defects (PRR 1.86, 95% CI 1.81-1.91), and 60 specific phenotypes, including novel (hypospadias, mitral stenosis) and previously reported phenotypes (renal a-/dysgenesis, spinal anomalies). Pregestational diabetes was a stronger risk factor for any defect (PRR 2.00, 95% CI 1.93-2.07), multiple defects (PRR 3.27, 95% CI 3.11-3.44), and the 60 specific phenotypes evaluated. Gestational diabetes was associated with any defect (PRR 1.21, 95% CI 1.19-1.23) and 47 specific birth defects phenotypes, although associations were weaker than for pregestational diabetes., Conclusions: The PheWAS is an efficient way to identify risk factors for disease using population-based registry data. Pregestational diabetes is associated with a broader range of phenotypes than previously reported. Because diabetes is diagnosed in 1% of women prior to pregnancy and 6%-9% during pregnancy, our results highlight a significant public health concern., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Although there is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) is linked with congenital heart defects (CHDs), few studies have examined the association in humans. We conducted a case-control study to examine the association between maternal exposure to PAHs and CHDs in offspring using data from the National Birth Defects Prevention Study (NBDPS) (1997-2011)., Methods: We obtained detailed information on maternal occupation during the month before to three months after conception. Expert raters, masked to case-control status, assessed job descriptions to assign categorical levels of exposure. Categories were quantitatively mapped to estimate cumulative exposure to PAHs, incorporating exposure intensity, frequency, work duration, and work hours. Quartiles were generated for cumulative maternal exposure to PAHs. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression for quartiles of PAH exposure and six CHD groupings (e.g. conotruncal) and specific subtypes (e.g. tetralogy of Fallot [ToF]). Final models were adjusted for maternal age, race/ethnicity, education, smoking, anticonvulsant use, folic acid supplementation, and study center., Results: There were 4,775 case and 7,734 control infants eligible for the study. The prevalence of occupational exposure to PAHs was 10.2% among both case and control mothers. In adjusted analysis, compared to mothers with no occupational PAH exposure, those in the highest quartile of exposure were more likely to have offspring in the conotruncal heart defects group (OR 1.41; 95% CI 1.00-2.00), and with ToF (OR 1.83; 95% CI 1.21-2.78)., Conclusions: Women in the highest quartile of estimated cumulative occupational PAH exposure during early pregnancy were more likely to have offspring with conotruncal heart defects, specifically ToF, compared to women with no occupational PAH exposure. Other comparisons between PAHs and other CHDs subgroups did not show any statistically precise associations., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Congenital limb deficiencies (CLDs) are a relatively common group of birth defects whose etiology is mostly unknown. Recent studies suggest maternal air pollution exposure as a potential risk factor., Aim: To investigate the relationship between ambient air pollution exposure during early pregnancy and offspring CLDs., Methods: The study population was identified from the National Birth Defects Prevention Study, a population-based multi-center case-control study, and consisted of 615 CLD cases and 5,701 controls with due dates during 1997 through 2006. Daily averages and/or maxima of six criteria air pollutants (particulate matter <2.5 μm [PM 2.5 ], particulate matter <10 μm [PM 10 ], nitrogen dioxide [NO 2 ], sulfur dioxide [SO 2 ], carbon monoxide [CO], and ozone [O 3 ]) were averaged over gestational weeks 2-8, as well as for individual weeks during this period, using data from EPA air monitors nearest to the maternal address. Logistic regression was used to estimate odds ratios (aORs) and 95% confidence intervals (CIs) adjusted for maternal age, race/ethnicity, education, and study center. We estimated aORs for any CLD and CLD subtypes (i.e., transverse, longitudinal, and preaxial). Potential confounding by co-pollutant was assessed by adjusting for one additional air pollutant. Using the single pollutant model, we further investigated effect measure modification by body mass index, cigarette smoking, and folic acid use. Sensitivity analyses were conducted restricting to those with a residence closer to an air monitor., Results: We observed near-null aORs for CLDs per interquartile range (IQR) increase in PM 10 , PM 2.5 , and O 3 . However, weekly averages of the daily average NO 2 and SO 2 , and daily max NO 2 , SO 2 , and CO concentrations were associated with increased odds of CLDs. The crude ORs ranged from 1.03 to 1.12 per IQR increase in these air pollution concentrations, and consistently elevated aORs were observed for CO. Stronger associations were observed for SO 2 and O 3 in subtype analysis (preaxial). In co-pollutant adjusted models, associations with CO remained elevated (aORs: 1.02-1.30); but aORs for SO 2 and NO 2 became near-null. The aORs for CO remained elevated among mothers who lived within 20 km of an air monitor. The aORs varied by maternal BMI, smoking status, and folic acid use., Conclusion: We observed modest associations between CLDs and air pollution exposures during pregnancy, including CO, SO 2 , and NO 2 , though replication through further epidemiologic research is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Studies suggest exposure to ambient particulate matter less than 2.5 μg/m 3 in aerodynamic diameter (PM 2.5 ) may be associated with preterm birth (PTB), but few have evaluated how this is modified by ambient temperature. We investigated the relationship between PM 2.5 exposure during pregnancy and PTB in infants without birth defects (1999-2006) and enrolled in the National Birth Defects Prevention Study and how it is modified by concurrent temperature., Methods: PTB was defined as spontaneous or iatrogenic delivery before 37 weeks. Exposure was assigned using inverse distance weighting with up to four monitors within 50 kilometers of maternal residence. To account for state-level variations, a Bayesian two-level hierarchal model was developed., Results: PTB was associated with PM 2.5 during the third and fourth months of pregnancy (range: (odds ratio (95% confidence interval) = 1.00 (0.35, 2.15) to 1.49 (0.82, 2.68) and 1.31 (0.56, 2.91) to 1.62 (0.7, 3.32), respectively); no week of exposure conveyed greater risk. Temperature may modify this relationship; higher local average temperatures during pregnancy yielded stronger positive relationships between PM 2.5 and PTB compared to nonstratified results., Conclusions: Results add to literature on associations between PM 2.5 and PTB, underscoring the importance of considering co-exposures when estimating effects of PM 2.5 exposure during pregnancy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Children with Down syndrome (DS) have a remarkably high risk of developing leukemia during childhood; the mechanisms driving that risk are not well understood, and no clear prevention strategies exist. We conducted a nested case-control study in a Texas DS birth cohort to investigate possible links between maternal health, labor/delivery conditions, and leukemia risk. For most of the factors studied there was no evidence of an increased risk of total leukemias, or the subtypes acute lymphoid or acute myeloid leukemia. Ultrasound use showed an almost 2-fold increased odds of leukemia, but this result is likely an example of confounding by indication. There was a pattern of increased risk seen for presence of co-occurring heart anomalies, including tetralogy of Fallot, ventricular septal defects, atrial septal defects, and patent ductus arteriosus. Further investigation of the links between co-occurring heart defects in children with DS and development of leukemia may provide new understanding of cancer mechanisms, and ultimately lead to prevention opportunities for this high-risk population., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Accurate estimates of air pollution exposure intensities are important to support environmental epidemiology analyses that require data covering large geographic areas over multiple years. The Emission Weighted Proximity Model (EWPM) and the National-Scale Air Toxics Assessment (NATA) are two viable approaches for obtaining estimate exposure intensities. The advantages of the EWPM include its simplicity and significantly lower costs of implementation. However, very limited data are available regarding the validity of the results from the EWPM and how these results would fare when compared with those from the NATA., Methods: This study evaluates the validity of the estimated exposure intensities from the EWPM through a correlation analysis with ground monitoring data obtained by the Texas Commission on Environmental Quality (TCEQ). The monitoring data used in the comparison included 27 non-criteria air pollutants at 48 monitoring sites in Texas in 2005. In addition, this study compares the results from the EWPM with those from NATA using the TCEQ data as a gold standard., Results: Analysis results suggest that estimated exposure intensities from the EWPM and the NATA were comparable when the intensities from both approaches are used to categorize environmental exposure intensities into different levels in relative terms., Conclusion: These findings suggest that the EWPM is a valid alternative approach to the NATA in situations where epidemiological analysis requires both environmental data and health outcome data that cover a large geographic area over multiple years., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: Previous research has suggested gastroschisis, a congenital malformation, may be linked to environmental or infectious factors and cases can occur in clusters. The objective of this study was to identify geographic areas of elevated gastroschisis risk., Methods: Cases of gastroschisis were identified from birth defect registries in Massachusetts and Texas. Random samples of live births were selected as controls. Generalized additive models were used to create a continuous map surface of odds ratios (ORs) by smoothing over latitude and longitude. Maternal age, race/ethnicity, education, cigarette smoking, and insurance status (MA only) were assessed for confounding. We used permutation tests to identify statistically significant areas of increased risk., Results: An area of increased risk was identified in North Central Massachusetts but was not significant after adjustment (P value = .07; OR = 2.0). In Texas, two statistically significant areas of increased risk were identified after adjustment (P value = .02; OR = 1.3 and 1.2). Texas had sufficient data to assess the combination of space and time, which identified an increased risk in 2003 and 2004., Conclusions: This study suggests there were areas of elevated gastroschisis risk in Massachusetts and Texas, which cannot be explained by the risk factors we assessed. Additional exploration of underlying artifactual, environmental, infectious, or behavioral factors may further our understanding of gastroschisis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: The etiology of orofacial clefts is complex and relatively unknown. Variation in cleft lip with or without palate (CLP) and cleft palate alone (CP) was examined in Texas across urban-rural residence (1999 to 2003)., Methods: Cases came from the Texas Birth Defects Registry (1,949 CLP and 1,054 CP) and denominator data came from vital records (254 counties; 1,827,317 live births). Variation in maternal residence was measured using four classification schemes: Rural Urban Continuum Codes, Urban Influence Codes, percentage of county in cropland, and Rural Urban Commuting Areas. Poisson regression was used to calculate rate ratios, adjusted for infant sex, plurality, gestational age, maternal parity, age, race/ethnicity, and education., Results: Compared to the most urban referent category, living in more rural areas was associated with an increased adjusted risk of CLP. For example, the Rural-Urban Continuum Codes demonstrated elevated risks for CLP in "thinly populated areas" compared to "metropolitan-urban areas" (adjusted prevalence ratio = 1.9; 95% confidence intervals (CI) 1.2-2.8); CP was not similarly associated. Percentage of county cropland was not consistently associated with any outcome., Conclusion: The association patterns between non-urban residence and risk of CLP, except for percentage of cropland, suggests a constellation of exposures that may differ across urban-rural residence.

Neural tube birth defects (NTDs) affect more than 4000 pregnancies in the US annually. The etiology of NTDs is believed to be multifactorial, but much remains unknown. We examined the pattern and magnitude of urban-rural variation in anencephaly, spina bifida without anencephaly, and encephalocele in Texas in relation with urban-rural residence for the period 1999-2003. There was no evidence that urban-rural residence was associated with changes in the rate of anencephaly or spina bifida without anencephaly in unadjusted or adjusted analyses. In contrast, rates of encephalocele were statistically significantly higher in areas classified as suburban or more rural compared to urban areas using four different urban-rural residence indicators.

Purpose: We examined the relationship between maternal proximity to hazardous waste sites and industrial facilities and neural tube defect (NTD) risk., Methods: Texas Birth Defects Registry cases were linked with their birth or fetal death certificates; controls (without defects) were randomly selected from birth certificates. Distances from maternal addresses at delivery to National Priority List (NPL) and state superfund sites and Toxic Release Inventory (TRI) facilities were determined for 655 cases and 4368 controls., Results: Living within 1 mile of an NPL or state superfund site was not related to NTD risk (adjusted odds ratio [OR] = 1.0; 95% confidence intervals [CI] = 0.6, 1.7). Living within 1 mile of a TRI facility carried a slight risk (adjusted OR = 1.2; 95% CI = 1.0, 1.5). The effect was highest among mothers 35 years and older (OR = 2.7; 95% CI = 1.4, 5.0) and among non-Hispanic white mothers (OR = 1.8; 95% CI = 1.1, 2.8)., Conclusions: Hazardous waste sites posed little risk for NTDs in offspring. Close proximity to industrial facilities with chemical air emissions was associated with NTD risk in some subgroups. Further investigation is needed to determine if the effects are real or due to unresolved confounding or bias.

Purpose: This study compares the match rate and positional accuracy of two geocoding methods: the popular geocoding tool in ArcGIS 9.1 and the Centrus GeoCoder for ArcGIS., Methods: We first geocoded 11,016 Texas addresses in a case-control study using both methods and obtained the match rate of each method. We then randomly selected 200 addresses from those geocoded by using both methods and obtained geographic coordinates of the 200 addresses by using a global positioning system (GPS) device. Of the 200 addresses, 110 were case maternal residence addresses and 90 were control maternal residence addresses. These GPS-surveyed coordinates were used as the "true" coordinates to calculate positional errors of geocoded locations. We used Wilcoxon signed rank test to evaluate whether differences in positional errors from the two methods were statistically significantly different from zero. In addition, we calculated the sensitivity and specificity of the two methods for classifying maternal addresses within 1500 m of toxic release inventory facilities when distance is used as a proxy of exposure., Results: The match rate of the Centrus GeoCoder was more than 10% greater than that of the geocoding tool in ArcGIS 9.1. Positional errors with the Centrus GeoCoder were less than those of the geocoding tool in ArcGIS 9.1, and this difference was statistically significant. Sensitivity and specificity of the two methods are similar., Conclusions: Centrus GeoCoder for ArcGIS for geocoding gives greater match rates than the geocoding tool in ArcGIS 9.1. Although the Centrus GeoCoder has better positional accuracy, both methods give similar results in classifying maternal addresses within 1500 m of toxic release inventory facilities when distance is used as a proxy of exposure.

Our population-based case-control study of air quality and birth defects in Texas relied on the geocoding of maternal residence from vital records for the assignment of air pollution exposures during early pregnancy. We attempted to geocode the maternal addresses for 5,338 birth defect cases and 4,574 frequency-matched controls using an automated procedure with standard matching criteria in ArcGIS 8.2 and 8.3. Initially, we matched 7,266 observations (73%). To increase the proportion of successful matches, we used an interactive procedure for the 2,646 addresses that were initially not geocoded by the software. This yielded an additional 985 matches (37%). Using the same 2,646 initially unmatched addresses, we compared the results of this interactive procedure to those of an automated procedure using lower standards. The automated procedure with lower standards yielded more matches (n=1,559, 59%) but with questionable accuracy. We included the interactively geocoded observations in our final data set. Their inclusion did not affect the estimates of air pollution exposure but increased our statistical power to detect associations between air quality and risk of selected birth defects. The geocoded and not geocoded populations differed in the distribution of Latino ethnicity (51% vs 59%) and ethnicity was independently associated with air pollution exposures (P<0.05). Geocoding status also appeared to modify the association between ethnicity and risk of birth defects; Latina women appeared to have a slightly lower risk of birth defects than non-Latina women in the geocoded population and to have a slightly higher risk in the not geocoded population. Incomplete geocoding may have resulted in a selection bias because of the under-representation of Latinas in our study population.