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Birth defects and genetic disorders are leading causes of infant morbidity and mortality in many countries. Population-based data on birth defects among Arab-American children have not been documented previously. Michigan has the second largest Arab-American community in the United States after California. Using data from the Michigan Birth Defects Registry (MBDR), which includes information on parents' country of birth and ancestry, birth prevalences were estimated in offspring of Michigan women of Arab ancestry for 21 major categories of birth defects and 12 congenital endocrine, metabolic, and hereditary disorders. Compared with other non-Hispanic white children in Michigan, Arab-American children had similar or lower birth prevalences of the selected types of structural birth defects, with higher rates of certain hereditary blood disorders and three categories of metabolic disorders. These estimates are important for planning preconception and antenatal health care, genetic counseling, and clinical care for Arab Americans. [ABSTRACT FROM AUTHOR]

Objective: To report on the first 3 years of mucopolysaccharidosis type I (MPS I) newborn screening (NBS) in the large and diverse state of California., Study Design: The California Genetic Disease Screening Program began universal NBS for MPS I on August 29, 2018. The screening uses a 2-tiered approach: an α-L-iduronidase (IDUA) enzyme activity assay followed by DNA sequencing for variants in the IDUA gene., Results: As of August 29, 2021, 1 295 515 California newborns were screened for MPS I. In tier 1 of screening, 329 (0.025%) had an IDUA enzyme measurement below the cutoff and underwent tier-2 IDUA DNA sequencing. After tier 2, 146 (0.011%) newborns were screen positive, all of whom were referred to a metabolic Special Care Center for follow-up. After long-term follow-up, 7 cases were resolved as severe MPS I (Hurler syndrome) and 2 cases as attenuated MPS I for an MPS I birth prevalence of 1/143 946. DNA sequencing identified 107 unique IDUA variants among a total of 524 variants; 65% were known pseudodeficiency alleles, 25% were variants of uncertain significance, and 10% were pathogenic variants., Conclusions: As a result of a 2-tiered NBS approach, 7 newborns diagnosed with Hurler syndrome had received early treatment for MPS I. Continuation of California's long-term follow-up program will be crucial for further understanding the complex genotype-phenotype relationships of MPS I., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Universal spinal muscular atrophy (SMA) newborn screening was implemented in California on June 24, 2020., Objective: We describe California's experience with the first 18 months of SMA newborn screening, including our assay methodology, timeliness of screening and follow-up milestones, and clinical and epidemiological outcomes observed., Methods: Dried blood spots are screened for SMA using multiplex real time polymerase chain reaction (RT-PCR) to detect deletions of exon 7 in the survival of motor neuron 1 (SMN1) gene. Short-term follow-up data is collected from clinical staff via an online data collection tool., Results: In the first 18 months, 628,791 newborns from California's diverse population were tested for SMA. Thirty-four screened positive and were confirmed to have the disorder. Infants were referred, diagnosed, and treated at a median of 8, 12, and 33 days of life, respectively. Nearly all infants received the desired treatment modality, and 62% received treatment while still asymptomatic., Conclusions: SMA newborn screening is a highly sensitive and specific test which identifies infants with SMA early when treatment is most effective. Even with newborn screening's success in facilitating early intervention, there is still work to be done to expedite treatment, especially for infants with the most severe form of the disease.

X-linked adrenoleukodystrophy (ALD) is a recent addition to the Recommended Uniform Screening Panel, prompting many states to begin screening newborns for the disorder. We provide California's experience with ALD newborn screening, highlighting the clinical and epidemiological outcomes observed as well as program implementation challenges. In this retrospective cohort study, we examine ALD newborn screening results and clinical outcomes for 1,854,631 newborns whose specimens were received by the California Genetic Disease Screening Program from 16 February 2016 through 15 February 2020. In the first four years of ALD newborn screening in California, 355 newborns screened positive for ALD, including 147 (41%) with an ABCD1 variant of uncertain significance (VUS) and 95 males diagnosed with ALD. After modifying cutoffs, we observed an ALD birth prevalence of 1 in 14,397 males. Long-term follow-up identified 14 males with signs of adrenal involvement. This study adds to a growing body of literature reporting on outcomes of newborn screening for ALD and offering a glimpse of what other large newborn screening programs can expect when adding ALD to their screening panel.

Background: Neural tube defects (NTD)s are common birth defects with a multifactorial etiology. Findings from human studies examining environmental (non-inherited) exposures tend to be inconclusive. In particular, although animal studies of alcohol exposure and NTDs support its teratogenic potential, human studies are equivocal. Using data from the National Birth Defects Prevention Study (NBDPS), associations between maternal periconceptional (1 month before through 1 month after conception) alcohol consumption and NTDs in offspring were examined., Methods: NTD cases and unaffected live born singleton controls with expected dates of delivery from October 1997-December 2011 were enrolled in the NBDPS. Interview reports of alcohol consumption (quantity, frequency, variability, type) from 1,922 case and 11,251 control mothers were analyzed. Crude and adjusted odds ratios (aOR)s and 95% confidence intervals (CI)s for alcohol consumption and all NTDs combined and selected subtypes (spina bifida, anencephaly, encephalocele) were estimated using unconditional logistic regression analysis., Results: Among mothers in the NBDPS, 28% of NTD case and 35% of control mothers reported any periconceptional alcohol consumption. For each measure of alcohol consumption, inverse associations were observed for all NTDs combined (aORs = 0.6-1.0). Results for NTD subtypes tended to be similar, but CIs for spina bifida and encephalocele were more likely to include the null., Conclusions: These findings suggest a lack of positive associations between maternal periconceptional alcohol consumption and NTDs. Future studies should continue to evaluate the association between maternal alcohol consumption and NTDs in offspring accounting for methodological limitations such as potential misclassification from self-reported alcohol consumption., (© 2020 Wiley Periodicals, Inc.)

The California Department of Public Health started universal newborn screening for Pompe disease in August 2018 with a two-tier process including: (1) acid alpha-glucosidase (GAA) enzyme activity assay followed by, (2) GAA gene sequencing analysis. This study examines results from the first year of screening in a large and diverse screening population. With 453,152 screened newborns, the birth prevalence and GAA enzyme activity associated with various types of Pompe disease classifications are described. The frequency of GAA gene mutations and allele variants are reported. Of 88 screen positives, 18 newborns were resolved as Pompe disease, including 2 classic infantile-onset and 16 suspected late-onset form. The c.-32-13T>G variant was the most common pathogenic mutation reported. African American and Asian/Pacific Islander newborns had higher allele frequencies for both pathogenic and pseudodeficiency variants. After the first year of Pompe disease screening in California, the disease distribution in the population is now better understood. With the ongoing long-term follow-up system currently in place, our understanding of the complex genotype-phenotype relationships will become more evident in the future, and this should help us better understand the clinical significance of identified cases., Competing Interests: Conflicts of InterestThe authors declare no conflict of interest., (© 2020 by the authors.)

Zika virus infection during pregnancy can cause congenital brain and eye abnormalities and is associated with neurodevelopmental abnormalities (1-3). In areas of the United States that experienced local Zika virus transmission, the prevalence of birth defects potentially related to Zika virus infection during pregnancy increased in the second half of 2016 compared with the first half (4). To update the previous report, CDC analyzed population-based surveillance data from 22 states and territories to estimate the prevalence of birth defects potentially related to Zika virus infection, regardless of laboratory evidence of or exposure to Zika virus, among pregnancies completed during January 1, 2016-June 30, 2017. Jurisdictions were categorized as those 1) with widespread local transmission of Zika virus; 2) with limited local transmission of Zika virus; and 3) without local transmission of Zika virus. Among 2,004,630 live births, 3,359 infants and fetuses with birth defects potentially related to Zika virus infection during pregnancy were identified (1.7 per 1,000 live births, 95% confidence interval [CI] = 1.6-1.7). In areas with widespread local Zika virus transmission, the prevalence of birth defects potentially related to Zika virus infection during pregnancy was significantly higher during the quarters comprising July 2016-March 2017 (July-September 2016 = 3.0; October-December 2016 = 4.0; and January-March 2017 = 5.6 per 1,000 live births) compared with the reference period (January-March 2016) (1.3 per 1,000). These findings suggest a fourfold increase (prevalence ratio [PR] = 4.1, 95% CI = 2.1-8.4) in birth defects potentially related to Zika virus in widespread local transmission areas during January-March 2017 compared with that during January-March 2016, with the highest prevalence (7.0 per 1,000 live births) in February 2017. Population-based birth defects surveillance is critical for identifying infants and fetuses with birth defects potentially related to Zika virus regardless of whether Zika virus testing was conducted, especially given the high prevalence of asymptomatic disease. These data can be used to inform follow-up care and services as well as strengthen surveillance., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Background: As maternal fever affects approximately 6-8% of early pregnancies, it is important to expand upon previous observations of an association between maternal fever and birth defects., Methods: We analyzed data from the National Birth Defects Prevention Study, a multistate, case-control study of major structural birth defects. Telephone interviews were completed by mothers of cases (n = 17,162) and controls (n = 10,127). Using multivariable logistic regression, we assessed the association between maternal self-report of cold or flu with fever and cold or flu without fever during early pregnancy and 30 categories of non-cardiac birth defects., Results: Maternal report of cold or flu with fever was significantly associated with 8 birth defects (anencephaly, spina bifida, encephalocele, cleft lip with or without cleft palate, colonic atresia/stenosis, bilateral renal agenesis/hypoplasia, limb reduction defects, and gastroschisis) with elevated adjusted odds ratios ranging from 1.2 to 3.7. Maternal report of cold or flu without fever was not associated with any of the birth defects studied., Conclusions: This study adds to the evidence that maternal fever during early pregnancy is associated with an increased risk for selected birth defects. Elevated associations were limited to mothers who reported a fever, suggesting that it is fever that contributes to the excess risk rather than illnesses associated with it. However, fever may also serve as a marker for more severe infections., (© 2017 Wiley Periodicals, Inc.)

Background: Population-based birth defects surveillance is a core public health activity in the United States (U.S.); however, the lack of national data quality standards has limited the use of birth defects surveillance data across state programs. Development of national standards will facilitate data aggregation and utilization across birth defects surveillance programs in the U.S., Methods: Based on national standards for other U.S. public health surveillance programs, existing National Birth Defects Prevention Network (NBDPN) guidelines for conducting birth defects surveillance, and information from birth defects surveillance programs regarding their current data quality practices, we developed 11 data quality measures that focused on data completeness (n = 5 measures), timeliness (n = 2), and accuracy (n = 4). For each measure, we established tri-level performance criteria (1 = rudimentary, 2 = essential, 3 = optimal). In January 2014, we sent birth defects surveillance programs in each state, District of Columbia, Puerto Rico, Centers for Disease Control and Prevention (CDC), and the U.S. Department of Defense Birth and Infant Health Registry an invitation to complete a self-administered NBDPN Standards Data Quality Assessment Tool. The completed forms were electronically submitted to the CDC for analyses., Results: Of 47 eligible population-based surveillance programs, 45 submitted a completed assessment tool. Two of the 45 programs did not meet minimum inclusion criteria and were excluded; thus, the final analysis included information from 43 programs. Average scores for four of the five completeness performance measures were above level 2. Conversely, the average scores for both timeliness measures and three of the four accuracy measures were below level 2. Surveillance programs using an active case-finding approach scored higher than programs using passive case-finding approaches for the completeness and accuracy measures, whereas their average scores were lower for timeliness measures., Conclusions: This initial, nation-wide assessment of data quality across U.S. population-based birth defects surveillance programs highlights areas for improvement. Using this information to identify strengths and weaknesses, the birth defects surveillance community, working through the NBDPN, can enhance and implement a consistent set of standards that can promote uniformity and enable surveillance programs to work towards improving the potential of these programs.

Background: The Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) is a population-based, multi-Center case-control study of modifiable risk factors for selected birth defects in the United States. BD-STEPS is the second major research effort of the Centers for Birth Defects Research and Prevention, which extends and expands the initial research effort, the National Birth Defects Prevention Study (NBDPS)., Methods: BD-STEPS focuses on 17 categories of structural birth defects selected based on severity, prevalence, consistent ascertainment, and previous findings that warrant additional research. Cases are identified through existing birth defects surveillance programs; controls are from vital records or birth hospital logs from the same catchment area. BD-STEPS uses a standardized computer-assisted telephone interview to collect information from case and control mothers on topics including demographics, health conditions, and medication use. Following the maternal interview, selected Centers request permission to sample residual newborn screening blood spots from state repositories for genetic analyses. New components planned for BD-STEPS include linkages with external datasets and use of online questionnaires to collect in-depth information on selected exposures., Results: BD-STEPS extends NBDPS by continuing to collect data on many exposures that were assessed in NBDPS, allowing data from both studies to be combined and providing an unprecedented sample size to analyze rare exposures. BD-STEPS expands upon NBDPS by collecting more detailed information on existing exposures as well as new exposures., Conclusion: The goal of BD-STEPS is to provide women and healthcare providers with information they need to make decisions to promote the healthiest pregnancy possible., (© 2015 Wiley Periodicals, Inc.)

Critical congenital heart defects (CCHD) occur in approximately two of every 1,000 live births. Newborn screening provides an opportunity for reducing infant morbidity and mortality. In September 2011, the U.S. Department of Health and Human Services (HHS) Secretary endorsed the recommendation that critical congenital heart defects be added to the Recommended Uniform Screening Panel (RUSP) for all newborns. In 2014, CDC collaborated with the American Academy of Pediatrics (AAP) Division of State Government Affairs and the Newborn Screening Technical Assistance and Evaluation Program (NewSTEPs) to assess states' actions for adopting newborn screening for CCHD. Forty-three states have taken action toward newborn screening for CCHD through legislation, regulations, or hospital guidelines. Among those 43, 32 (74%) are collecting or planning to collect CCHD screening data; however, the type of data collected by CCHD newborn screening programs varies by state. State mandates for newborn screening for CCHD will likely increase the number of newborns screened, allowing for the possibility of early identification and prevention of morbidity and mortality. Data collection at the state level is important for surveillance, monitoring of outcomes, and evaluation of state CCHD newborn screening programs.

In 2011, statewide newborn screening programs for critical congenital heart defects began in the United States, and subsequently screening has been implemented widely. In this review, we focus on data reports and collection efforts related to both prenatal diagnosis and newborn screening. Defect-specific, maternal, and geographic factors are associated with variations in prenatal detection, so newborn screening provides a population-wide safety net for early diagnosis. A new web-based repository is collecting information on newborn screening program policies, quality indicators related to screening programs, and specific case-level data on infants with these defects. Birth defects surveillance programs also collect data about critical congenital heart defects, particularly related to diagnostic timing, mortality, and services. Individuals from state programs, federal agencies, and national organizations will be interested in these data to further refine algorithms for screening in normal newborn nurseries, neonatal intensive care settings, and other special populations; and ultimately to evaluate the impact of screening on outcomes., (Published by Elsevier Inc.)

Background: Little is known about population-based maternal, child, and system characteristics associated with high hospital resource use for children with orofacial clefts (OFC) in the US., Methods: This was a statewide, population-based, retrospective observational study of children with OFC born between 1998 and 2006, identified by the Florida Birth Defects Registry whose records were linked with longitudinal hospital discharge records. We stratified the descriptive results by cleft type [cleft lip with cleft palate, cleft lip, and cleft palate] and by isolated versus nonisolated OFC (accompanied by other coded major birth defects). We used Poisson regression to analyze associations between selected characteristics and high hospital resource use (≥90th percentile of estimated hospitalized days and inpatient costs) for birth, postbirth, and total hospitalizations initiated before age 2 years., Results: Our analysis included 2,129 children with OFC. Infants who were born low birth weight (<2500 grams) were significantly more likely to have high birth hospitalization costs for CLP (adjusted prevalence ratio: 1.6 [95% confidence interval: 1.0-2.7]), CL (adjusted prevalence ratio: 3.0 [95% confidence interval: 1.1-8.1]), and CP (adjusted prevalence ratio: 2.3 [95% confidence interval: 1.3-4.0]). Presence of multiple birth defects was significantly associated with a three- to eleven-fold and a three- to nine-fold increase in the prevalence of high costs and number of hospitalized days, respectively; at birth, postbirth before age 2 years and overall hospitalizations., Conclusion: Children with cleft palate had the greatest hospital resources use. Additionally, the presence of multiple birth defects contributed to greater inpatient days and costs for children with OFC., (© 2015 Wiley Periodicals, Inc.)

Background: Cerebral palsy (CP) is defined by its nonprogressive features. Therefore, a standard definition and list of progressive disorders to exclude would be useful for CP monitoring and epidemiologic studies., Methods: We reviewed the literature on this topic to 1) develop selection criteria for progressive brain disorders of childhood for public health surveillance purposes, 2) identify categories of disorders likely to include individual conditions that are progressive, and 3) ascertain information about the relative frequency and natural history of candidate disorders., Results: Based on 19 criteria that we developed, we ascertained a total of 104 progressive brain disorders of childhood, almost all of which were Mendelian disorders., Discussion: Our list is meant for CP surveillance programs and does not represent a complete catalog of progressive genetic conditions, nor is the list meant to comprehensively characterize disorders that might be mistaken for cerebral palsy. The criteria for progressive disorders that we developed could be applied by public health investigators in the future, as more children with very rare conditions are followed and new candidate disorders are identified.

© 2014 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc., (© 2014 Wiley Periodicals, Inc.)

Background: Women of childbearing age report high rates of alcohol consumption, which may result in alcohol exposure during early pregnancy. Epidemiological research on congenital limb deficiencies (LDs) and periconceptional exposure to alcohol is inconclusive., Methods: Data from the National Birth Defects Prevention Study (NBDPS) were examined for associations between LDs and patterns of maternal periconceptional (1 month before conception through the first trimester) alcohol consumption among LD case (n = 906) and unaffected control (n = 8352) pregnancies with expected delivery dates from 10/1997 through 12/2007. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated from unconditional logistic regression analysis for all LDs combined, specific LD subtypes (preaxial/terminal transverse), and LD anatomic groups (upper/lower limbs); interactions with folic acid (FA) supplementation were tested., Results: When compared with nondrinkers, inverse associations were found between all LDs combined, preaxial, and upper LDs and any reported periconceptional alcohol consumption (aORs ranged from 0.56-0.83), drinking without binging (aORs: 0.53-0.75), and binge drinking (≥4 drinks/occasion) (aORs: 0.64-0.94); however, none of the binge drinking aORs were statistically significant. Stratification by alcohol type showed inverse associations between all LDs combined, preaxial, transverse, and upper and lower LDs for drinking without binging of wine only (aORs: 0.39-0.67) and between all LDs combined and upper LDs for drinking without binging of combinations of alcohol (aORs: 0.63-0.87). FA did not modify observed associations., Conclusion: Maternal periconceptional alcohol consumption did not emerge as a teratogen for selected LDs in the NBDPS. Future studies should evaluate additional rare LDs among more highly exposed populations., (© 2014 Wiley Periodicals, Inc.)

Background: Adverse associations between maternal pesticide exposure and neural tube defects (NTDs) have been suggested but not consistently observed. This study used data from the multisite National Birth Defects Prevention Study to examine associations between maternal periconceptional (1 month preconception through 2 months postconception) occupational pesticide exposure and NTDs., Methods: Mothers of 502 NTD cases and 2950 unaffected live-born control infants with estimated delivery dates from 1997 through 2002 were included. Duration, categorical intensity scores, and categorical frequency scores for pesticide classes (e.g., insecticides) were assigned using a modified, literature-based job-exposure matrix and maternal-reported occupational histories. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated based on fitted multivariable logistic regression models that described associations between maternal periconceptional occupational pesticide exposure and NTDs. The aORs were estimated for pesticide exposure (any [yes/no] and cumulative exposure [intensity × frequency × duration] to any pesticide class, each pesticide class, or combination of pesticide classes) and all NTD cases combined and NTD subtypes., Results: Positive, but marginally significant or nonsignificant, aORs were observed for exposure to insecticides + herbicides for all NTD cases combined and for spina bifida alone. Similarly, positive aORs were observed for any exposure and cumulative exposure to insecticides + herbicides + fungicides and anencephaly alone and encephalocele alone. All other aORs were near unity., Conclusion: Pesticide exposure associations varied by NTD subtype and pesticide class. Several aORs were increased, but not significantly. Future work should continue to examine associations between pesticide classes and NTD subtypes using a detailed occupational pesticide exposure assessment and examine pesticide exposures outside the workplace., (© 2014 Wiley Periodicals, Inc.)

Background: Our objective was to examine differences in hospital resource usage for children with Down syndrome by age and the presence of other birth defects, particularly severe and nonsevere congenital heart defects (CHDs)., Methods: This was a retrospective, population-based, statewide study of children with Down syndrome born 1998 to 2007, identified by the Florida Birth Defects Registry (FBDR) and linked to hospital discharge records for 1 to 10 years after birth. To evaluate hospital resource usage, descriptive statistics on number of hospitalized days and hospital costs were calculated. Results were stratified by isolated Down syndrome (no other coded major birth defect); presence of severe and nonsevere CHDs; and presence of major FBDR-eligible birth defects without CHDs., Results: For 2552 children with Down syndrome, there were 6856 inpatient admissions, of which 68.9% occurred during the first year of life (infancy). Of the 2552 children, 31.7% (n = 808) had isolated Down syndrome, 24.0% (n = 612) had severe CHDs, 36.3% (n = 927) had nonsevere CHDs, and 8.0% (n = 205) had a major FBDR-eligible birth defect in the absence of CHD. Infants in all three nonisolated DS groups had significantly higher hospital costs compared with those with isolated Down syndrome. From infancy through age 4, children with severe CHDs had the highest inpatient costs compared with children in the other sub-groups., Conclusion: Results support findings that for children with Down syndrome the presence of other anomalies influences hospital use and costs, and children with severe CHDs have greater hospital resource usage than children with other CHDs or major birth defects without CHDs., (© 2014 Wiley Periodicals, Inc.)

Objectives: We investigated the relationship between race/ethnicity and 27 major birth defects., Methods: We pooled data from 12 population-based birth defects surveillance systems in the United States that included 13.5 million live births (1 of 3 of US births) from 1999 to 2007. Using Poisson regression, we calculated prevalence estimates for each birth defect and 13 racial/ethnic groupings, along with crude and adjusted prevalence ratios (aPRs). Non-Hispanic Whites served as the referent group., Results: American Indians/Alaska Natives had a significantly higher and 50% or greater prevalence for 7 conditions (aPR = 3.97; 95% confidence interval [CI] = 2.89, 5.44 for anotia or microtia); aPRs of 1.5 to 2.1 for cleft lip, trisomy 18, and encephalocele, and lower, upper, and any limb deficiency). Cubans and Asians, especially Chinese and Asian Indians, had either significantly lower or similar prevalences of these defects compared with non-Hispanic Whites, with the exception of anotia or microtia among Chinese (aPR = 2.08; 95% CI = 1.30, 3.33) and Filipinos (aPR = 1.90; 95% CI = 1.10, 3.30) and tetralogy of Fallot among Vietnamese (aPR = 1.60; 95% CI = 1.11, 2.32)., Conclusions: This is the largest population-based study to our knowledge to systematically examine the prevalence of a range of major birth defects across many racial/ethnic groups, including Asian and Hispanic subgroups. The relatively high prevalence of birth defects in American Indians/Alaska Natives warrants further attention.

Background: Hypospadias is a frequent birth defect with three phenotypic subtypes. With data from the National Birth Defects Prevention Study, a large, multi-state, population-based, case-control study, we compared risk factors for second and third degree hypospadias., Methods: A wide variety of data on maternal and pregnancy-related risk factors for isolated second and third degree hypospadias was collected by means of computer-assisted telephone interviews to identify potential etiological differences between the two phenotypes. Logistic regression was used to calculate odds ratios including a random effect by study center., Results: In total, 1547 second degree cases, 389 third degree cases, and 5183 male controls were included in our study. Third degree cases were more likely to have a non-Hispanic black or Asian/Pacific Islander mother, be delivered preterm, have a low birth weight, be small for gestational age, and be conceived with fertility treatments than second degree cases and controls. Associations with both second and third degree hypospadias were observed for maternal age, family history, parity, plurality, and hypertension during pregnancy. Risk estimates were generally higher for third degree hypospadias except for family history., Conclusion: Most risk factors were associated with both or neither phenotype. Therefore, it is likely that the underlying mechanism is at least partly similar for both phenotypes. However, some associations were different between second and third degree hypospadias, and went in opposite directions for second and third degree hypospadias for Asian/Pacific Islander mothers. Effect estimates for subtypes of hypospadias may be over- or underestimated in studies without stratification by phenotype., (© 2014 Wiley Periodicals, Inc.)

Purpose: The aim of this study was to describe the methods, cases, and initial results of a pilot project using existing public health data collection programs (birth defect surveillance or newborn screening) to conduct long-term follow-up of children with metabolic disorders., Methods: California, Iowa, New York, and Utah expanded birth defect surveillance or newborn screening programs to collect long-term follow-up data on 19 metabolic disorders. Data elements to monitor health status and services delivered were identified, and record abstraction and data linkages were conducted. Children were followed up through to the age of 3 years., Results: A total of 261 metabolic cases were diagnosed in 1,343,696 live births (19.4 cases/100,000; 95% confidence interval = 17.1-21.8). Four deaths were identified. Children with fatty acid oxidation disorders had a higher percentage of health service encounters compared with children with other disorders of at least one health service encounter (hospitalization, emergency room, metabolic clinic, genetic service provider, or social worker) except for hospitalizations; children with organic acid disorders had a higher percentage of at least one hospitalization during their third year of life than children with other disorders., Conclusion: Existing public health data programs can be leveraged to conduct population-based newborn screening long-term follow-up. This approach is flexible according to state needs and resources. These data will enable the states in assessing health burden, assuring access to services, and supporting policy development.

Importance: Critical congenital heart disease (CCHD) was added to the Recommended Uniform Screening Panel for Newborns in the United States in 2011. Many states have recently adopted or are considering requirements for universal CCHD screening through pulse oximetry in birth hospitals. Limited previous research is directly applicable to the question of how many US infants with CCHD might be identified through screening., Objectives: To estimate the proportion of US infants with late detection of CCHD (>3 days after birth) based on existing clinical practice and to investigate factors associated with late detection., Design, Setting, and Participants: Descriptive and multivariable analysis. Data were obtained from a multisite population-based study of birth defects in the United States, the National Birth Defects Prevention Study (NBDPS). We included all live-born infants with estimated dates of delivery from January 1, 1998, through December 31, 2007, and nonsyndromic, clinically verified CCHD conditions potentially detectable through screening via pulse oximetry., Main Outcomes and Measures: The main outcome measure was the proportion of infants with late detection of CCHD through echocardiography or at autopsy under the assumption that universal screening at birth hospitals might reduce the number of such late diagnoses. Secondary outcome measures included prevalence ratios for associations between selected demographic and clinical factors and late detection of CCHD., Results: Of 3746 live-born infants with nonsyndromic CCHD, late detection occurred in 1106 (29.5% [95% CI, 28.1%-31.0%]), including 6 (0.2%) (0.1%-0.4%) first receiving a diagnosis at autopsy more than 3 days after birth. Late detection varied by CCHD type from 9 of 120 infants (7.5% [95% CI, 3.5%-13.8%]) with pulmonary atresia to 497 of 801 (62.0% [58.7%-65.4%]) with coarctation of the aorta. In multivariable analysis, late detection varied significantly by CCHD type and study site, and infants with extracardiac defects were significantly less likely to have late detection of CCHD (adjusted prevalence ratio, 0.58 [95% CI, 0.49-0.69])., Conclusions and Relevance: We estimate that 29.5% of live-born infants with nonsyndromic CCHD in the NBDPS received a diagnosis more than 3 days after birth and therefore might have benefited from routine CCHD screening at birth hospitals. The number of infants in whom CCHD was detected through screening likely varies by several factors, including CCHD type. Additional population-based studies of screening in practice are needed.

Choanal atresia causes serious posterior nasal obstruction. This defect is the leading cause of nasal surgery in newborns, although its etiology is largely unknown. Data from the National Birth Defects Prevention Study, a population-based case-control study, were used to examine associations between maternal self-reports of exposures and occurrence of choanal atresia in their offspring. Overall, 117 case and 8350 control mothers with deliveries from 1997 through 2007 provided telephone interview reports of pre-pregnancy (one year before conception) and periconceptional (one month before through three months after conception) exposures. The exposures analyzed were pre-pregnancy dietary intake, pre-pregnancy and periconceptional caffeine consumption, and periconceptional cigarette smoking, alcohol drinking, and medication use. Independent associations between each exposure and all choanal atresia cases combined (n = 117) and isolated choanal atresia cases (those without additional unrelated major defects; n = 61) were examined. Odds ratios (ORs), both unadjusted (uORs) and adjusted (aORs) for potential confounders, and 95% confidence intervals (CIs) were estimated using unconditional logistic regression analysis. For all choanal atresia cases combined, positive associations were observed with maternal pre-pregnancy intake in the highest quartile for vitamin B-12 (aOR = 1.9; CI = 1.1,3.1), zinc (aOR = 1.7; CI = 1.0,3.1), and niacin (aOR = 1.8; CI = 1.0,3.1), and intake in the lowest quartile for methionine (aOR = 1.6; CI = 1.0,2.6) and vitamin D (aOR = 1.6; CI = 1.0,2.4) compared to intake in the two intermediate quartiles combined. Further, a positive association was observed with periconceptional use of thyroid medications (uOR = 2.6; CI = 1.0,6.3) compared to no use of such medications. Among isolated choanal atresia cases, negative associations were observed for pantothenic acid (aOR = 0.4; CI = 0.2,0.9) and fat (aOR = 0.5; 95% CI = 0.2,1.0) intake in the lowest quartile compared to that in the intermediate quartiles, and positive associations were observed for periconceptional cigarette smoking (aOR = 2.3; CI = 1.1,4.7) compared to no smoking and pre-pregnancy daily coffee intake of 3 or more cups (aOR = 2.5; CI = 1.1,5.6) compared to intake of less than 1 cup per day. The positive association for periconceptional exposure to thyroid medications also persisted for isolated choanal atresia cases (uOR = 4.0; CI = 1.1,11.2). Because of the large number of associations tested, these findings may be due to chance. Alternatively, they may contribute new hypotheses regarding the etiology of choanal atresia; thus, requiring replication in additional studies., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

This population-based U.S. study investigated the association between major musculoskeletal malformations and periconceptional maternal occupational pesticide exposure for a wide range of occupations. We conducted a multi-site case-control analysis using data from the National Birth Defects Prevention Study among employed women with due dates from October 1, 1997 through December 31, 2002. Cases included 871 live-born, stillborn, or electively terminated fetuses with isolated craniosynostosis, gastroschisis, diaphragmatic hernia, or transverse limb deficiencies. Controls included 2857 live-born infants without major malformations. Using self-reported maternal occupational information, an industrial hygienist used a job-exposure matrix and expert opinion to evaluate the potential for exposure to insecticides, herbicides or fungicides for each job held during one month pre-conception through three months post-conception. Exposures analyzed included any exposure (yes/no) to pesticides, to insecticides only, to both insecticides and herbicides (I+H) and to insecticides, herbicides and fungicides (I+H+F). We used logistic regression to evaluate the association between exposures and defects, controlling for infant and maternal risk factors. Occupational exposure to I+H+F was associated with gastroschisis among infants of women aged 20 years or older (adjusted odds ratio [aOR]=1.88; 95% confidence interval [CI]: 1.16-3.05), but not for women under age 20 (aOR=0.48; 95% CI: 0.20-1.16). We found no significant associations for the other defects. Additional research is needed to validate these findings in a separate population., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

The prevalence of trisomy 21 has been reported to differ by race-ethnicity, however, the results are inconsistent and the cause of the differences is unknown. Using data from 1996 to 2005 from the Metropolitan Atlanta Congenital Defects Program (MACDP), we analyzed the use of prenatal cytogenetic testing and the subsequent use of elective termination among pregnancies affected with any MACDP-eligible birth defect and trisomy 21, by maternal race-ethnicity. We then examined whether these factors could explain the observed differences in the prevalence of trisomy 21 among race-ethnicity groups. Among all pregnancies with birth defects, prenatal cytogenetic testing as well as elective terminations after an abnormal prenatal cytogenetic test result were observed less frequently among Hispanic women than among non-Hispanic white women (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.56-0.78, respectively). In pregnancies affected by trisomy 21, both the Hispanic and the non-Hispanic black populations had more live births (89.5% and 77.8%, respectively) and fewer elective terminations (5.7% and 15.2%, respectively) compared to the non-Hispanic white population (63.0% live births, 32.3% elective terminations). After adjusting for elective terminations, non-Hispanic white mothers had a higher live birth prevalence of trisomy 21 compared to non-Hispanic black (OR 0.64, 95% CI 0.54-0.76) or Hispanic mothers (OR 0.69, 95% CI 0.55-0.86). Overall, our data suggest that factors associated with decisions made about the use of prenatal testing, and about pregnancy management after testing, might play a large role in the race-ethnicity differences observed in the live birth prevalence of trisomy 21., (© 2013 Wiley Periodicals, Inc.)

Background: We investigated whether maternal exposure to cigarette smoke was associated with omphalocoele and whether periconceptional folic acid modified the association., Methods:  : We analysed data from the National Birth Defects Prevention Study on omphalocoele case (n = 301) and control (n = 8135) mothers for infants born from 1997 through 2007. Mothers who reported active smoking or exposure to second-hand smoke during the periconceptional period (1 month before conception to 3 months after) were considered exposed. Those who reported use of folic acid supplements during the same period were considered supplement users. Odds ratios and 95% confidence intervals were estimated using multivariable logistic regression adjusted for alcohol use, preconception body mass index, and race/ethnicity., Results: One hundred fifteen (38.2%) case and 2592 (31.9%) control mothers reported exposure to cigarette smoke during the periconceptional period. Adjusted odds ratios [95% confidence intervals] were 1.19 [0.94, 1.53] for any smoke exposure, 0.87 [0.54, 1.40] for active smoking, 1.38 [1.00, 1.90] for second-hand smoke exposure, and 1.16 [0.80, 1.67] for both exposures combined. No dose-response relationship was observed. Folic acid-containing supplements did not reduce the risk for omphalocoele among women with active or second-hand smoke exposure., Conclusions: Self-reported active maternal smoking, with or without exposure to second-hand smoke, during the periconceptional period was not associated with omphalocoele. In contrast, there was a possible association with periconceptional exposure to second-hand smoke., (© 2013 John Wiley & Sons Ltd.)

Objective: Critical congenital heart disease (CCHD) was recently added to the U.S. Recommended Uniform Screening Panel for newborns. This evaluation aimed to estimate screening time and hospital cost per newborn screened for CCHD using pulse oximetry as part of a public health economic assessment of CCHD screening., Methods: A cost survey and time and motion study were conducted in well-newborn and special/intensive care nurseries in a random sample of seven birthing hospitals in New Jersey, where the state legislature mandated CCHD screening in 2011. The sample was stratified by hospital facility level, hospital birth census, and geographic location. At the time of the evaluation, all hospitals had conducted CCHD screening for at least four months., Results: Mean screening time per newborn was 9.1 (standard deviation = 3.4) minutes. Hospitals' total mean estimated cost per newborn screened was $14.19 (in 2011 U.S. dollars), consisting of $7.36 in labor costs and $6.83 in equipment and supply costs., Conclusions: This federal agency-state health department collaborative assessment is the first state-level analysis of time and hospital costs for CCHD screening using pulse oximetry conducted in the U.S. Hospitals' cost per newborn screened for CCHD with pulse oximetry is comparable with cost estimates of existing newborn screening tests. Hospitals' equipment costs varied substantially based on the pulse oximetry technology employed, with lower costs among hospitals that used reusable screening sensors. In combination with estimates of screening accuracy, effectiveness, and avoided costs, information from this evaluation suggests that CCHD screening is cost-effective.

Background: Congenital limb deficiencies (LD)s are characterised by the failure or disruption in formation of limbs or digits. Epidemiological research on maternal exposure to cigarette smoke and LDs is inconclusive., Methods: Data from the National Birth Defects Prevention Study were used to examine LDs and maternal exposure to active or passive cigarette smoke. Mothers of LD case (n = 906) and unaffected control (n = 8352) pregnancies from October 1997 through December 2007 reported on exposure type and quantity. Logistic regression was used to estimate adjusted odds ratio (OR) and 95% confidence interval [95% CI]; interactions with folic acid (FA) intake were tested., Results: For any LD, ORs were elevated for active (1.24 [95% CI 1.01, 1.53]), passive (home) (1.28 [95% CI 1.03, 1.59]), and 'active and passive' (1.34 [95% CI 1.05, 1.70]) exposures. The ORs for longitudinal LDs were elevated for passive (home) (1.62 [95% CI 1.14, 2.31]) and 'active and passive' (1.62 [95% CI 1.09, 2.41]) exposures. The OR for pre-axial LDs were elevated for any (1.39 [95% CI 1.01, 1.90]), active (1.53 [95% CI 1.03, 2.29]), passive (home) (1.82 [95% CI 1.23, 2.69]), and 'active and passive' (1.87 [95% CI 1.20, 2.92]) exposures. For lower limbs, ORs were elevated for passive (home) (1.44 [95% CI 1.01, 2.04]) and smoking 15 or more cigarettes/day (2.25 [95% CI 1.27, 3.97]). Interactions showed that ORs for any passive smoke exposure were 0.43 and 0.59 higher in the absence of FA intake for any and terminal transverse LDs., Conclusions: Maternal active smoking and exposure to passive cigarette smoke emerged as a potential teratogen that affects limb and digit formation. FA was not found to mitigate the impact., (© 2013 John Wiley & Sons Ltd.)

Background: Critical congenital heart disease (CCHD) was recently added to the U.S. Recommended Uniform Screening Panel for newborns. States considering screening requirements may want more information about the potential impact of screening. This study examined potentially avoidable mortality among infants with late detected CCHD and assessed whether late detection was associated with increased hospital resource use during infancy., Methods: This was a state-wide, population-based, observational study of infants with CCHD (n = 3603) born 1998 to 2007 identified by the Florida Birth Defects Registry. We examined 12 CCHD conditions that are targets of newborn screening. Late detection was defined as CCHD diagnosis after the birth hospitalization. Deaths potentially avoidable through screening were defined as those that occurred outside a hospital following birth hospitalization discharge and those that occurred within 3 days of an emergency readmission., Results: For 23% (n = 825) of infants, CCHD was not detected during the birth hospitalization. Death occurred among 20% (n = 568/2,778) of infants with timely detected CCHD and 8% (n = 66/825) of infants with late detected CCHD, unadjusted for clinical characteristics. Potentially preventable deaths occurred in 1.8% (n = 15/825) of infants with late detected CCHD (0.4% of all infants with CCHD). In multivariable models adjusted for selected characteristics, late CCHD detection was significantly associated with 52% more admissions, 18% more hospitalized days, and 35% higher inpatient costs during infancy., Conclusion: Increased CCHD detection at birth hospitals through screening may lead to decreased hospital costs and avoid some deaths during infancy. Additional studies conducted after screening implementation are needed to confirm these findings., (Copyright © 2013 Wiley Periodicals, Inc.)

Objectives: Clinical evidence indicates newborn critical congenital heart disease (CCHD) screening through pulse oximetry is lifesaving. In 2011, CCHD was added to the US Recommended Uniform Screening Panel for newborns. Several states have implemented or are considering screening mandates. This study aimed to estimate the cost-effectiveness of routine screening among US newborns unsuspected of having CCHD., Methods: We developed a cohort model with a time horizon of infancy to estimate the inpatient medical costs and health benefits of CCHD screening. Model inputs were derived from new estimates of hospital screening costs and inpatient care for infants with late-detected CCHD, defined as no diagnosis at the birth hospital. We estimated the number of newborns with CCHD detected at birth hospitals and life-years saved with routine screening compared with no screening., Results: Screening was estimated to incur an additional cost of $6.28 per newborn, with incremental costs of $20 862 per newborn with CCHD detected at birth hospitals and $40 385 per life-year gained (2011 US dollars). We estimated 1189 more newborns with CCHD would be identified at birth hospitals and 20 infant deaths averted annually with screening. Another 1975 false-positive results not associated with CCHD were estimated to occur, although these results had a minimal impact on total estimated costs., Conclusions: This study provides the first US cost-effectiveness analysis of CCHD screening in the United States could be reasonably cost-effective. We anticipate data from states that have recently approved or initiated CCHD screening will become available over the next few years to refine these projections.

Objectives: Critical congenital heart disease (CCHD) was recently added to the US Recommended Uniform Screening Panel for newborns. This study assessed whether maternal/household and infant characteristics were associated with late CCHD detection., Methods: This was a statewide, population-based, retrospective, observational study of infants with CCHD born between 1998 and 2007 identified by using the Florida Birth Defects Registry. We examined 12 CCHD conditions that are primary and secondary targets of newborn CCHD screening using pulse oximetry. We used Poisson regression models to analyze associations between selected characteristics (eg, CCHD type, birth hospital nursery level [highest level available in the hospital]) and late CCHD detection (defined as diagnosis after the birth hospitalization)., Results: Of 3603 infants with CCHD and linked hospitalizations, CCHD was not detected during the birth hospitalization for 22.9% (n = 825) of infants. The likelihood of late detection varied by CCHD condition. Infants born in a birth hospital with a level I nursery only (adjusted prevalence ratio: 1.9 [95% confidence interval: 1.6-2.2]) or level II nursery (adjusted prevalence ratio: 1.5 [95% confidence interval: 1.3-1.7]) were significantly more likely to have late-detected CCHD compared with infants born in a birth hospital with a level III (highest) nursery., Conclusions: After controlling for the selected characteristics, hospital nursery level seems to have an independent association with late CCHD detection. Thus, perhaps universal newborn screening for CCHD could be particularly beneficial in level I and II nurseries and may reduce differences in the frequency of late diagnosis between birth hospital facilities.

Experimental data indicate that gestational exposures to estrogenic compounds impact risk of hypospadias. We examined whether risk of hypospadias (i.e., a congenital malformation in which the opening of the penile urethra occurs on the ventral side of the penis) was associated with maternal intake of phytoestrogens, given their potential impact on estrogen metabolism. The analysis included data on mothers of 1,250 hypospadias cases and 3,118 controls who delivered their infants from 1997 to 2005 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. After adjustment for several covariates, high intakes of daidzein, genistein, glycetin, secoisolariciresinol, total isoflavones, total lignans, and total phytoestrogens were associated with reduced risks; odds ratios comparing intakes ≥90th percentile with intakes between the 11th and 89th percentiles ranged from 0.6 to 0.8. For example, the odds ratio for total phytoestrogen intake was 0.7 (95% confidence interval: 0.5, 1.0). This study represents the first large-scale analysis of phytoestrogen intake and hypospadias. The observed associations merit investigation in additional populations before firm conclusions can be reached.

Background and Objective: New Jersey was the first state to implement legislatively mandated newborn pulse oximetry screening (POxS) in all licensed birthing facilities to detect critical congenital heart defects (CCHDs). The objective of this report was to evaluate implementation of New Jersey's statewide POxS mandate., Methods: A 2-pronged approach was used to collect data on infants screened in all New Jersey birthing facilities from August 31, 2011, through May 31, 2012. Aggregate screening results were submitted by each birthing facility. Data on failed screens and clinical characteristics of those newborns were reported to the New Jersey Birth Defects Registry (NJBDR). Three indicators were used to distinguish the added value of mandated POxS from standard clinical care: prenatal congenital heart defect diagnosis, cardiology consultation or echocardiogram indicated or performed before PoxS, or clinical findings at the time of POxS warranting a pulse oximetry measurement., Results: Of 75,324 live births in licensed New Jersey birthing facilities, 73,320 were eligible for screening, of which 99% were screened. Forty-nine infants with failed POxS were reported to the NJBDR, 30 of whom had diagnostic evaluations solely attributable to the mandated screening. Three of the 30 infants had previously unsuspected CCHDs and 17 had other diagnoses or non-CCHD echocardiogram findings., Conclusions: In the first 9 months after implementation, New Jersey achieved a high statewide screening rate and established surveillance mechanisms to evaluate the unique contribution of POxS. The screening mandate identified 3 infants with previously unsuspected CCHDs that otherwise might have resulted in significant morbidity and mortality and also identified other significant secondary targets such as sepsis and pneumonia.

Purpose: To investigate associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants., Methods: We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1537 infants with second-degree or third-degree isolated hypospadias and 4314 live-born male control infants without major birth defects, with estimated dates of delivery from 1997 to 2007. Exposure was reported use of prescription or over-the-counter medications or herbal products, from 1 month before to 4 months after conception. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, previous live births, maternal subfertility, study site, and year., Results: We assessed 64 medication and 24 herbal components. Maternal uses of most components were not associated with an increased risk of hypospadias. A new associations was observed for venlafaxine (aOR 2.4; 95%CI 1.0, 6.0) [Correction made here after initial online publication.]. The previously reported association for clomiphene citrate was confirmed (aOR 1.9; 95%CI 1.2, 3.0). Numbers were relatively small for exposure to other specific patterns of fertility agents, but elevated aORs were observed for the most common of them., Conclusions: Overall, findings were reassuring that hypospadias is not associated with most medication components examined in this analysis. New associations will need to be confirmed in other studies. Increased risks for hypospadias associated with various fertility agents raise the possibility of confounding by underlying subfertility., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: Neural tube defects (NTD)s, which occur when the neural tube fails to close during early gestation, are some of the most common birth defects worldwide. Alcohol is a known teratogen and has been shown to induce NTDs in animal studies, although most human studies have failed to corroborate these results. Using data from the National Birth Defects Prevention Study, associations between maternal reports of periconceptional (1 month prior through 2 months postconception) alcohol consumption and NTDs were examined., Methods: NTD cases and unaffected live born control infants, delivered from 1997 through 2005, were included. Interview reports of alcohol consumption (quantity, frequency, variability, and type) were obtained from 1223 case mothers and 6807 control mothers. Adjusted odds ratios (aOR)s and 95% confidence intervals were estimated using multivariable logistic regression analysis., Results: For all NTDs combined, most aORs for any alcohol consumption, one or more binge episodes, and different type(s) of alcohol consumed were near unity or modestly reduced (≥ 0.7 < aOR ≤ 1.1) and were not statistically significant. Findings were similar for individual NTD subtypes., Conclusions: These findings suggest no elevated association between maternal periconceptional alcohol consumption and NTDs. Underreporting of alcohol consumption, due to negative social stigma associated with alcohol consumption during pregnancy, and limited reports for mothers with early pregnancy loss of a fetus with an NTD may have affected the estimated odds ratios. Future studies should aim to increase sample sizes for less prevalent subtypes, reduce exposure misclassification, and improve ascertainment of fetal deaths and elective terminations., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Animal studies have shown that high doses of caffeine might cause congenital limb deficiencies (LDs); however, no epidemiologic studies have explored this relation., Methods: This case-control study assessed associations between maternal dietary caffeine and congenital LDs using data from the National Birth Defects Prevention Study (NBDPS), with 844 LD cases and 8069 controls from 1997 to 2007. Caffeine intakes from beverages (coffee, tea, and soda) and chocolate combined and by beverage type were examined. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated for subtypes of isolated LDs (no additional major anomalies) and LDs with other major anomalies separately, comparing the odds of 10 to <100, 100 to <200, 200 to <300, and 300+ mg/day total caffeine intake to 0 to <10 mg/day., Results: All total dietary caffeine intake categories of 10 mg/day and above were marginally associated with odds of all isolated LDs combined (aOR, 1.4-1.7), isolated longitudinal LDs (aOR, 1.2-1.6), and isolated transverse LDs (aOR, 1.3-1.8) compared to the lowest intake category. A dose-response pattern for total dietary caffeine intake was not observed., Conclusions: A weak increased risk of congenital LDs associated with maternal dietary caffeine consumption was observed in this study; however, risk did not vary by amount of caffeine consumed., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: We examined whether hypospadias was associated with several aspects of the diet, including intake of animal products, intake of several nutrients and food groups related to a vegetarian diet and oestrogen metabolism, and diet quality., Methods: The study included deliveries from 1997 to 2005 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews, and two diet quality indices were developed based on existing indices. Analyses included 1250 cases with second- or third-degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 3118 male, liveborn, non-malformed controls. All odds ratios (OR) and 95% confidence intervals [CI] were estimated from logistic regression models that included several potential confounders, including energy intake., Results: Intake of animal products was not associated with hypospadias; for example, the adjusted OR for any vs. no intake of meat was 1.0 [95% CI 0.6, 1.6]. Frequency of intake of meat or other animal products was also not associated with hypospadias, nor was intake of iron or several nutrients that are potentially related to oestrogen metabolism. Diet quality was also not associated with hypospadias; the OR for diet quality in the highest vs. lowest quartile for the two diet quality indices were 1.0 [95% CI 0.6, 1.6] and 0.9 [95% CI 0.7, 1.1]., Conclusion: This large study does not support an association of a vegetarian diet or worse diet quality with hypospadias., (© 2012 Blackwell Publishing Ltd.)

Objectives: Approximately 4% to 12% of pregnant women have asthma; few studies have examined the effects of maternal asthma medication use on birth defects. We examined whether maternal asthma medication use during early pregnancy increased the risk of selected birth defects., Methods: National Birth Defects Prevention Study data for 2853 infants with 1 or more selected birth defects (diaphragmatic hernia, esophageal atresia, small intestinal atresia, anorectal atresia, neural tube defects, omphalocele, or limb deficiencies) and 6726 unaffected control infants delivered from October 1997 through December 2005 were analyzed. Mothers of cases and controls provided telephone interviews of medication use and additional potential risk factors. Exposure was defined as maternal periconceptional (1 month prior through the third month of pregnancy) asthma medication use (bronchodilator or anti-inflammatory). Associations between maternal periconceptional asthma medication use and individual major birth defects were estimated by using adjusted odds ratios (aOR) and 95% confidence intervals (95%CI)., Results: No statistically significant associations were observed for maternal periconceptional asthma medication use and most defects studied; however, positive associations were observed between maternal asthma medication use and isolated esophageal atresia (bronchodilator use: aOR = 2.39, 95%CI = 1.23, 4.66), isolated anorectal atresia (anti-inflammatory use: aOR = 2.12, 95%CI = 1.09, 4.12), and omphalocele (bronchodilator and anti-inflammatory use: aOR = 4.13, 95%CI = 1.43, 11.95)., Conclusions: Positive associations were observed for anorectal atresia, esophageal atresia, and omphalocele and maternal periconceptional asthma medication use, but not for other defects studied. It is possible that observed associations may be chance findings or may be a result of maternal asthma severity and related hypoxia rather than medication use.

Spina bifida refers to a collection of neural tube defects, including myelomeningocele, meningocele, and myelocele (SB(M) ), as well as lipomyelomeningocele and lipomeningocele (SB(L) ). Maternal race/ethnicity has been associated with an increased risk for spina bifida among offspring. To better understand this relationship, we evaluated different spina bifida subtypes (SB(M) vs. SB(L) ) and sub-phenotypes (anatomic level or presence of additional malformations) by maternal race/ethnicity using data from the National Birth Defects Prevention Study. This study is a large, multisite, population-based study of nonsyndromic birth defects. Prevalence estimates were obtained using data from spina bifida cases (live births, fetal deaths, and elective terminations) and total live births in the study regions. From October 1997 through December 2005, 1,046 infants/fetuses with spina bifida were delivered, yielding a prevalence of 3.06 per 10,000 live births. Differences in the prevalences of SB(M) vs. SB(L) , isolated versus non-isolated SB(M) , and lesion level in isolated SB(M) among case offspring were observed by maternal race/ethnicity. Compared to non-Hispanic (NH) White mothers, offspring of Hispanic mothers had higher prevalences of each subtype and most sub-phenotypes, while offspring of NH Black mothers generally had lower prevalences. Furthermore, differences in race/ethnicity among those with isolated SB(M) were more pronounced by sex. For instance, among male offspring, the prevalence of isolated SB(M) was significantly higher for those with Hispanic mothers compared to NH White mothers [prevalence ratio (PR): 1.55, 95% confidence interval: 1.23-1.95]. These findings provide evidence that certain spina bifida subtypes and sub-phenotypes may be etiologically distinct., (Copyright © 2011 Wiley Periodicals, Inc.)

The purpose of this study was to examine changes in the use of cytogenetic testing and identification of chromosomal abnormalities among pregnancies and children with birth defects. Utilizing data from 1968 to 2005 from the Metropolitan Atlanta Congenital Defects Program, we analyzed trends in the frequency and timing (prenatal or postnatal) of cytogenetic testing and the prevalence of recognized chromosome abnormalities among pregnancies and children with birth defects (n = 51,424). Cytogenetic testing of pregnancies and children with birth defects increased from 7.2% in 1968 to 25.0% in 2005, as did the identification of chromosomal abnormalities (2.2% in 1968 to 6.8% in 2005). The use of prenatal cytogenetic testing decreased from 1996 to 2005 among women aged ≥35 years. Identification of chromosomal abnormalities in pregnancies and children with birth defects increased from 1968 to 2005, possibly due to increased testing, improved diagnostic techniques, or increasing maternal age. The decline in prenatal cytogenetic testing observed among mothers aged ≥35 years may be related to the availability of improved prenatal screening techniques, resulting in a reduction in the utilization of invasive diagnostic tests., (Published 2011 Wiley Periodicals, Inc. This article is a U.S. Government work and is in the public domain in the USA.)

Bladder exstrophy (BE) is a complex congenital anomaly characterized by a defect in the closure of the lower abdominal wall and bladder. We aimed to provide an overview of the literature and conduct an epidemiologic study to describe the prevalence, and maternal and case characteristics of BE. We used data from 22 participating member programs of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). All cases were reviewed and classified as isolated, syndrome, and multiple congenital anomalies. We estimated the total prevalence of BE and calculated the frequency and odds ratios for various maternal and case characteristics. A total of 546 cases with BE were identified among 26,355,094 births. The total prevalence of BE was 2.07 per 100,000 births (95% CI: 1.90-2.25) and varied between 0.52 and 4.63 among surveillance programs participating in the study. BE was nearly twice as common among male as among female cases. The proportion of isolated cases was 71%. Prevalence appeared to increase with increasing categories of maternal age, particularly among isolated cases. The total prevalence of BE showed some variations by geographical region, which is most likely attributable to differences in registration of cases. The higher total prevalence among male cases and older mothers, especially among isolated cases, warrants further attention., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Hypospadias is a common congenital malformation among men in which the urethral opening is ventrally displaced. Pesticide exposure has been suggested as a possible etiologic factor, but previous epidemiologic studies have produced inconsistent results., Methods: We used data from the National Birth Defects Prevention Study (NBDPS), a population-based case-control study, to examine maternal occupational exposure to fungicides, insecticides, and herbicides among 647 hypospadias case infants and 1496 unaffected male control infants with estimated delivery dates from October 1997 to December 2002. Periconceptional (1 month before conception through the first trimester of pregnancy) pesticide exposures were assigned by an expert rater, assisted by a job-exposure matrix (JEM), from a job history completed by mothers during a telephone interview. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with multivariable logistic regression, and adjusted for relevant covariates., Results: Maternal periconceptional occupational exposure to any pesticides (yes/no) was not associated with an increased risk of hypospadias (OR = 0.78; 95% CI = 0.61-1.01). Maternal occupational periconceptional pesticide exposure type (insecticides, fungicides, and herbicides) and estimated quantity also showed no significantly increased risk of hypospadias and no evidence of a dose-response relationship; however, the estimated pesticide exposure levels in this population were low., Conclusion: Using broad classes of insecticides, herbicides, and fungicides, we found no evidence that low intensity maternal periconceptional occupational pesticide exposure was a risk factor for hypospadias., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Genital tract infections are common during pregnancy and can result in adverse outcomes including preterm birth and neonatal infection. This hypothesis-generating study examined whether these infections are associated with selected birth defects., Methods: We conducted a case-control study of 5913 children identified as controls and 12,158 cases with birth defects from the National Birth Defects Prevention Study (1997-2004). Maternal interviews provided data on genital tract infections that occurred from one month before pregnancy through the end of the first trimester. Infections were either grouped together as a single overall exposure or were considered as a subgroup that included chlamydia/gonorrhea/pelvic inflammatory disease. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression with adjustment for potential confounders., Results: Genital tract infections were associated with bilateral renal agenesis/hypoplasia (OR, 2.89; 95% CI, 1.11-7.50), cleft lip with or without cleft palate (OR, 1.46; 95% CI, 1.03-2.06), and transverse limb deficiency (OR, 1.84; 95% CI, 1.04-3.26). Chlamydia/gonorrhea/pelvic inflammatory disease was associated with cleft lip only (OR, 2.81; 95% CI, 1.39-5.69). These findings were not statistically significant after adjustment for multiple comparisons., Conclusions: Caution is needed in interpreting these findings due to the possible misclassification of infection, the limited sample size that constrained consideration of the effects of treatment, and the possibility of chance associations. Although these data do not provide strong evidence for an association between genital tract infections and birth defects, additional research on the possible effects of these relatively common infections is needed., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Investigations of maternal caffeine intake and neural tube defects (NTDs) have not considered genetic influences. Caffeine metabolism gene effects were examined in the National Birth Defects Prevention Study., Methods: Average daily caffeine was summed from self-reported coffee, tea, soda, and chocolate intake for mothers of 768 NTD cases, and 4143 controls delivered from 1997 to 2002. A subset of 306 NTD and 669 control infants and their parents were genotyped for CYP1A2*1F, NAT2 481C>T, and NAT2 590G>A. CYP1A2*1F was classified by fast or slow oxidation status, and NAT2 variants were categorized into rapid or slow acetylation status. Case-control logistic regression analyses, family-based transmission/disequilibrium tests and log-linear analyses, and hybrid log-linear analyses were conducted to produce odds ratios (ORs) or relative risks (RRs) and 95% confidence intervals (CIs) for caffeine intake and maternal and infant gene variants, and to examine interaction effects., Results: NTDs were independently associated with infant slow NAT2 acetylator status (RR, 2.00; 95% CI, 1.10-3.64) and maternal CYP1A2*1F fast oxidation status (OR, 1.49; 95% CI, 1.10-2.03). Mothers who consumed caffeine, oxidized CYP1A2*1F quickly, and acetylized NAT2 slowly had a nonsignificantly elevated estimated risk for an NTD-affected pregnancy (OR, 3.10; 95% CI, 0.86-11.21). Multiplicative interaction effects were observed between maternal caffeine and infant CYP1A2*1F fast oxidizer status (p(interaction) = 0.03)., Conclusions: The association identified between maternal CYP1A2*1F fast oxidation status and NTDs should be examined further in the context of the other substrates of CYP1A2. Maternal caffeine and its metabolites may be associated with increased risk for NTD-affected pregnancies in genetically susceptible subgroups., (2010 Wiley-Liss, Inc.)