Early Childhood Inpatient Costs of Critical Congenital Heart Disease.

OBJECTIVE: To assess longitudinal estimates of inpatient costs through early childhood in patients with critical congenital heart defects (CCHDs), for whom reliable estimates are scarce, using a population-based cohort of clinically validated CCHD cases. STUDY DESIGN: Longitudinal retrospective cohort of infants with CCHDs live born from 1997 to 2012 in Utah. Cases identified from birth defect registry data were linked to inpatient discharge abstracts and vital records to track inpatient days and costs through age 10 years. Costs were adjusted for inflation and discounted by 3% per year to generate present value estimates. Multivariable models identified infant and maternal factors potentially associated with higher resource utilization and were used to calculate adjusted costs by defect type. RESULTS: The final statewide cohort included 1439 CCHD cases among 803 509 livebirths (1.8/1000). The average cost per affected child through age 10 years was $136 682 with a median of $74 924 because of a small number of extremely high cost children; costs were highest for pulmonary atresia with ventricular septal defect and hypoplastic left heart syndrome. Inpatient costs increased by 1.6% per year during the study period. A single birth year cohort (~50 000 births/year) had estimated expenditures of $11 902 899 through age 10 years. Extrapolating to the US population, inpatient costs for a single birth year cohort through age 10 years were ~$1 billion. CONCLUSIONS: Inpatient costs for CCHDs throughout childhood are high and rising. These revised estimates will contribute to comparative effectiveness research aimed at improving the value of care on a patient and population level.

Does Maternal Exposure to Secondhand Tobacco Smoke During Pregnancy Increase the Risk for Preterm or Small-for-Gestational Age Birth?

Introduction While associations between active smoking and various adverse birth outcomes (ABOs) have been reported in the literature, less is known about the impact of secondhand smoke (SHS) on many pregnancy outcomes. Methods We examined the relationship between maternal exposure to SHS during pregnancy and preterm (< 37 weeks gestation) and small-for-gestational age (SGA; assessed using sex-, race/ethnic-, and parity-specific growth curves) singleton births using non-smoking controls from the National Birth Defects Prevention Study (1997-2011). Multivariable logistic regression models for household, workplace/school, and combined SHS exposure-controlled for maternal education, race/ethnicity, pre-pregnancy body mass index, and high blood pressure-were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Interaction was assessed for maternal folic acid supplementation, alcohol use, age at delivery, and infant sex. Results Infants of 8855 mothers were examined in the preterm birth analysis with 666 (7.5%) categorized as preterm, 574 moderately preterm (32-36 weeks), and 92 very preterm (< 32 weeks). For the SGA analysis, infants of 8684 mothers were examined with 670 (7.7%) categorized as SGA. The aORs for mothers reporting both household and workplace/school SHS were elevated for preterm (aOR 1.99; 95% CI 1.13-3.50) and moderately preterm birth (32-36 weeks) (aOR 2.17; 95% CI 1.22-3.88). No results for the SGA analysis achieved significance, nor was evidence of interaction evident. Conclusion The findings suggest an association between SHS from multiple exposure sources and preterm birth, but no evidence for association with SGA births. Continued study of SHS and ABOs is needed to best inform public health prevention programs.

Clinical presentation and survival in a population-based cohort of infants with gastroschisis in Utah, 1997-2011.

Typically gastroschisis is considered an isolated birth defect; however, other major malformations are reported to occur in 5-35% of cases depending on inclusion criteria. This study evaluated the associated malformations, small for gestational age, and survival among a clinically well-characterized population-based gastroschisis cohort, delivered from 1997-2011. We used data from Utah's statewide population-based surveillance system, which monitors major structural birth defects among all pregnancy outcomes (i.e., live births, stillbirths, pregnancy terminations, and miscarriages). Of the initial 387 gastroschisis cases, we excluded 51 (13.2%) for the following reasons: inadequately described or macerated fetuses, part of a specific malformation complex or sequence (limb-body wall complex, amniotic band sequence, or a severe form of abdominoschisis), leaving a study sample of 336 clinically confirmed cases. Gastroschisis was isolated non-syndromic in 284 cases (84.5%). One case was syndromic (trisomy 16; 0.3%) and the remaining 51 (15.2%) were classified as multiple: one unrelated major malformation (27; 52.9%); two or more unrelated major malformation or one major with multiple minor anomalies or mild malformations (6; 11.8%); ≥ one distinctive minor anomaly or mild malformation (13; 25.5%); amyoplasia (5; 1.5%). Of the liveborn infants, 63.3% were preterm (delivered at <37 weeks of gestation) and 21.8% were small for gestational age (SGA). SGA was more common in males (38.8%) than females (16%) (P = 0.008). Overall first year survival was high (95.6%); however, preterm infants with congenital intestinal atresia had the highest mortality (13.8%). The high proportion of isolated cases (84.5%) in gastroschisis is similar to that observed in many other phenotypes and not unique to gastroschisis. Because one in every six infants with gastroschisis had a major unrelated malformation, additional malformations should be sought in every newborn with gastroschisis. Infant mortality was low overall but still a significant concern in affected preterm infants with associated congenital intestinal atresia.

Associations between maternal periconceptional exposure to secondhand tobacco smoke and major birth defects.

BACKGROUND: While associations between secondhand smoke and a few birth defects (namely, oral clefts and neural tube defects) have been noted in the scientific literature, to our knowledge, there is no single or comprehensive source of population-based information on its associations with a range of birth defects among nonsmoking mothers. OBJECTIVE: We utilized data from the National Birth Defects Prevention Study, a large population-based multisite case-control study, to examine associations between maternal reports of periconceptional exposure to secondhand smoke in the household or workplace/school and major birth defects. STUDY DESIGN: The multisite National Birth Defects Prevention Study is the largest case-control study of birth defects to date in the United States. We selected cases from birth defect groups having >100 total cases, as well as all nonmalformed controls (10,200), from delivery years 1997 through 2009; 44 birth defects were examined. After excluding cases and controls from multiple births and whose mothers reported active smoking or pregestational diabetes, we analyzed data on periconceptional secondhand smoke exposure-encompassing the period 1 month prior to conception through the first trimester. For the birth defect craniosynostosis, we additionally examined the effect of exposure in the second and third trimesters as well due to the potential sensitivity to teratogens for this defect throughout pregnancy. Covariates included in all final models of birth defects with ≥5 exposed mothers were study site, previous live births, time between estimated date of delivery and interview date, maternal age at estimated date of delivery, race/ethnicity, education, body mass index, nativity, household income divided by number of people supported by this income, periconceptional alcohol consumption, and folic acid supplementation. For each birth defect examined, we used logistic regression analyses to estimate both crude and adjusted odds ratios and 95% confidence intervals for both isolated and total case groups for various sources of exposure (household only; workplace/school only; household and workplace/school; household or workplace/school). RESULTS: The prevalence of secondhand smoke exposure only across all sources ranged from 12.9-27.8% for cases and 14.5-15.8% for controls. The adjusted odds ratios for any vs no secondhand smoke exposure in the household or workplace/school and isolated birth defects were significantly elevated for neural tube defects (anencephaly: adjusted odds ratio, 1.66; 95% confidence interval, 1.22-2.25; and spina bifida: adjusted odds ratio, 1.49; 95% confidence interval, 1.20-1.86); orofacial clefts (cleft lip without cleft palate: adjusted odds ratio, 1.41; 95% confidence interval, 1.10-1.81; cleft lip with or without cleft palate: adjusted odds ratio, 1.24; 95% confidence interval, 1.05-1.46; cleft palate alone: adjusted odds ratio, 1.31; 95% confidence interval, 1.06-1.63); bilateral renal agenesis (adjusted odds ratio, 1.99; 95% confidence interval, 1.05-3.75); amniotic band syndrome-limb body wall complex (adjusted odds ratio, 1.66; 95% confidence interval, 1.10-2.51); and atrial septal defects, secundum (adjusted odds ratio, 1.37; 95% confidence interval, 1.09-1.72). There were no significant inverse associations observed. CONCLUSION: Additional studies replicating the findings are needed to better understand the moderate positive associations observed between periconceptional secondhand smoke and several birth defects in this analysis. Increased odds ratios resulting from chance (eg, multiple comparisons) or recall bias cannot be ruled out.

Evaluating cost and resource use associated with pulse oximetry screening for critical congenital heart disease: Empiric estimates and sources of variation.

BACKGROUND: Newborn screening for critical congenital heart disease (CCHD) using pulse oximetry is being implemented in the United States and internationally; however, few data are available on the associated in-hospital costs and use of resources. METHODS: Time and motion study in well-baby nurseries at two large urban hospitals in Utah using different approaches to pulse oximetry screening. Two observers recorded the time for each screening step together with provider and equipment characteristics. Structured questionnaire provided additional information on labor and equipment costs. RESULTS: Fifty-three CCHD screens were observed. At site A (n = 22), screening was mostly done by medical assistants (95%) using disposable probes (100%); at site B (n = 31), screening was mostly performed by certified nursing assistants (90%) using reusable probes (90%). Considering only first screens (n = 53), the median screen time was 8.6 min (range: 3.2-23.2), with no significant difference between sites. The overall cost ($ in 2014) of screening per baby was $24.52 at site A and $2.60 at site B. Nearly all the variation in cost (90%) was due to the cost of disposable probes; labor costs were similar between sites. CONCLUSION: CCHD screening by means of pulse oximetry is reasonably fast for most babies, leading to relative small labor costs with little variation by provider type. The main driver of costs is equipment: in a high throughput setting, reusable probes are currently associated with considerable cost saving compared with disposable probes. As programs expand to universal screening, improved and cheaper technologies could lead to considerable economies of scale.

Development and implementation of the first national data quality standards for population-based birth defects surveillance programs in the United States.

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.

Better diet quality before pregnancy is associated with reduced risk of gastroschisis in Hispanic women.

BACKGROUND: Gastroschisis is unique because of its substantial risk in pregnancies of adolescent women. Adolescents may have poor diet quality, which places them at higher risk of gastroschisis. OBJECTIVE: We investigated whether better maternal diet quality, measured by 2 different indices, reduced the risk of gastroschisis. METHODS: We used case-control data from the National Birth Defects Prevention Study to investigate maternal diet quality among 1125 gastroschisis cases and 9483 controls (estimated delivery dates between 1997 and 2009). Cases were ascertained from 10 U.S. birth defect surveillance systems. Control subjects were randomly selected from birth certificates or hospital records. Using a 58-item food-frequency questionnaire, interviewers queried mothers about their average food and cereal intake during the year before conception. Diet quality scores [Diet Quality Index (DQI) and Mediterranean diet score (MDS)] were calculated using specific components. Women were excluded if they consumed <500 or >5000 kcal/d, reported pregestational diabetes, or had >1 missing food item. Quartile-specific adjusted ORs (aORs) were calculated, using as reference the lowest quartile. RESULTS: Overall, we observed a statistically significant decrease with increasing diet quality for both the DQI and MDS. When stratified by maternal race/ethnicity, this finding was confined to Hispanic women. Among Hispanic women, the risk of gastroschisis decreased significantly with increasing DQI quartiles: quartile 2, aOR = 0.58 (95% CI: 0.40, 0.86); quartile 3, aOR = 0.52 (95% CI: 0.36, 0.79); and quartile 4, aOR = 0.48 (95% CI: 0.32, 0.76). Increasing diet quality, as measured by the MDS, showed reduced risk of gastroschisis among women, mostly Hispanic, who were born outside the United States: quartile 2, aOR = 0.62 (95% CI: 0.33, 1.16); quartile 3, aOR = 0.51 (95% CI: 0.28, 0.94); and quartile 4, aOR = 0.50 (95% CI: 0.28, 0.90). CONCLUSIONS: Increasing diet quality was associated with a reduced risk of gastroschisis only among Hispanic and foreign-born women, but these findings require replication.

Laterality defects in the national birth defects prevention study (1998-2007): birth prevalence and descriptive epidemiology.

Little is known epidemiologically about laterality defects. Using data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, we analyzed prevalence and selected characteristics in children born with laterality defects born from 1998 to 2007. We identified 517 nonsyndromic cases (378 heterotaxy, 73.1%; 139 situs inversus totalis [SIT], 26.9%) resulting in an estimated birth prevalence of 1.1 per 10,000 live births (95% confidence interval 1.0­1.2). Prevalence did not differ significantly across sites, over time, or by inclusion of pregnancy termination. Laterality defects were more common among preterm cases compared to term cases, and in children born to mothers who were non-white or younger than 20 years compared to white mothers or those age 25­29 years. The distribution of associated cardiac and extra-cardiac defects, excluding the expected heterotaxy anomalies, varied by type of laterality defect. Cases with heterotaxy were significantly more likely than those with SIT to have double outlet right ventricle, atrioventricular canal defects, pulmonary stenosis, non-tetralogy of Fallot pulmonary atresia with ventricular septal defect, totally and partially anomalous pulmonary venous return; also more likely to have orofacial clefts, esophageal atresia, bowel atresias, and omphalocele, though not reaching statistical significance. Relatively more common among cases with SIT were Dandy- Walker malformation, anotia/microtia, and limb deficiency. The similarity in the demographic characteristics of heterotaxy and SIT supports the hypothesis that they are part of a continuum of abnormal left-right axis patterning. These findings on laterality defects may help guide clinical care, future research, and prevention strategies.

Congenital heart defects after maternal fever.

OBJECTIVE: The purpose of this study was to evaluate whether maternal febrile illnesses in early pregnancy are associated with increased risk for congenital heart defects in the offspring and whether such risk is mitigated by multivitamin supplement use. STUDY DESIGN: From a multistate population-based case-control study (National Birth Defects Prevention Study), we compared maternal reports of first-trimester febrile illness from 7020 subjects with heart defects and 6746 unaffected control subjects who were born from 1997 through 2005. Relative risks were computed with no fever or infection during the first trimester as reference group and were adjusted for potential confounders. RESULTS: First-trimester febrile illness was reported by 7.4% of control mothers (1 in 13). Febrile genitourinary infections were associated with selected heart defects, particularly right-sided obstructive defects (odds ratios, >3) and possibly others, whereas common respiratory illnesses were associated with low-to-negligible risks for most heart defects. When risk estimates were elevated, they tended to be mitigated when multivitamin supplements had been taken in the periconceptional period. CONCLUSION: The source of fever and the use of supplements appear to influence the risk for heart defects. This information can be helpful in counseling and research, in particular with regard to primary prevention.

Gastroschisis prevalence patterns in 27 surveillance programs from 24 countries, International Clearinghouse for Birth Defects Surveillance and Research, 1980-2017.

BACKGROUND: Gastroschisis is a serious birth defect with midgut prolapse into the amniotic cavity. The objectives of this study were to evaluate the prevalence and time trends of gastroschisis among programs in the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), focusing on regional variations and maternal age changes in the population. METHODS: We analyzed data on births from 1980 to 2017 from 27 ICBDSR member programs, representing 24 countries and three regions (Europe+ (includes Iran) , Latin America, North America). Cases were identified using diagnostic codes (i.e., 756.7, 756.71, or Q79.3). We excluded cases of amniotic band syndrome, limb-body wall defect, and ruptured omphalocele. Programs provided annual counts for gastroschisis cases (live births, stillbirths, and legally permitted pregnancy terminations for fetal anomalies) and source population (live births, stillbirths), by maternal age. RESULTS: Overall, gastroschisis occurred in 1 of every 3268 births (3.06 per 10,000 births; 95% confidence intervals [CI]: 3.01, 3.11), with marked regional variation. European+ prevalence was 1.49 (95%CI: 1.44, 1.55), Latin American 3.80 (95%CI: 3.69, 3.92) and North American 4.32 (95%CI: 4.22, 4.42). A statistically significant increasing time trend was observed among six European+ , four Latin American, and four North American programs. Women <20 years of age had the highest prevalence in all programs except the Slovak Republic. CONCLUSIONS: Gastroschisis prevalence increased over time in 61% of participating programs, and the highest increase in prevalence was observed among the youngest women. Additional inquiry will help to assess the impact of the changing maternal age proportions in the birth population on gastroschisis prevalence.

Self-reported maternal smoking during pregnancy by source in Utah, 2003-2007.

BACKGROUND: Maternal self-report is the most common method for assessment of past cigarette exposure to assess birth defect risk. This study compared maternal smoking prior to and during pregnancy based on self-reports obtained from the medical records abstracted for the Utah Birth Defect Network (UBDN), the birth certificate, and the computer-assisted telephone interview (CATI) in the National Birth Defects Prevention Study (NBDPS). The study also investigated how the different sources for maternal smoking data affect estimates in an empirical study. METHODS: A total of 1774 case and 618 control mothers who had participated in the NBDPS and whose live born infants were delivered between January 1, 2003, and December 31, 2007, were included in this study. Among the case mothers, we compared data from all three sources, whereas for control mothers only two data sources were available for comparison (i.e., birth certificate and CATI). RESULTS: Smoking prevalence was highest in the CATI. Compared to the CATI, data from the UBDN had a higher sensitivity (61.3%) and better agreement (kappa = 0.63) than birth certificates (51.8%; kappa = 0.56). Adjusted odds ratios for all and specific birth defects (i.e., holoprosencephaly, hydrocephalus, anophthalmia/microphthalmia, anotia/microtia, total anomalous pulmonary venous return/partial anomalous pulmonary venous return [TAPVR/PAPVR], heterotaxy, and gastroschisis) were different between the birth certificate and CATI. The change in the effect estimates between the two sources ranged from 19% to 56%. CONCLUSIONS: Based on our findings, maternal smoking exposure from interview data was shown to be of higher quality with less misclassification compared to data obtained from medical records or birth certificates.

Prenatally diagnosed congenital heart disease: the cost of maternal care.

OBJECTIVE: Little is known regarding the effects of a prenatal diagnosis of congenital heart disease (CHD) on the cost of antenatal and delivery care. We sought to compare the maternal costs of care in pregnancies where the fetus or child was diagnosed prenatally vs. postnatally. METHODS: Costs of maternal care were determined for pregnancies in which the fetus or child was diagnosed with CHD between 1997 and 2012 in the state of Utah. Cases of CHD were identified via a statewide birth defect surveillance program which included data on the timing of diagnosis, maternal demographic and clinical data, and linked to statewide inpatient maternal hospital discharge records. Antenatal testing costs were determined using Medicaid fee estimates and total facility costs were determined for all hospitalizations including delivery. The association of timing of diagnosis of CHD with costs was analyzed using univariable and multivariable models. RESULTS: Of 2128 pregnancies included in the study, 36% had a fetus prenatally diagnosed with CHD. The prenatal diagnosis group was more likely to have a termination or stillbirth and were younger at delivery (gestational age 37.3 vs 38.0 weeks, p < .001). Labor induction and cesarean delivery rates were similar between groups. Antenatal testing and delivery hospitalization costs were higher in the prenatal diagnosis group: $5819 vs $4041 (p < .001) and $10,509 vs $7802 (p < .001), respectively. Patients in the prenatal diagnosis group had longer lengths of hospital stays (3.5 vs 2.4 d, p > .001). After controlling for significant differences between the groups, including lesion severity, the prenatal diagnosis remained directly associated with antenatal testing costs (+$1472), maternal hospitalization costs (+$2713), and maternal hospital length of stay (+1.0 d). CONCLUSION: A prenatal diagnosis of fetal CHD was associated with increased prenatal costs, hospitalization costs, and hospital length of stay for affected pregnant patients.

Health Care Usage Among Adolescents With Congenital Heart Defects at 5 Sites in the United States, 2011 to 2013.

Background We sought to characterize health care usage for adolescents with congenital heart defects (CHDs) using population-based multisite surveillance data. Methods and Results Adolescents aged 11 to 18 years with ≥1 CHD-related diagnosis code and residing in 5 US sites were identified in clinical and administrative data sources for the years 2011 to 2013. Sites linked data on all inpatient, emergency department (ED), and outpatient visits. Multivariable log-binomial regression models including age, sex, unweighted Charlson comorbidity index, CHD severity, cardiology visits, and insurance status, were used to identify associations with inpatient, ED, and outpatient visits. Of 9626 eligible adolescents, 26.4% (n=2543) had severe CHDs and 21.4% had Charlson comorbidity index >0. At least 1 inpatient, ED, or outpatient visit was reported for 21%, 25%, and 96% of cases, respectively. Cardiology visits, cardiac imaging, cardiac procedures, and vascular procedures were reported for 38%, 73%, 10%, and 5% of cases, respectively. Inpatient, ED, and outpatient visits were consistently higher for adolescents with severe CHDs compared with nonsevere CHDs. Adolescents with severe and nonsevere CHDs had higher health care usage compared with the 2011 to 2013 general adolescent US population. Adolescents with severe CHDs versus nonsevere CHDs were twice as likely to have at least 1 inpatient visit when Charlson comorbidity index was low (Charlson comorbidity index =0). Adolescents with CHDs and public insurance, compared with private insurance, were more likely to have inpatient (adjusted prevalence ratio, 1.5 [95% CI, 1.3-1.7]) and ED (adjusted prevalence ratio, 1.6 [95% CI, 1.4-1.7]) visits. Conclusions High resource usage by adolescents with CHDs indicates a substantial burden of disease, especially with public insurance, severe CHDs, and more comorbidities.

Is gastroschisis truly a sporadic defect?: familial cases of gastroschisis in Utah, 1997 to 2008.

BACKGROUND: Gastroschisis remains an epidemiologic and pathogenetic dilemma, with genetics not thought to play a significant role in its etiology. The purpose of this study was to determine which gastroschisis cases in the Utah Birth Defect Network (UBDN) were related and the excess familial risk among multigenerational families. METHODS: Gastroschisis cases born from 1997 through 2008 were identified from the statewide population-based UBDN and linked with the Utah Population Database (UPDB) to access multigenerational pedigrees. We analyzed these pedigrees using the familial standardized incidence ratio (FSIR). RESULTS: Of the 284 UBDN gastroschisis cases, one in 40 (n = 7; 2.5%) were reported to have another affected family member. Among these seven cases, three had affected sib pairs and four reported either a distant cousin, paternal uncle, maternal half-uncle, or paternal cousin with gastroschisis. UBDN-UPDB-linked cases resulted in many multigenerational pedigrees with the same affected descendents through marriage. We selected 30 pedigrees for repeated analysis based on two parameters: highest FSIRs with a p ≤ 0.01 and ≥2 cases. In these 30 pedigrees, FSIRs ranged from 3.7 to 93.5 (p < 0.009), each with two to eight distantly related cases (n = 64 distinct cases, representing 23% of the 284). CONCLUSIONS: We found a statistically significant excess risk for gastroschisis because of familial factors. Similar to many other birth defects, gastroschisis may fit a multifactorial model of inheritance. The UBDN-UPDB linkage provides a robust approach to investigating genetic factors. Genetic susceptibility should be further investigated because it may have a greater role in the etiology of gastroschisis than currently appreciated.

Shared genomic segments in high-risk multigenerational pedigrees with gastroschisis.

OBJECTIVES: Gastroschisis remains an etiologic dilemma. We posit that an underlying genetic susceptibility either separately or coupled with a periconceptional environmental exposure stimulates an inflammatory response resulting in gastroschisis. To investigate the genetic link, we applied shared genomic segment (SGS) analysis, a novel approach to discover chromosomal segments that inherit in high-risk multigenerational pedigrees. METHODS: We studied pedigrees containing distantly related children with gastroschisis originating from a common ancestor. We used the Illumina OmniExpress genotyping array with >700,000 SNPs. Samples from 40 affected children in 13 pedigrees (≥3 affected children) were genotyped to generate the high-density SNP data necessary to perform SGS analysis. Assessment of significance in SGS was determined empirically using simulations based on precise pedigree structure and modeling linkage disequilibrium (LD) for SNPs in the general population to properly account for genetic architecture. The LD model was estimated from the 1000 Genome Project using the same set of SNPs. Genome-wide significance thresholds were determined for each pedigree. RESULTS: We identified six pedigrees that contained genome-wide statistically significant SGS regions inherited from a common founder. These regions were different in each pedigree, all contained immune pathway genes. DISCUSSION: The genome-wide significant regions support a genetic susceptibility for gastroschisis. The regions are compelling candidates for regionally focused genome sequencing, enabling the discovery of coding or noncoding (e.g., regulatory) risk variants, the latter of which are unlikely to be found using conventional exomic/gene-focused approaches. This technique provides a comprehensive and focused genomic interrogation that will help to advance our understanding of gastroschisis.

Risk of gastroschisis with maternal genitourinary infections: the US National birth defects prevention study 1997-2011.

OBJECTIVE: To assess the association between occurrence and timing of maternal self-reported genitourinary tract infection (urinary tract infections [UTIs] and/or sexually transmitted infection [STI]) and risk for gastroschisis in the offspring. DESIGN: Population-based case-control study. SETTING: National Birth Defects Prevention Study, a multisite study in the USA. PARTICIPANTS: Mothers of 1366 gastroschisis cases and 11 238 healthy controls. MAIN OUTCOME MEASURES: Crude and adjusted ORs (aORs) with 95% CIs. RESULTS: Genitourinary infections were frequent in case (19.3%) and control women (9.9%) during the periconceptional period (defined as 3 months prior to 3 months after conception). UTI and/or STI in the periconceptional period were associated with similarly increased risks for gastroschisis (aOR 1.5, 95% CI 1.3 to 1.8; aOR 1.6, 95% CI 1.2 to 2.3, respectively). The risk was increased with a UTI before (aOR 2.5; 95% CI 1.4 to 4.5) or after (aOR 1.7; 95% CI 1.1 to 2.6) conception only among women ≥25 years of age. The risk was highest among women <20 years of age with an STI before conception (aOR 3.6; 95% CI 1.5 to 8.4) and in women ≥25 years of age, the risk was similar for before (aOR 2.9; 95% CI 1.0 to 8.5) and after (aOR 2.8; 95% CI 1.3 to 6.1) conception. A specific STI pathogen was reported in 89.3% (50/56) of cases and 84.3% (162/191) of controls with Chlamydia trachomatis the most common (25/50 cases, 50%; 58/162 controls, 36%) and highest among women <20 years of age (16/25 cases, 64%; 22/33 controls, 67%). CONCLUSIONS: UTI and/or STI were associated with an increased risk for gastroschisis, with the strength of the association varying by maternal age and timing of infection.

Prenatal diagnosis and prevalence of critical congenital heart defects: an international retrospective cohort study.

OBJECTIVES: To assess international trends and patterns of prenatal diagnosis of critical congenital heart defects (CCHDs) and their relation to total and live birth CCHD prevalence and mortality. SETTING: Fifteen birth defect surveillance programmes that participate in the International Clearinghouse for Birth Defects Surveillance and Research from 12 countries in Europe, North and South America and Asia. PARTICIPANTS: Live births, stillbirths and elective terminations of pregnancy for fetal anomaly diagnosed with 1 of 12 selected CCHD, ascertained by the 15 programmes for delivery years 2000 to 2014. RESULTS: 18 243 CCHD cases were reported among 8 847 081 births. The median total prevalence was 19.1 per 10 000 births but varied threefold between programmes from 10.1 to 31.0 per 10 000. CCHD were prenatally detected for at least 50% of the cases in one-third of the programmes. However, prenatal detection varied from 13% in Slovak Republic to 87% in some areas in France. Prenatal detection was consistently high for hypoplastic left heart syndrome (64% overall) and was lowest for total anomalous pulmonary venous return (28% overall). Surveillance programmes in countries that do not legally permit terminations of pregnancy tended to have higher live birth prevalence of CCHD. Most programmes showed an increasing trend in prenatally diagnosed CCHD cases. DISCUSSION AND CONCLUSIONS: Prenatal detection already accounts for 50% or more of CCHD detected in many programmes and is increasing. Local policies and access likely account for the wide variability of reported occurrence and prenatal diagnosis. Detection rates are high especially for CCHD that are more easily diagnosed on a standard obstetric four-chamber ultrasound or for fetuses that have extracardiac anomalies. These ongoing trends in prenatal diagnosis, potentially in combination with newborn pulse oximetry, are likely to modify the epidemiology and clinical outcomes of CCHD in the near future.

Epidemiology and Prognosis of Congenital Diaphragmatic Hernia: A Population-Based Cohort Study in Utah.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a relatively frequent and severe malformation. Population-based data on clinical presentation and associated mortality are scarce. We examined a state-wide cohort of infants with a clinically validated diagnosis of CDH to assess their clinical profile, sociodemographic patterns, and infant mortality. METHODS: We identified CDH cases from Utah's statewide population-based surveillance program among the cohort of all pregnancy outcomes (live births, stillbirths, and pregnancy terminations) delivered from 1999 to 2011. Clinical geneticists reviewed all cases and classified them based on etiology (known, unknown), and whether they were isolated, multiple (additional unrelated major malformations or unique minor malformation), or syndromic (genetic, chromosomal). RESULTS: CDH occurred in 1 in 3156 births (227/718,990, or 3.17 per 10,000), with no time trend during the 13 years (p = 0.85). CDH was much more common in males (male to female ratio, 1.72:1; p < 0.01). Clinically, 64% of the cases were isolated, 23% were multiples, and 13% were syndromic. Most cases were live born (90%), with fewer stillbirths (7%) and pregnancy terminations (3%). Overall infant mortality was 32.5%, and varied considerably by underlying etiology (isolated 21%; multiple 44%; syndromic 82%). Prognosis was related to specific clinical findings within each etiologic group (e.g., prematurity, low Apgar score, and intrathoracic liver). CONCLUSION: This information on specific clinical and etiologic factors associated with prognosis can help clinicians and parents in the complex discussions about care planning and management that often occur in a crisis situation, following the diagnosis of CDH, whether prior or after delivery. Birth Defects Research 109:1451-1459, 2017.© 2017 Wiley Periodicals, Inc.

Etiology and clinical presentation of birth defects: population based study.

Objective To assess causation and clinical presentation of major birth defects.Design Population based case cohort.Setting Cases of birth defects in children born 2005-09 to resident women, ascertained through Utah's population based surveillance system. All records underwent clinical re-review.Participants 5504 cases among 270 878 births (prevalence 2.03%), excluding mild isolated conditions (such as muscular ventricular septal defects, distal hypospadias).Main outcome measures The primary outcomes were the proportion of birth defects with a known etiology (chromosomal, genetic, human teratogen, twinning) or unknown etiology, by morphology (isolated, multiple, minors only), and by pathogenesis (sequence, developmental field defect, or known pattern of birth defects).Results Definite cause was assigned in 20.2% (n=1114) of cases: chromosomal or genetic conditions accounted for 94.4% (n=1052), teratogens for 4.1% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.4% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified as unknown etiology; of these 88.2% (n=3874) were isolated birth defects. Family history (similarly affected first degree relative) was documented in 4.8% (n=266). In this cohort, 92.1% (5067/5504) were live born infants (isolated and non-isolated birth defects): 75.3% (4147/5504) were classified as having an isolated birth defect (unknown or known etiology).Conclusions These findings underscore the gaps in our knowledge regarding the causes of birth defects. For the causes that are known, such as smoking or diabetes, assigning causation in individual cases remains challenging. Nevertheless, the ongoing impact of these exposures on fetal development highlights the urgency and benefits of population based preventive interventions. For the causes that are still unknown, better strategies are needed. These can include greater integration of the key elements of etiology, morphology, and pathogenesis into epidemiologic studies; greater collaboration between researchers (such as developmental biologists), clinicians (such as medical geneticists), and epidemiologists; and better ways to objectively measure fetal exposures (beyond maternal self reports) and closer (prenatally) to the critical period of organogenesis.

Costs, mortality, and hospital usage in relation to prenatal diagnosis in d-transposition of the great arteries.

BACKGROUND: The impact of prenatal diagnosis of d-transposition of the great arteries (dTGA) on health-care usage is largely unknown. We evaluated a population-based cohort to assess costs, mortality and inpatient encounters by whether dTGA was prenatally diagnosed or not. METHODS: The dTGA cases (born 1997-2011) identified at the Utah Birth Defect Network, which includes data on timing of diagnosis, were linked to statewide inpatient discharge data. We excluded preterm cases or cases with additional major heart defects. We evaluated hospitalizations and costs for infants (first year of life) and mothers (10 months before birth) using multivariable models adjusted for demographic and clinical risk factors. RESULTS: Of 119 cases, 14 (12%) were prenatally diagnosed. Birth weight, surgical complexity and extracardiac defects/syndromes were similar between groups. Of 7 deaths (6%), two occurred pre-intervention in postnatally diagnosed infants. Prenatal diagnosis was associated with more in-hospital days (estimate 13 additional days, p = 0.03) and higher mean costs for mothers ($4,141 vs $12,148) and infants (90,419 vs $49,576). Prenatal diagnosis independently predicted higher adjusted costs for the overall cohort ($22,570, p = 0.045). After excluding deaths, total costs were no longer significantly different. CONCLUSION: Mothers of prenatally diagnosed infants with dTGA had higher inpatient costs compared with those postnatally diagnosed. Costs trended higher for their infants, although were not significantly different. Linkage of population-based surveillance systems and outcome databases can be a powerful tool to further explore the complex relationship of prenatal diagnosis to costs and outcomes in other types of congenital heart diseases. Birth Defects Research 109:262-270, 2017. © 2017 Wiley Periodicals, Inc.