Birth Defects Registry Research Articles

Male Sex and the Risk of Childhood Cancer: The Mediating Effect of Birth Defects.

BackgroundThere is a persistent, unexplained disparity in sex ratio among childhood cancer cases, whereby males are more likely to develop most cancers. This male predominance is also seen for most birth defects, which are strongly associated with risk of childhood cancer. We conducted mediation analysis to estimate whether the increased risk of cancer among males is partially explained by birth defect status.MethodsWe used a population-based birth cohort with linked data from birth certificates, birth defects registries, and cancer registries from Arkansas, Michigan, North Carolina, and Texas. We conducted counterfactual mediation analysis to estimate the natural direct and indirect effects of sex on cancer risk, modeling birth defect status as mediator. State; birth year; plurality; and maternal race and ethnicity, age, and education were considered confounders. We conducted separate analyses limited to cancers diagnosed younger than 1 year of age.ResultsOur dataset included 10 181 074 children: 15 110 diagnosed with cancer, 539 567 diagnosed with birth defects, and 2124 co-occurring cases. Birth defect status mediated 38% of the association between sex and cancer overall. The proportion mediated varied by cancer type, including acute myeloid leukemia (93%), neuroblastoma (35%), and non-Hodgkin lymphoma (6%). Among children younger than 1 year of age at cancer diagnosis, the proportion mediated was substantially higher (82%).ConclusionsOur results suggest that birth defects mediate a statistically significant proportion of the relationship between sex and childhood cancer. The proportion mediated varied by cancer type and diagnosis age. These findings improve our understanding of the causal pathway underlying male sex as a risk factor for childhood cancer.

The Antiretroviral Pregnancy Registry: 30 Years of Monitoring for Congenital Anomalies [OP04-6D

INTRODUCTION: Antiretroviral (ARV) treatment saves lives and prevents vertical transmission of HIV. The Antiretroviral Pregnancy Registry (APR) began prospectively monitoring prenatal ARV use for potential teratogenicity in 1989 and depends on voluntary registration of ARV exposed pregnancies (www.APRegistry.com). METHODS: The APR is an IRB approved, prospective exposure-registration cohort study with data from 70 countries. Prevalence of congenital anomalies (CAs) are estimated and compared to internal and external comparison groups. Twenty-two ARVs have sufficient 1st trimester exposures to detect at least a 2-fold increase in risk of CAs overall, of which 11 can detect a 1.5-fold increase. RESULTS: Of the 20,759 pregnancies prospectively enrolled through 31 July 2019, reported outcomes include 19,642 live births (LB) with ARV exposure at any time during pregnancy and 554 CAs. Prevalence of CAs was 2.8% (95% CI 2.6-3.1) overall, 2.8% (95% CI 2.5-3.1) among 1st trimester exposures and 2.8% (95% CI 2.5-3.2) among 2nd/3rd trimester exposures to ARVs (prevalence ratio 1.00 [95% CI 0.85-1.18]). CONCLUSION: The APR has not detected a significant difference in overall CA prevalence compared to two population based surveillance systems: 2.72/100 LB (95% CI 2.68-2.76) Metropolitan Atlanta Congenital Defects Program (MACDP) and 4.17/100 LB (95% CI 4.15-4.19) Texas Birth Defects Registry (TBDR). Two ARVs, didanosine and nelfinavir, have modest statistically significant increased prevalence compared to MACDP but not TBDR. The APR independent Advisory Committee concludes, “The Registry finds no apparent increases in frequency of specific defects with first trimester exposures and no pattern to suggest a common cause; however, potential limitations of registries should be recognized.”

P134 Collaborating with the National Congenital Anomaly and Rare Disease Registration Service to estimate national incidence of Kawasaki disease in England

Abstract Background The true incidence of Kawasaki disease (KD) in England is unknown. In KD treatment with intravenous immunoglobulin (IVIG) can be lifesaving, but it is both expensive and in limited supply. In collaboration with Public Health England’s National Congenital Anomaly and Rare Disease Registration Service (NCARDRS) we aimed to determine the incidence of KD in England. Methods We worked within NCARDRS to access patient-identifiable Hospital Episode Statistics (HES) data, enabled by their legal permissions (CAG 10-02(d)/2015). We extracted all patients receiving a primary or additional diagnostic code for KD between April 2003 -March 2017. For patients identified in Nottingham University Hospitals Trust, we reviewed the coding accuracy in their medical records. We calculated incidence with 95% Poisson confidence intervals among children in England using the total number of cases newly diagnosed in the study period. We used the ONS mid-year estimates for 2016 for the denominator. Results 37 patients were coded as having KD in our Trust. All had a clinical diagnosis of KD (positive predictive value 100%). 32 patients were paediatric cases treated for KD; the remaining 5 patients were diagnosed in adult life on the basis of pathognomonic angiogram findings. It was not possible to apply classification criteria because the required information was not always available. During the 13-year study period we identified 3345 cases in children aged <5, and 4234 cases in children <16 in England. The incidence in children aged <5 years was 7.50 (95% CI: 7.25-7.76)/100,000 person-years, and 40.7% of cases were female. Incidence in children aged <16 was 3.09 (95% CI: 3.00-3.19)/100,000 person-years, and 41% of cases were female. Conclusion Analysis of HES data within NCARDRS has provided population-based estimates of incidence of KD for the whole of England. Our estimates are higher than in previous studies. Validation of coding accuracy has shown our methods were specific, and they are likely to be sensitive given KD is always treated in hospital. Accurate incidence estimates are essential for appropriate resource allocation, given the limited availability of lifesaving IVIG treatment. Disclosures M. Rutter None. P.C. Lanyon None. M. Bythell None. S. Stevens None. J. Aston None. F.A. Pearce None.

O36 Validation of methods to enable national registration for rare autoimmune rheumatic diseases

Abstract Background The National Congenital Anomaly and Rare Disease Registration Service (NCARDRS) records those people with congenital anomalies and rare diseases across the whole of England. The NCARDRS Rare Rheumatology Project is establishing methodologies to identify and register people with rare rheumatic diseases. Hospital Episode Statistics (HES), comprising data from all admitted-patient NHS care in England, provides a promising source for case ascertainment. We aimed to confirm the reliability of diagnostic ICD codes for rare autoimmune rheumatic diseases within HES. Methods We used NCARDRS’ legal permissions (CAG 10-02(d)/2015) to extract cases who had at least one inpatient or daycase admission recorded in HES during 2003 to 2017 with a primary or additional diagnostic code for Kawasaki disease, Takayasu’s arteritis, Adult-onset Still’s disease, Relapsing polychondritis, Polyarteritis nodosa, Granulomatosis with polyangiitis (GPA), Microscopic polyangiitis (MPA) or Eosinophilic granulomatosis with polyangiitis (EGPA). Using Data Sharing Agreements between NCARDRS and NHS Trusts, we reviewed medical records for all cases admitted to one NHS Trust to confirm diagnoses. For ANCA-associated vasculitis (AAV), up to 20 randomly selected cases admitted to 5 Trusts with a diagnostic code of GPA, MPA and EGPA were reviewed. Results Table 1 shows the positive predictive value (PPV) of each diagnosis at one Trust: Kawasaki disease 100%, Takayasu’s arteritis 91.7%, Adult-onset Still’s disease 42.8%, Relapsing polychondritis 40.0%, and Polyarteritis nodosa 5.0%. For AAV, which had a PPV at the index Trust of 92.0%, the PPV across the 5 Trusts varied from 92.9% to 74.0%. Combining all 5 Trusts PPV for AAV was 85.9%. It was higher in MPA (PPV=98.4%) than in GPA (PPV=83.3%) and EGPA (PPV=77.4). Conclusion This is the first study to validate the coding of rare rheumatic disease diagnoses within HES data. Our results highlight heterogeneity in coding accuracy both between conditions and between NHS Trusts. Further work is needed to develop and validate algorithms for conditions where HES coding alone has poor positive predictive value, and test sensitivity. National rare disease registration will enable robust, cost-effective and reproducible population-based epidemiology of rare rheumatic diseases across England which is needed to inform service provision and aid development of new treatments. Disclosures F.A. Pearce None. M. Rutter None. B. Griffiths None. C. Mukhtyar None. R. Al-Jayoussi None. R.A. Watts None. J. Aston None. M. Bythell None. S. Stevens None. P.C. Lanyon None.

P182 Prevalence and mortality of ANCA-associated vasculitis in England

Abstract Background The contemporary prevalence of ANCA-associated vasculitis (AAV) in England is unknown. Hospital Episode Statistics (HES) contain data on every hospital and day case NHS admission in England since 1997. In collaboration with the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS) we validated the diagnosis of AAV using ICD codes in HES. The positive predictive value of these codes was 86%, which compares favourably to a median coding accuracy of 80% in a recent systematic review of NHS coding studies. This justifies using this novel dataset for population-based epidemiology with coverage of the whole population of England. Methods We worked within NCARDRS enabled by their Section 251 legal permissions (CAG 10-02(d)/2015). We extracted all cases of AAV from HES 2011/12 to 2016/17 using ICD-10 codes M313 Granulomatosis with polyangiitis (GPA), M317 Microscopic polyangiitis (MPA), and M301 Eosinophilic granulomatosis with polyangiitis (EGPA). We used the Summary Care Record to check vital status and record date of death where appropriate. We estimated point prevalence on 1 July 2016 using ONS mid-year population estimates for England in 2016 as the denominator. Standardised mortality ratio (SMR) was calculated using the Office for National Statistics death summary tables 2016 to provide expected number of deaths for each 5-year age-band and sex. Results We identified 9,890 patients who were coded as having AAV during a hospital admission 2011-2017. This included 6,856 (69.3%) with GPA, 964 (9.8%) with MPA and 2,070 (20.9%) with EGPA. On 1 July 2016, our dataset found 8,040 people in England were living with ANCA associated vasculitis. We estimate the prevalence was 14.55 (95% CI: 14.23-14.87)/100,000 adult population. The median age of these patients was 65.3 years (interquartile range 52.3-74.2). 47% were female. The prevalence of GPA was 9.97/100.000 (95% CI: 9.71-10.24), MPA was 1.40/100,000 (95% CI: 1.30-1.50), and EGPA was 3.18/100,000 (95% CI: 3.03-3.33). People with AAV were 4.6 times more likely to die than the background population of the same age and sex (Standardised Mortality Ratio = 4.58). Conclusion There are no recent UK prevalence estimates for all types of ANCA-associated vasculitis. Studies in Australia, Germany, Southern Sweden and the USA have found estimated prevalence to be between 4.6-18.4 cases per 100,000 individuals. Our estimate of 14.6/100,000 in England is consistent with this, and towards the higher end of the range. However, our estimates underestimate the prevalence of MPA compared to other studies, and further work is needed to increase the routine identification of cases of MPA. Further work within NCARDRS using their unique data linkages will enable more specific AAV case ascertainment as well as nationwide population-based studies on cause of death and studies using the database of English prescriptions dispensed in the community. Disclosures F.A. Pearce None. B. Griffiths None. C. Mukhtyar None. R. Al-Jayoussi None. R.A. Watts None. J. Aston None. M. Bythell None. S. Stevens None. P.C. Lanyon None.

Utility of follow-up standard sonography for fetal anomaly detection

In 2014, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Imaging Workshop consensus recommended that sonograms be offered routinely to all pregnant women. In the absence of another indication, this examination is recommended at 18-22 weeks of gestation. Studies of anomaly detection often focus on pregnancies at risk for anomalies and on the yield of detailed sonography, topics less applicable to counseling low-risk pregnancies about the benefits and limitations of standard sonography. The clinical utility of follow-up sonogram in low-risk pregnancies for the purpose of fetal anomaly detection has not been established. The objective of the study was to evaluate the utility of follow-up standard sonography for anomaly detection among low-risk pregnancies in a nonreferred population. We performed a retrospective cohort study of singleton pregnancies that underwent standard sonography at 18-21 6/7 weeks of gestation from October 2011 through March 2018 with subsequent delivery of a live-born infant at our hospital. Pregnancies with indications for detailed sonography in our system were excluded to evaluate fetal anomalies first identified with standard sonography. Anomalies were categorized according to the European Registration of Congenital Anomalies and Twins (EUROCAT) system, with confirmation based on neonatal evaluation. Among those with no anomaly detected initially, we evaluated the rate of subsequent detection according to number of follow-up sonograms, gestational age at sonography, organ system(s) affected, and anomaly severity. Statistical analyses were performed using χ2 and a Mantel-Haenszel test. Standard sonography was performed in 40,335 pregnancies at 18-21 6/7 weeks, and 11,770 (29%) had at least 1 follow-up sonogram, with a second follow-up sonogram in 3520 (9%). Major abnormalities were confirmed in 387 infants (1%), with 248 (64%) detected initially and 28 (7%) and 5 (1%) detected on the first and second follow-up sonograms. Detection of residual anomalies on follow-up sonograms was significantly lower than detection on the initial standard examination: 64% on initial examination, 45% for first follow-up, and 45% for second follow-up (P < .01). A larger number of follow-up examinations were required per anomalous fetus detected: 163 examinations per anomalous fetus detected initially, 420 per fetus detected at the first follow-up examination, and 705 per fetus detected at the second follow-up sonogram (P < .01). The number of follow-up examinations to detect each additional anomalous fetus was not affected by gestational age (P= .7). Survival to hospital discharge was significantly lower for fetuses with anomalies detected on initial (88%) than for fetuses with anomalies undetected until delivery (90 of 91, 99%; P < .002). In a low-risk, nonreferred cohort with fetal anomaly prevalence of 1%, follow-up sonography resulted in detection of 45% of fetal anomalies that had not been identified during the initial standard sonogram. Significantly more follow-up sonograms were required to detect each additional anomalous fetus.

Bayesian hierarchical methods in the detection of potentially teratogenic first-trimester medications.

Bayesian hierarchical models (BHMs) have been used to identify adverse drug reactions, allowing information sharing amongst adverse reactions and drugs expected to have similar properties. This study evaluated the use of BHMs in the routine signal detection analyses of potential first-trimester teratogens, where these models have not previously been applied. Data on 15 058 malformed foetuses exposed to first trimester medications (1995-2011) from 13 European congenital anomaly (CA) registries were analysed. The proportion of each CA in women taking a specific medication was compared with the proportion of that CA in all other women in the dataset (55 CAs × 523 medications). BHMs were grouped by either medications or CAs or by both simultaneously, and the results compared with analysing each medication-CA combination separately and adjusting for multiplicity using a double false discovery rate (FDR) procedure. The proportions of "high-risk" medications (medications which have been shown to carry a moderate to high risk of foetal malformations) identified as potential signals were compared, as well as the total number of potential signals requiring follow up (the effective workload). BHMs identified more high-risk medications than the double FDR method, but the effective workload was larger. A BHM grouping both medications and CAs, for example, identified 23% of high-risk medications compared with 14% by the double FDR; however, there was an increase from 16 to 71 potential signals requiring follow up. For comparable effective workloads, BHMs did not outperform the double FDR, which is comparatively straightforward to implement and is therefore recommended for continued use in teratogenic signal detection analyses.

Change in prepregnancy body mass index and gastroschisis

PurposeMaternal body mass index (BMI) is inversely associated with gastroschisis, but a causal relationship has not been established. As data demonstrating that a change in exposure status is related to a change in the frequency of the outcome can add to the evidence for causality, we conducted a case–control study of change in maternal BMI, assessed using interpregnancy change in BMI (IPC-BMI), and gastroschisis. MethodsData for 258 gastroschisis cases and 2561 controls were obtained from the Texas Birth Defects Registry and vital records (2006–2012). Logistic regression was used to estimate the adjusted association between IPC-BMI and gastroschisis. ResultsThe continuous IPC-BMI variable was inversely associated with gastroschisis (adjusted odds ratio [aOR] = 0.90, 95% confidence interval [CI]: 0.86, 0.95). When assessed as a six-level categorical variable, with weight stable women as the referent, the odds of gastroschisis were higher following a BMI decrease of greater than 1 unit (aOR = 1.37, 95% CI: 0.91, 2.06) and lower after a BMI increase of ≥3 units (aOR = 0.62, 95% CI: 0.42, 0.94). ConclusionsOur findings suggest that maternal change in BMI is associated with gastroschisis and, thus, add to the epidemiological evidence that can be used to inform our understanding of the relationship between BMI and gastroschisis.

RETRACTED ARTICLE: Epidemiological characteristic of Orofacial clefts and its associated congenital anomalies: retrospective study

BackgroundTo evaluate the relationship between gender, ethnicity/citizenship, clinical phenotype, total prevalence, and the various congenital malformations associated with oral clefts (OC) in Italy across the period 2001–2014.MethodsA retrospective analysis (2001–2014) was conducted based on the National Congenital Malformation Registries network of Italy (Emilia-Romagna Registry of Birth Defects [IMER] and Registro Toscano Difetti Congeniti [RTDC]), which were analyzed to investigate time trends, geographical/ethnic clusters, topography, sex ratio, and associated congenital anomalies of OC phenotypes.ResultsAmong 739 registered cases, 29.8% were syndromic or had multi-malformed associated anomalies, compared with 70.2% having isolated orofacial cleft. Cleft lip (CL) was observed in 22%, cleft palate (CP) in 40%, and cleft lip and palate (CLP) in 38% of live births, stillbirths, and terminations of pregnancy for fetal anomaly cases. Other associated conditions were major anomalies of cardiovascular defects (39%), followed by defects of the limbs (28%), neuroectodermal defects (23%), and urogenital malformations (10%).Male-to-female sex ratio was 1:1.14 in CP, 1.22:1 in CL, and 1.9:1 in CLP. Foreigners were represented by 29% from Southeast Asia, 25% from Balkans, 25% from North-Central Africa, 9% from the East, 7% from Western Europe, and 5% from South America. Total prevalence of OC cases ranged from 0.9 (RTDC) to 1.1 (IMER) of 1000 births.ConclusionsThis retrospective study provides a population-based, clinical-epidemiological description of the orofacial cleft phenomenon. As a relatively frequent congenital malformation, its social and economic impact is worthy of further study. These abnormalities can cause significant problems that may be solved or minimized by early diagnosis and treatment.

Mortality by mode of delivery among infants with spina bifida in Texas.

It is hypothesized that cesarean delivery may reduce mortality among infants with spina bifida (e.g., by reducing trauma to the open lesion); however, few studies have assessed this relationship. We used the Texas Birth Defects Registry to identify neonates with spina bifida born between 1999 and 2014. The mode of delivery (main exposure) was abstracted from each subject's birth certificate. The vital status (main outcome) was determined based on the presence or absence of a death certificate. When a death certificate was present, survival time was calculated by subtracting the date of birth from the date of death. We then conducted multivariable Cox proportional hazards regression to estimate the adjusted hazard ratio between cesarean delivery and death prior to 29 days. We adjusted for maternal race/ethnicity, maternal education, gestational age/birthweight, and breech presentation. This analysis was repeated for death prior to 365 days. We analyzed 1,983 nonsyndromic, liveborn neonates with spina bifida, and 68% of these neonates were delivered by cesarean. After adjusting for potential confounders, the adjusted hazard ratio [aHR] for death prior to 29 days was 0.77 (95% confidence interval [CI] 0.49, 1.21) and the aHR for death prior to 365 days was 0.93 (95% CI 0.63, 1.38) comparing infants delivered by cesarean to those delivered vaginally. Despite a lack of strong prior epidemiologic evidence, cesarean rates for neonates with spina bifida were high. Further investigations of the relationship between mode of delivery and infant outcomes, including mortality, complications, and long-term prognosis, are warranted.

Associations between Cumulative Environmental Quality and Neural Tube Defects

TPS 741: Adverse birth outcomes 2, Exhibition Hall, Ground floor, August 28, 2019, 3:00 PM - 4:30 PM Background/Aims: Neural tube defects (NTD), including anencephaly, spina bifida (SB), and encephalocele, are some of the most severe birth defects. The impact of how cumulative environmental quality contributes to associations with NTDs is unknown. The Environmental Quality Index (EQI) is a comprehensive measure of cumulative environmental exposures for five domains (air, water, land, sociodemographic, built) from 2000-2005. Methods: We conducted a county-level analysis to assess the associations between the EQI and four birth defects (NTD, anencephaly, SB, and encephalocele) using data from the Texas Birth Defects Registry and live birth records from 2000-2006. Prevalence ratios (PR) and 95% confidence intervals (CI) were estimated from Poisson regression models between the NTD defects and the EQI, represented by three exposure categories based on percentiles (<50%, or “better” environmental quality; 50-75%, “mid”; >75%, “worst”), adjusted for potential confounders. Results: We observed non-linear trends for overall EQI and the water domain, with increased prevalence of birth defects observed in the mid versus better environmental quality categories. For overall EQI, mid environmental quality was associated with higher prevalence of NTDs [PR=1.27, 95%CI: 1.06, 1.52], anencephaly [1.39 (1.16, 1.66)], SB [1.18 (0.98, 1.42)], and encephalocele [1.34 (1.11, 1.60)], as compared to better environmental quality. In the water domain, mid environmental quality was associated with higher prevalence of each of these four outcomes [NTDs: 1.58 (1.14, 1.78); anencephaly: 2.29 (2.03, 2.57); SB: 1.46 (1.30, 1.65); encephalocele 1.01 (0.90, 1.13)]. Comparing worst environmental quality to better environmental quality for the sociodemographic domain, the PRs were 2.14 (1.93, 2.37) for NTDs, 3.32 (3.00, 3.68) for anencephaly, 1.91 (1.72, 2.12) for SB, and 1.12 (1.00, 1.25) for encephalocele. In the air, land, and built domains, inverse associations were observed with all birth defects studies. Conclusions: We found that sociodemographic factors, water quality, and overall environmental quality contribute to associations with these NTD outcomes, but not with air, land or built environmental quality. This abstract does not reflect EPA policy.

Trisomy 13 and 18-Prevalence and mortality-A multi-registry population based analysis.

The aim of the study is to determine the prevalence, outcomes, and survival (among live births [LB]), in pregnancies diagnosed with trisomy 13 (T13) and 18 (T18), by congenital anomaly register and region. Twenty-four population- and hospital-based birth defects surveillance registers from 18 countries, contributed data on T13 and T18 between 1974 and 2014 using a common data-reporting protocol. The mean total birth prevalence (i.e., LB, stillbirths, and elective termination of pregnancy for fetal anomalies [ETOPFA]) in the registers with ETOPFA (n = 15) for T13 was 1.68 (95% CI 1.3-2.06), and for T18 was 4.08 (95% CI 3.01-5.15), per 10,000 births. The prevalence varied among the various registers. The mean prevalence among LB in all registers for T13 was 0.55 (95%CI 0.38-0.72), and for T18 was 1.07 (95% CI 0.77-1.38), per 10,000 births. The median mortality in the first week of life was 48% for T13 and 42% for T18, across all registers, half of which occurred on the first day of life. Across 16 registers with complete 1-year follow-up, mortality in first year of life was 87% for T13 and 88% for T18. This study provides an international perspective on prevalence and mortality of T13 and T18. Overall outcomes and survival among LB were poor with about half of live born infants not surviving first week of life; nevertheless about 10% survived the first year of life. Prevalence and outcomes varied by country and termination policies. The study highlights the variation in screening, data collection, and reporting practices for these conditions.

Impact evaluation of Zika epidemic on congenital anomalies registration in Brazil: An interrupted time series analysis

This study aimed to assess the impact of the Zika epidemic on the registration of birth defects in Brazil. We used an interrupted time series analysis design to identify changes in the trends in the registration of congenital anomalies. We obtained monthly data from Brazilian Live Birth Information System and used two outcome definitions: 1) rate of congenital malformation of the brain and eye (likely to be affected by Zika and its complications) 2) rate of congenital malformation not related to the brain or eye unlikely to be causally affected by Zika. The period between maternal infection with Zika and diagnosis of congenital abnormality attributable to the infection is around six months. We therefore used September 2015 as the interruption point in the time series, six months following March 2015 when cases of Zika started to increase. For the purposes of this analysis, we considered the period from January 2010 to September 2015 to be “pre-Zika event,” and the period from just after September 2015 to December 2017 to be “post-Zika event.” We found that immediately after the interruption point, there was a great increase in the notification rate of congenital anomalies of 14.9/10,000 live births in the brain and eye group and of 5.2/10,000 live births in the group not related with brain or eye malformations. This increase in reporting was in all regions of the country (except in the South) and especially in the Northeast. In the period “post-Zika event”, unlike the brain and eye group which showed a monthly decrease, the group without brain or eye malformations showed a slow but significant increase (relative to the pre-Zika trend) of 0.2/10,000 live births. These findings suggest an overall improvement in the registration of birth malformations, including malformations that were not attributed to Zika, during and after the Zika epidemic.

Likelihood of meeting defined VATER/VACTERL phenotype in infants with esophageal atresia with or without tracheoesophageal fistula.

Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is a foregut defect that is a major component of the VATER/VACTERL association. The specific diagnostic criteria for the VATER/VACTERL association phenotype have changed over time. The current definition is presence of at least three of the following: Vertebral defects, Anal atresia, Cardiac defects, TE fistula, or Renal and Limb anomalies in the absence of a specific genetic diagnosis. Using the Texas Birth Defect Registry, 1,175 cases of EA+/-TEF (174 EA; 1,001 EA + TEF) were evaluated against strict definitions of VATER/VACTERL. Nine (5.2%) cases of EA alone and 164 (16.3%) cases of EA + TEF met criteria for a diagnosis of VATER; and 20 (11.5%) and 223 (22.2%), respectively, met criteria for VACTERL. Trisomy 21, Trisomy 18, 22q11 deletion, and CHARGE were the most common syndromic diagnoses. About 88.5% (154) cases of EA and 77.8% (778) cases of EA + TEF were likely not to meet the criteria for VACTERL. EA+/-TEF is more likely to be an isolated defect or part of a multiple malformation syndrome in a pattern other than VACTERL, than be part of the defined association. This study reinforces the need to consider broader evaluation for alternate diagnoses in the presence of these defects.

Síndrome lumbocostovertebral: primer reporte de caso en Argentina

Lumbocostovertebral syndrome is defined by the presence of lumbar hernia, hemivertebrae and costal anomalies. Our aim was to describe the first case reported in Argentina. The patient was reported to the National Registry of Congenital Anomalies of Argentina. The clinical picture, differential diagnoses and possible pathogenic mechanisms involved are described. We suggest considering this as a lumbocostovertebral association. Lumbar hernia in a newborn is an infrequent finding and other associated anomalies should be evaluated.

Maternal exposure to ambient cadmium levels, maternal smoking during pregnancy, and congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a rare musculoskeletal birth defect with a prevalence of 2.61 per 10,000 in the United States. There is limited evidence for ambient air pollutants in the etiology of CDH in humans. We investigated the role of maternal exposure to ambient cadmium as a risk factor for CDH (overall and stratified by isolated and non-isolated subtypes) in Florida and whether maternal smoking during pregnancy was an effect modifier of this association. We conducted a population-based, retrospective cohort study using data from the 1999-2012 Florida Birth Defects Registry linked to the National Air Toxic Assessment database. Analyses included chi-square tests; multilevel Poisson regression models to calculate measures of association between cadmium and CDH; and stratified analyses to examine effect modification by maternal smoking status. The study population consisted of 2,591,395 live births including 840 CDH cases. We did not find evidence for an association between maternal exposure to ambient cadmium concentration and CDH. We observed a 24% increased risk of CDH among isolated cases in the highest quartile of cadmium exposure (95% confidence interval [CI]: 1.00, 1.55). Although we were limited by small sample size for CDH cases, we found that among mothers who smoked during pregnancy, exposure to the highest quartile of cadmium was associated with more than two times higher risk for CDH among overall (95%CI: 1.04, 4.39) and isolated (95%CI: 1.07, 5.57) cases. Additional research is needed to elucidate the mechanism by which maternal ambient cadmium exposure may increase the risk of CDH in offspring, and the extent to which maternal smoking during pregnancy modifies this association.

Down syndrome among primiparae at older maternal age: A test of the relaxed filter hypothesis.

Down syndrome (DS) ranks as one of the most common birth defects in the United States. The relaxed filter hypothesis (RFH) asserts that mothers with no previous children but nearing reproductive senescence reduce fetal selectivity against DS pregnancies in the first trimester given the high probability of having no offspring at all if the DS pregnancy is not carried to term. We test the parity prediction of RFH-specifically, that pregnancies to older mothers with no previous live births show an elevated prevalence of DS above values expected from the separate contributions of older maternal age and primiparity. We retrieved maternal age and parity information on 2,748 DS cases (live, stillborn, or terminated due to anomaly) from the Paris Birth Defects Registry, 1983-2015. We used two waves of the Enquête Fertility Survey (n = 5,460) and counts of stillbirths to calculate total prevalence of DS by maternal age and parity. Primiparous mothers 35+ years show the greatest prevalence of any parity group (9.78 cases per 1,000 deliveries). Tests for additive interaction of primiparity and older maternal age reject the null (relative excess risk due to interaction = 1.01; 95% confidence interval: 0.33, 1.69; null value on additive scale is 0). Relaxed selection may account for 10% of the increase in the prevalence, among older primiparous mothers, of DS detected during or after the 11th week. Future work may hold implications for understanding, among older mothers, the strength of this maternal screen against other defects.

Co-occurring defect analysis: A platform for analyzing birth defect co-occurrence in registries.

Few studies have systematically evaluated birth defect co-occurrence patterns, perhaps, in part, due to the lack of software designed to implement large-scale, complex analytic methods. We created an R-based platform, "co-occurring defect analysis" (CODA), designed to implement analyses of birth defect co-occurrence patterns in birth defect registries. CODA uses an established algorithm for calculating the observed-to-expected ratio of a given birth defect combination, accounting for the known tendency of birth defects to co-occur nonspecifically. To demonstrate CODA's feasibility, we evaluated the computational time needed to assess 2- to 5-way combinations of major birth defects in the Texas Birth Defects Registry (TBDR) (1999-2014). We report on two examples of pairwise patterns, defects co-occurring with trisomy 21 or with non-syndromic spina bifida, to demonstrate proof-of-concept. We evaluated combinations of 175 major birth defects among 206,784 infants in the TBDR. CODA performed efficiently in the data set, analyzing 1.5 million 5-way combinations in 18 hr. As anticipated, we identified large observed-to-expected ratios for the birth defects that co-occur with trisomy 21 or spina bifida. CODA is available for application to birth defect data sets and can be used to better understand co-occurrence patterns. Co-occurrence patterns elucidated by using CODA may be helpful for identifying new birth defect associations and may provide etiological insights regarding potentially shared pathogenic mechanisms. CODA may also have wider applications, such as assessing patterns of additional types of co-occurrence patterns in other large data sets (e.g., medical records).

Nuclear radiation and prevalence of structural birth defects among infants born to women from the Marshall Islands.

With their unique history of exposure to extensive nuclear testing between 1946 and 1958, descendants of Marshall Island residents may have underappreciated genetic abnormalities, increasing their risk of birth defects. We conducted a retrospective cohort study of resident women with at least one singleton live birth between 1997 and 2013 in northwest Arkansas using state birth certificate data linked to data from the Arkansas Reproductive Health Monitoring System, a statewide birth defects registry. We calculated unadjusted and adjusted prevalence ratios (PR) and 95% confidence intervals (CI) from modified Poisson regression analyses for non-Hispanic (NH) whites, NH-blacks, Hispanics and Marshallese, using NH-whites as the reference group. Of the 91,662 singleton births during the study period, 2,488 were to Marshallese women. Due to the relatively small number of Marshallese births, we could not calculate prevalence estimates for some defects. Marshallese infants had higher rates of congenital cataracts (PR = 9.3; 95% CI: 3.1, 27.9). Although the number of defects was low, Marshallese infants also had higher rates of truncus arteriosus (PR = 44.0; 95% CI: 2.2, 896.1). Marshallese infants may have increased risk of specific birth defects, but estimates are unstable because of small sample size so results are inconclusive. Larger population-based studies would allow for further investigation of this potential risk among Marshallese infants.

Epidemiology of Dandy-Walker Malformation in Europe: A EUROCAT Population-Based Registry Study

Background: Dandy-Walker (DW) malformation is a rare and severe congenital anomaly of the posterior fossa affecting the development of the cerebellum and the fourth ventricle. Objective: The aim of this study was to investigate the epidemiology of DW malformation, using data from the European population-based registries of congenital anomalies in the European Surveillance of Congenital Anomalies network. Methods: Anonymous individual data on cases of DW malformation diagnosed in 2002–2015 from 28 registries in 17 countries were included. Prevalence, prenatal detection rate, proportions and types of associated anomalies were estimated. Cases of DW variant were considered and analysed separately. Results: Out of 8,028,454 surveyed births we identified a total of 734 cases, including 562 DW malformation cases and 172 DW variant cases. The overall prevalence of DW malformation was 6.79 per 100,000 births (95% CI 5.79–7.96) with 39.2% livebirths, 4.3% foetal deaths from 20 weeks gestational age, and 56.5% terminations of pregnancy after prenatal diagnosis of foetal anomaly at any gestation (TOPFA). The livebirth prevalence was 2.74 per 100,000 births (95% CI 2.08–3.61). The prenatal detection rate was 87.6%. Two-hundred and seventy-three cases (48.6%) had an isolated cerebral anomaly and 24.2, 19.2 and 5.5% cases were associated with other structural non-cerebral anomalies, chromosomal anomalies and genetic syndromes respectively. The prevalence of DW variant was 2.08 per 100,000 (95% CI 1.39–3.13). Conclusions: This European population-based study provides the epidemiological profile of DW malformation. All birth outcomes were analysed and TOPFA represented more than half of the cases. About 50% of the cases of DW malformation were associated with other non-cerebral anomalies. Large populations and all birth outcomes are essential in epidemiological studies of rare and severe congenital anomalies.