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Objective: To evaluate survival, hospitalisations and surgical procedures for children born with Pierre Robin sequence (PRS) across Europe., Design: Multicentre population-based cohort study., Setting: Data on 463 live births with PRS from a population of 4 984 793 from 12 EUROCAT congenital anomaly registries., Methods: Data on children with PRS born 1995-2014 were linked electronically to data on mortality, hospitalisations and surgical procedures up to 10 years of age. Each registry applied a common data model to standardise the linked data and ran common syntax scripts to produce aggregate tables. Results from each registry were pooled using random-effect meta-analyses., Main Outcome Measures: Probability of survival, proportion of children hospitalised and undergoing surgery, and median length of hospital stay., Results: The majority of deaths occurred in the first year of life with a survival rate of 96.0% (95% CI 93.5% to 98.5%); 95.1% (95% CI 92.7% to 97.7%) survived to age 10. In the first year of life, 99.2% (95% CI 95.0% to 99.9%) of children were hospitalised with a median stay of 21.4 days (95% CI 15.6 to 27.2), and 67.6% (95% CI 46.6% to 81.8%) underwent surgery. In the first 5 years of life, 99.2% of children underwent a median of two surgical procedures. Between ages 5 and 9, 58.3% (95% CI 44.7% to 69.7%) were hospitalised with a median annual stay of 0.3 days., Conclusions: Children with PRS had high mortality and morbidity with long hospital stays in the first year of life, and almost all had surgery before 5 years of age. Survival improved after infancy with fewer hospitalisations after age 5. This study provides reliable estimates of the survival and morbidity of children with PRS for families and healthcare providers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the survival to 10 years of age of children with trisomy 13 (T13) and children with trisomy 18 (T18), born 1995-2014., Design: Population-based cohort study that linked mortality data to data on children born with T13 or T18, including translocations and mosaicisms, from 13 member registries of EUROCAT, a European network for the surveillance of congenital anomalies., Setting: 13 regions in nine Western European countries., Patients: 252 live births with T13 and 602 with T18., Main Outcome Measures: Survival at 1 week, 4 weeks and 1, 5 and 10 years of age estimated by random-effects meta-analyses of registry-specific Kaplan-Meier survival estimates., Results: Survival estimates of children with T13 were 34% (95% CI 26% to 46%), 17% (95% CI 11% to 29%) and 11% (95% CI 6% to 18%) at 4 weeks, 1 and 10 years, respectively. The corresponding survival estimates were 38% (95% CI 31% to 45%), 13% (95% CI 10% to 17%) and 8% (95% CI 5% to 13%) for children with T18. The 10-year survival conditional on surviving to 4 weeks was 32% (95% CI 23% to 41%) and 21% (95% CI 15% to 28%) for children with T13 and T18, respectively., Conclusions: This multi-registry European study found that despite extremely high neonatal mortality in children with T13 and T18, 32% and 21%, respectively, of those who survived to 4 weeks were likely to survive to age 10 years. These reliable survival estimates are useful to inform counselling of parents after prenatal diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The vast majority of prenatally diagnosed congenital pulmonary malformations (CPM) remain asymptomatic at birth. The maximal value of the CPM volume ratio (CVRmax) predicts the risk of neonatal respiratory distress (NRD), and should allow for better assessment of the level of expertise needed at the delivery site., Aim: This study evaluated the level of maternity units currently chosen for the delivery of CPMs, and determined the impact of the choice of delivery site based on the CVRmax, with a threshold of 0.4 cm 2 ., Methods: Data were extracted from the French prospective MALFPULM cohort, with inclusion between March 2015 and June 2018., Results: The final study population consisted of 383 women. Deliveries in level 1 or 2 maternity units (n = 98, 25%) involved CPMs with lower CVRmax (p<0.001), causing fewer signs of prenatal compression (p = 0.025). Among the 62 children (16%) who presented with NRD, only seven (11%) were born in level 1 or 2 units (p = 0.0078). Choosing the maternity level according to the CVRmax would have increased the number of births in level 1 or 2 maternity hospitals by 70%. In these maternity units, the percentage of children with NRD would have increased from 8% in the actual distribution to 10% in the new strategy., Conclusion: Our results showed an overuse of level 3 maternity hospitals for the delivery of newborns with a prenatal diagnosis of CPM. The use of CVRmax should enable a reduction in the use of expertise centers without an adverse impact on newborns., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Background: Aplasia cutis congenita (ACC) is a rare congenital anomaly characterized by localized or widespread absence of skin at birth, mainly affecting the scalp. Most information about ACC exists as individual case reports and medium-sized studies., Objectives: This study aimed to investigate the epidemiology of ACC, using data from a large European network of population-based registries for congenital anomalies (EUROCAT)., Methods: Twenty-eight EUROCAT population-based registries in 16 European countries were involved. Poisson regression models were exploited to estimate the overall and live birth prevalence, to test time trends in prevalence between four 5-year periods and to evaluate the impact of the change of coding for ACC from the unspecific ICD9-BPA code to the specific ICD10 code. Proportions of ACC cases associated with other anomalies were reported., Results: Five hundred cases were identified in the period 1998-2017 (prevalence: 5.10 per 100,000 births). Prevalence across 5-year periods did not differ significantly and no significant differences were evident due to the change from ICD9 to ICD10 in ACC coding. Heterogeneity in prevalence was observed across registries. The scalp was the most common site for ACC (96.4%) and associated congenital anomalies were present in 33.8% of cases. Patau and Adams-Oliver syndromes were the most frequent among the associated chromosomal anomalies (88.3%) and the associated genetic syndromes (57.7%), respectively. 16% of cases were associated with limb anomalies and 15.4% with congenital heart defects. A family history of ACC was found in 2% of cases., Conclusion: To our knowledge, this is the only population-based study on ACC. The EUROCAT methodologies provide reliable prevalence estimates and proportions of associated anomalies., (© 2022 European Academy of Dermatology and Venereology.)

Purpose: We examined the total prevalence, trends in prevalence, and age-specific mortality among individuals with anorectal malformation (ARM) METHODS: We conducted a retrospective cohort study using data from 24 population- and hospital-based birth defects surveillance programs affiliated with the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) from 18 countries and for births from 1974 to 2014. We estimated pooled and program-specific total prevalence per 10,000 total births. Poisson regression was used to assess time trends in prevalence from 2001 to 2012 when most programs contributed data. We calculated selected age-specific proportions of deaths, stratified by case status RESULTS: The pooled total prevalence of ARM was 3.26 per 10,000 total births (95% Confidence Interval = 3.19, 3.32) for birth years 1974-2014. About 60% of cases were multiple or syndromic. Prevalence of multiple, syndromic, and stillborn cases decreased from 2001 to 2012. The first week mortality proportion was 12.5%, 3.2%, 28.3%, and 18.2% among all, isolated, multiple, and syndromic cases, respectively CONCLUSIONS: ARM is relatively rare, with multiple and syndromic cases showing decreasing prevalence during the study period. Mortality is a concern during the first week of life, and especially among multiple and syndromic cases. Our descriptive epidemiological findings increase our understanding of geographic variation in the prevalence of ARM and can be used to plan needed clinical services. Exploring factors influencing prevalence and mortality among individuals with ARM could inform future studies., (© 2022 The Authors. Birth Defects Research published by Wiley Periodicals LLC.)

Background: Younger mothers are at a greater risk of having a pregnancy with gastroschisis and the risk is higher in the United Kingdom than other European countries. Gastroschisis is thought to be a vascular disruption anomaly and the aim of this study was to analyze the prevalence of other possible vascular disruption anomalies to determine whether both the younger maternal age and the UK associations also occur with these anomalies., Methods: All pregnancies with anomalies considered potentially due to vascular disruption from January 1, 2005 to December 31, 2017 from 26 European population-based congenital anomaly registries who were members of EUROCAT were analyzed. Multilevel models were used to allow for differences between registries when analyzing associations with maternal age, year of birth and whether the registry was in the United Kingdom., Results: There were 5,220 cases with potential vascular disruption anomalies, excluding chromosomal and genetic conditions, with a prevalence of 8.85 per 10,000 births in the United Kingdom and 5.44 in the other European countries. The prevalence per 10,000 births of gastroschisis (4.45 vs. 1.56) and congenital constriction bands (0.83 vs. 0.42) was significantly higher in the United Kingdom, even after adjusting for maternal age. However, transverse limb reduction defects had a similar prevalence (2.16 vs. 2.14 per 10,000). The expected increased prevalence in younger mothers was observed for vascular disruption anomalies overall and for the individual anomalies: gastroschisis and congenital constriction bands., Conclusion: Vascular disruption anomalies that had an increased risk for younger mothers (such as gastroschisis) had a higher maternal age standardized prevalence in the United Kingdom, while vascular disruption anomalies with weaker associations with younger mothers (such as transverse limb reduction defects) did not have an increased prevalence in the United Kingdom, which may indicate a different etiology for these anomalies., (© 2022 The Authors. Birth Defects Research published by Wiley Periodicals LLC.)

Objective: To report results of the 2021 French National Perinatal Survey (ENP) in metropolitan France and assess trends in the main indicators of perinatal health, medical practices, and risk factors in France since 1995., Population and Method: All the samples included all women giving birth at a gestational age of at least 22 weeks of gestation and/or to an infant weighing at least 500 grams in all maternity units in metropolitan France during one week in 1995 (N=13 048), 2003 (N=14 324), 2010 (N=14 546), 2016 (N=12 553), and 2021 (N=12 088). The data came from postpartum interviews of the women at the hospital and their medical records. Comparisons between surveys showed trends over time., Results: Between 1995 and 2021, maternal characteristics changed. Maternal age and the frequency of women with obesity rose: in 2021, 24.6% of women were 35 years or older (21.1% in 2016, 19.2% in 2010, 15.9% in 2003 and 12.4% in 1995) and 14.4% were obese (11.8% in 2016, 9.9% in 2010 and 7.4% in 2003). Some antenatal prevention behaviors that improved in 2021 were not smoking during the third trimester, acid folic administration before pregnancy, and vaccination against influenza. The percentage of women with an early prenatal appointment ("4 th month appointment"), implemented to facilitate screening of maternal vulnerability during pregnancy, has continued to rise. The percentage of women receiving prenatal care by midwives has risen markedly (39.0% in 2021 versus 11.7% in 2016). Serum screening for Down syndrome continues to increase (91.8% of women in 2021). The rate of induction of labor has risen significantly (20.2% in 1995 and 25.8% in 2021). The mode of delivery has not varied significantly since 2003; in 2021, the cesarean rate was 21.4% and the instrumental vaginal delivery rate 12.4%. Episiotomy was increasingly rare, among both primiparous and multiparous women (16.5% and 2.9% in 2021, respectively). The prevalence of coronavirus (SARS-CoV2) infection during pregnancy was 5.7%. Preterm live births increased regularly, slightly but significantly over the 1995-2016 period and then remained stable between 2016 and 2021 (7.0%). In 2021, 56.3% of women exclusively breastfed during their hospital stay, a modest increase in comparison with 2016 (54.6%)., Conclusion: Routine national perinatal surveys highlight positive trends over time in some preventive practices, decreases in some medical interventions consistent with national guidelines, and the increasing role of midwives in prenatal care. Nonetheless, some indicators remain less than optimal and require more detailed analyses., Competing Interests: Disclosure or interest The authors have no conflict of interest to declare, (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Congenital anomalies are a major cause of perinatal, neonatal and infant mortality., Objectives: The aim was to investigate temporal changes and geographical variation in survival of children with major congenital anomalies (CA) in different European areas., Methods: In this population-based linkage cohort study, 17 CA registries members of EUROCAT, the European network for the surveillance of CAs, successfully linked data on 115,219 live births with CAs to mortality records. Registries estimated Kaplan-Meier survival at 28 days and 5 years of age and fitted Cox's proportional hazards models comparing mortality at 1 year and 1-9 years of age for children born during 2005-2014 with those born during 1995-2004. The hazard ratios (HR) from each registry were combined centrally using a random-effects model. The 5-year survival conditional on having survived to 28 days of age was calculated., Results: The overall risk of death by 1 year of age for children born with any major CA in 2005-2014 decreased compared to 1995-2004 (HR 0.68, 95% confidence interval [CI] 0.53, 0.89). Survival at 5 years of age ranged between registries from 97.6% to 87.0%. The lowest survival was observed for the registry of OMNI-Net (Ukraine) (87.0%, 95% CI 86.1, 87.9)., Conclusions: Survival of children with CAs improved for births in 2005-2014 compared with 1995-2004. The use of CA registry data linked to mortality data enables investigation of survival of children with CAs. Factors such as defining major CAs, proportion of terminations of pregnancy for foetal anomaly, source of mortality data and linkage methods are important to consider in the design of future studies and in the interpretation of the results on survival of children with CAs., (© 2022 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Background: Congenital hydrocephalus (CH) comprises a heterogeneous group of birth anomalies with a wide-ranging prevalence across geographic regions and registry type. The aim of the present study was to analyze the early neonatal case fatality rate (CFR) and total birth prevalence of newborns diagnosed with CH., Methods: Data were provided by 25 registries from four continents participating in the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) on births ascertained between 2000 and 2014. Two CH rates were calculated using a Poisson distribution: early neonatal CFR (death within 7 days) per 100 liveborn CH cases (CFR) and total birth prevalence rate (BPR) per 10,000 births (including live births and stillbirths) (BPR). Heterogeneity between registries was calculated using a meta-analysis approach with random effects. Temporal trends in CFR and BPR within registries were evaluated through Poisson regression modeling., Results: A total of 13,112 CH cases among 19,293,280 total births were analyzed. The early neonatal CFR was 5.9 per 100 liveborn cases, 95% confidence interval (CI): 5.4-6.8. The CFR among syndromic cases was 2.7 times (95% CI: 2.2-3.3) higher than among non-syndromic cases (10.4% [95% CI: 9.3-11.7] and 4.4% [95% CI: 3.7-5.2], respectively). The total BPR was 6.8 per 10,000 births (95% CI: 6.7-6.9). Stratified by elective termination of pregnancy for fetal anomalies (ETOPFA), region and system, higher CFR were observed alongside higher BPR rates. The early neonatal CFR and total BPR did not show temporal variation, with the exception of a CFR decrease in one registry., Conclusions: Findings of early neonatal CFR and total BPR were highly heterogeneous among registries participating in ICBDSR. Most registries with higher CFR also had higher BPR. Differences were attributable to type of registry (hospital-based vs. population-based), ETOPFA (allowed yes or no) and geographical regions. These findings contribute to the understanding of regional differences of CH occurrence and early neonatal deaths., (© 2022 Wiley Periodicals LLC.)

Objectives: To identify subgroups with a congenital heart defect (CHD) at risk of health-related quality of life (QoL) impairment at 8 years of age according to their medical and surgical management., Study Design: From a prospective population-based cohort study, 598 patients with CHD were subdivided according to their medical and surgical management: (1) CHD followed-up in an outpatient clinic, (2) complete repair before age 3 years, (3) complete repair after age 3 years, (4) palliative repair, or (5) CHD with spontaneous resolution (reference subgroup). Self-reported QoL and parent-reported QoL were measured using the Pediatric Quality of Life Inventory version 4.0 (score range, 0-100) at age 8 years. Multivariable regression analysis and Cohen effect size were used to compare outcomes across the CHD groups., Results: Self-reported and parent-reported QoL scores for the palliative repair subgroup were lower (β = -2.1 [95% CI, -3.9 to -0.2] and β = -16.0 [95% CI, -22.4 to -9.5], respectively), with a large effect size (δ = -0.9 [95% CI, -1.4 to -0.4] and δ = -1.3 [95% CI, -1.8 to -0.7], respectively). Parent-reported QoL scores for the complete repair after age 3 years subgroup were lower (β = -9.2; 95% CI, -15.0 to -3.5), with a large effect size (δ = -0.9; 95% CI, -1.4 to -0.5). Self-reported QoL scores for the complete repair before age 3 years subgroup was lower (β = -1.3; 95% CI, -1.9 to -0.6), with a small effect size (δ = -0.4; 95% CI, -0.6 to -0.2)., Conclusions: The QoL of children with CHD who experienced a hospital intervention is reduced at age 8 years. Patient age at the last cardiac intervention might influence QoL at 8 years., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Congenital anomalies are the leading cause of perinatal, neonatal and infant mortality in developed countries. Large long-term follow-up studies investigating survival beyond the first year of life in children with rare congenital anomalies are costly and sufficiently large standardized cohorts are difficult to obtain due to the rarity of some anomalies. This study aimed to investigate the survival up to 10 years of age of children born with a rare structural congenital anomaly in the period 1995-2014 in Western Europe., Methods: Live births from thirteen EUROCAT (European network for the epidemiological surveillance of congenital anomalies) population-based registries were linked to mortality records. Survival for 12,685 live births with one of the 31 investigated rare structural congenital anomalies (CAs) was estimated at 1 week, 4 weeks and 1, 5 and 10 years of age within each registry and combined across Europe using random effects meta-analyses. Differences between registries were evaluated for the eight rare CAs with at least 500 live births., Results: Amongst the investigated CAs, arhinencephaly/holoprosencephaly had the lowest survival at all ages (58.1%, 95% Confidence Interval (CI): 44.3-76.2% at 1 week; 47.4%, CI: 36.4-61.6% at 1 year; 35.6%, CI: 22.2-56.9% at 10 years). Overall, children with rare CAs of the digestive system had the highest survival (> 95% at 1 week, > 84% at 10 years). Most deaths occurred within the first four weeks of life, resulting in a 10-year survival conditional on surviving 4 weeks of over 95% for 17 out of 31 rare CAs. A moderate variability in survival between participating registries was observed for the eight selected rare CAs., Conclusions: Pooling standardised data across 13 European CA registries and the linkage to mortality data enabled reliable survival estimates to be obtained at five ages up to ten years. Such estimates are useful for clinical practice and parental counselling., (© 2022. The Author(s).)

Objectives: To investigate the survival up to age 10 for children born alive with a major congenital anomaly (CA)., Methods: This population-based linked cohort study (EUROlinkCAT) linked data on live births from 2005 to 2014 from 13 European CA registries with mortality data. Pooled Kaplan-Meier survival estimates up to age 10 were calculated for these children (77 054 children with isolated structural anomalies and 4011 children with Down syndrome)., Results: The highest mortality of children with isolated structural CAs was within infancy, with survival of 97.3% (95% confidence interval [CI]: 96.6%-98.1%) and 96.9% (95% CI: 96.0%-97.7%) at age 1 and 10, respectively. The 10-year survival exceeded 90% for the majority of specific CAs (27 of 32), with considerable variations between CAs of different severity. Survival of children with a specific isolated anomaly was higher than in all children with the same anomaly when those with associated anomalies were included. For children with Down syndrome, the 10-year survival was significantly higher for those without associated cardiac or digestive system anomalies (97.6%; 95% CI: 96.5%-98.7%) compared with children with Down syndrome associated with a cardiac anomaly (92.3%; 95% CI: 89.4%-95.3%), digestive system anomaly (92.8%; 95% CI: 87.7%-98.2%), or both (88.6%; 95% CI: 83.2%-94.3%)., Conclusions: Ten-year survival of children born with congenital anomalies in Western Europe from 2005 to 2014 was relatively high. Reliable information on long-term survival of children born with specific CAs is of major importance for parents of these children and for the health care professionals involved in their care., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest to disclose.

Background: The infant mortality rate (IMR) serves as a key indicator of population health., Methods: We used data from the French National Institute of Statistics and Economic Studies on births and deaths during the first year of life from 2001 to 2019 to calculate IMR aggregated by month. We ran joinpoint regressions to identify inflection points and assess the linear trend of each segment. Exploratory analyses were performed for overall IMR, as well as by age at death subgroups (early neonatal [D0-D6], late neonatal [D7-27], and post-neonatal [D28-364]), and by sex. We performed sensitivity analyses by excluding deaths at D0 and using other time-series modeling strategies., Results: Over the 19-year study period, 53,077 infant deaths occurred, for an average IMR of 3·63/1000 (4·00 in male, 3·25 in female); 24·4% of these deaths occurred during the first day of life and 47·8% during the early neonatal period. Joinpoint analysis identified two inflection points in 2005 and 2012. The IMR decreased sharply from 2001 to 2005 (slope: -0·0167 deaths/1000 live births/month; 95%CI: -0·0219 to -0·0116) and then decreased slowly between 2005 and 2012 (slope: -0·0041; 95%CI: -0·0065 to -0·0016). From 2012 onwards, a significant increase in IMR was observed (slope: 0·0033; 95%CI: 0·0011 to 0·0056). Subgroup analyses indicated that these trends were driven notably by an increase in the early neonatal period. Sensitivity analyses provided consistent results., Interpretation: The recent historic increase in IMR since 2012 in France should prompt urgent in-depth investigation to understand the causes and prepare corrective actions., Funding: No financial relationships with any organizations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work., Competing Interests: The authors have no conflict of interest to declare. We affirm that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of any organization or company., (© 2022 The Authors.)

Objectives: Most children with prenatally diagnosed congenital pulmonary malformations (CPMs) are asymptomatic at birth. We aimed to develop a parsimonious prognostic model for predicting the risk of neonatal respiratory distress (NRD) in preterm and term infants with CPM, based on the prenatal attributes of the malformation., Methods: MALFPULM is a prospective population-based nationally representative cohort including 436 pregnant women. The main predictive variable was the CPM volume ratio (CVR) measured at diagnosis (CVR first) and the highest CVR measured (CVR max). Separate models were estimated for preterm and term infants and were validated by bootstrapping., Results: In total, 67 of the 383 neonates studied (17%) had NRD. For infants born at term (>37 weeks, n=351), the most parsimonious model included CVR max as the only predictive variable (receiver operating characteristic (ROC) curve area: 0.70±0.04, negative predictive value: 0.91). The probability of NRD increased linearly with increasing CVR max and remained below 10% for CVR max <0.4. In preterm infants (n=32), both CVR max and gestational age were important predictors of the risk of NRD (ROC: 0.85±0.07). Models based on CVR first had a similar predictive ability., Conclusions: Predictive models based exclusively on CVR measurements had a high negative predictive value in infants born at term. Our study results could contribute to the individualised general risk assessment to guide decisions about the need for newborns with prenatally diagnosed CPM to be delivered at specialised centres., Competing Interests: Conflict of interest: C. Delacourt has nothing to disclose. Conflict of interest: N. Bertille has nothing to disclose. Conflict of interest: L.J. Salomon has nothing to disclose. Conflict of interest: M. Rahshenas has nothing to disclose. Conflict of interest: A. Benachi has nothing to disclose. Conflict of interest: A. Bonnard has nothing to disclose. Conflict of interest: L. Choupeaux has nothing to disclose. Conflict of interest: V. Fouquet has nothing to disclose. Conflict of interest: V. Goua has nothing to disclose. Conflict of interest: F. Hameury has nothing to disclose. Conflict of interest: E. Hervieux has nothing to disclose. Conflict of interest: J-M. Jouannic has nothing to disclose. Conflict of interest: N. Khen-Dunlop has nothing to disclose. Conflict of interest: G. Le Bouar has nothing to disclose. Conflict of interest: J. Massardier has nothing to disclose. Conflict of interest: L. Roditis has nothing to disclose. Conflict of interest: J. Rosenblatt has nothing to disclose. Conflict of interest: A. Sartor has nothing to disclose. Conflict of interest: C. Thong-Vanh has nothing to disclose. Conflict of interest: N. Lelong has nothing to disclose. Conflict of interest: B. Khoshnood has nothing to disclose., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Objective: To evaluate the respiratory outcome in children with congenital heart disease (CHD), considering recent management procedures and the CHD pathophysiology., Design and Setting: Clinical and functional respiratory outcome were evaluated in 8-year-old children with isolated CHD followed up from birth in the prospective population-based EPICARD cohort., Patients: Children were assigned to two groups, based on the pathophysiology of the CHD: CHDs with left-to-right shunt (n = 212) and CHDs with right outflow tract obstruction (n = 113)., Results: Current wheezing episodes were observed in 15% of the children with isolated CHD and left-to-right shunt, and 11% of the children with isolated CHD and right outflow tract obstruction (not significant). Total lung capacity (TLC) was the only respiratory function parameter that significantly differed between the two groups. It was lower in children with left-to-right shunt (88.72 ± 0.65% predicted) than in those with right outflow tract obstruction (91.84 ± 0.96, p = 0.006). In multivariate analysis, CHD with left-to-right shunt (coeff. [95% CI]: -3.17 [-5.45; -0.89]) and surgery before the age of 2 months (-6.52 [-10.90; -2.15]) were identified as independent factors associated with significantly lower TLC values., Conclusion: Lower TLC remains a long-term complication in CHD, particularly in cases with left-to-right shunt and in patients requiring early repair. These findings suggest that an increase in pulmonary blood flow may directly impair lung development., (Copyright © 2021 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Objective: To assess whether children with symptomatic congenital heart defects (CHDs) at birth (cyanosis and/or heart failure) are at greater risk of adverse neurodevelopmental outcomes at 8 years of age., Study Design: From a prospective population-based cohort study of newborns with CHDs (EPICARD), we included 473 children with available neurodevelopmental assessments at 8 years of age. We grouped the CHD based on symptoms at birth and need for early neonatal intervention. Ventricular septal defects that closed spontaneously within the first year of life were considered the control group. Neurodevelopmental outcomes were assessed using the Kauffman Assessment Battery Test for Children, Second Edition, for IQ (mean 100 ± 15), and the Developmental NEuroPSYchological Assessment Battery, Second Edition, for detailed assessment of specific neurocognitive domains (mean 10 ± 3). Multivariable regression analysis was used to compare the outcomes across the CHD groups after considering potentially confounding variables., Results: Compared with the control group, children with cyanotic CHD without heart failure had lower scores for IQ, -7.2 (95% CI -13.4 to -1.2). Children with noncyanotic CHD with heart failure had lower scores in the specific domains of language -1.5 (95% CI -2.2 to -0.7), and memory and learning -1.3 (95% CI -2.4; -0.3). Those with both cyanotic CHD and heart failure had lower scores for IQ, -7.6 (95% CI -13.5 to -1.8), as well as the specific domains of language and memory and learning, -2.0 (95% CI -2.9 to -1.0) and -1.1 (95% CI -2.3 to -0.1), respectively., Conclusions: Children with symptomatic CHD at birth are at greater risk of adverse neurodevelopmental outcomes at 8 years of age, with the greatest risk for those who were born with both cyanosis and heart failure., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Pierre Robin sequence (PRS) is a rare congenital anomaly. Respiratory disorders and feeding difficulties represent the main burden., Objective: The aim of this study was to investigate the epidemiology of PRS using a cohort of cases from EUROCAT, the European network of population-based registries of congenital anomalies., Methods: We analysed cases of PRS born in the period 1998-2017 collected by 29 population-based congenital anomaly registries in 17 different countries. We calculated prevalence estimates, prenatal detection rate, survival up to 1 week, and proportions of associated anomalies. The effect of maternal age was tested using a Poisson regression model., Results: Out of 11 669 155 surveyed births, a total of 1294 cases of PRS were identified. The estimate of the overall prevalence was 12.0 per 100 000 births (95% CI 9.9, 14.5). There was a total of 882 (68.2%) isolated cases, and the prevalence was 7.8 per 100 000 births (95% CI 6.7, 9.2). A total of 250 cases (19.3%) were associated with other structural congenital anomalies, 77 cases (6.0%) were associated with chromosomal anomalies and 77 (6.0%) with genetic syndromes. The prenatal detection rate in isolated cases was 12.0% (95% CI 9.8, 14.5) and increased to 16.0% (95% CI 12.7, 19.7) in the sub-period 2008-2017. The prevalence rate ratio of non-chromosomal cases with maternal age ≥35 was higher than in cases with maternal age <25 for total (PRR 1.26, 95% CI 1.05, 1.51) and isolated cases (PRR 1.33, 95% CI 1.00, 1.64). Survival of chromosomal cases (94.2%) and multiple anomaly cases (95.3%) were lower than survival of isolated cases (99.4%)., Conclusions: This epidemiological study using a large series of cases of PRS provides insights into the epidemiological profile of PRS in Europe. We observed an association with higher maternal age, but further investigations are needed to test potential risk factors for PRS., (© 2021 John Wiley & Sons Ltd.)

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Despite the guidelines in effect, too few women in France receive folic acid supplementation. The principal objective of this study was to identify the factors associated with the inadequacy of this supplementation in the periconceptional period. The secondary objective was to assess women's knowledge about the prevention of neural tube defects (NTDs)., Methods: This study included 400 women and took place in 8 Parisian maternity. Folic acid supplementation was inadequate when started after the beginning of the pregnancy., Results: Among the women questioned, 68% had inadequate folic acid supplementation. They were significantly younger (ORa= 1,8; 95% IC [1,1-2,8]), didn't had health insurance (ORa=3,9; 95% IC [1,5-10,1]), had not studied after high school (ORa=2,9; 95% IC [1,2-6,9]) and had regular gynecological care less often than the women with adequate supplementation (ORa=3,0; 95% IC [1,6-5,6]). More than half (55.5%) had insufficient knowledge of the benefits of folic acid; the factors related to this lack of knowledge were the absence of regular gynecological care and of health insurance., Conclusion: Individual factors associated with a lack of supplementation have been identified. These results provide health professionals and supervisors with useful information for developing strategies adapted to certain subgroups of women for better prevention of AFTN in these populations., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Introduction: Knowledge on the safety of medication use during pregnancy is often sparse. Pregnant women are generally excluded from clinical trials, and there is a dependence on post-marketing surveillance to identify teratogenic medications., Aims: This study aimed to identify signals of potentially teratogenic medications using EUROmediCAT registry data on medication exposure in pregnancies with a congenital anomaly, and to investigate the use of VigiBase reports of adverse events of medications in the evaluation of these signals., Methods: Signals of medication-congenital anomaly associations were identified in EUROmediCAT (21,636 congenital anomaly cases with 32,619 medication exposures), then investigated in a subset of VigiBase (45,749 cases and 165,121 exposures), by reviewing statistical reporting patterns and VigiBase case reports. Evidence from the literature and quantitative and qualitative aspects of both datasets were considered before recommending signals as warranting further independent investigation., Results: EUROmediCAT analysis identified 49 signals of medication-congenital anomaly associations. Incorporating investigation in VigiBase and the literature, these were categorised as follows: four non-specific medications; 11 likely due to maternal disease; 11 well-established teratogens; two reviewed in previous EUROmediCAT studies with limited additional evidence; and 13 with insufficient basis for recommending follow-up. Independent investigations are recommended for eight signals: pregnen (4) derivatives with limb reduction; nitrofuran derivatives with cleft palate and patent ductus arteriosus; salicylic acid and derivatives with atresia or stenosis of other parts of the small intestine and tetralogy of Fallot; carbamazepine with atrioventricular septal defect and severe congenital heart defect; and selective beta-2-adrenoreceptor agonists with posterior urethral valve and/or prune belly., Conclusion: EUROmediCAT data should continue to be used for signal detection, accompanied by information from VigiBase and review of the existing literature to prioritise signals for further independent evaluation.

Objective: Thirty years ago it was demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). Despite Public Health Initiatives across Europe recommending that women take 0.4 mg folic acid before becoming pregnant and during the first trimester, the prevalence of NTD pregnancies has not materially decreased in the EU since 1998, in contrast to the dramatic fall observed in the USA. This study aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in Europe from 1998 as it had been in the USA. Design and Setting: The number of NTD pregnancies from 1998 to 2017 that would have been prevented if folic acid fortification had been implemented in the 28 countries who were members of the European Union in 2019 was predicted was predicted using data on NTD prevalence from 35 EUROCAT congenital anomaly registries and literature searches for population serum folate levels and folic acid supplementation. Results: From 1998 to 2017 an estimated 95,213 NTD pregnancies occurred amongst 104 million births in the 28 countries in the EU, a prevalence of 0.92 per 1,000 births. The median serum folate level in Europe over this time period was estimated to be 14.1 μg/L. There is a lack of information about women taking folic acid supplements before becoming pregnant and during the first trimester of pregnancy, with one meta-analysis indicating that around 25% of women did so. An estimated 14,600 NTD pregnancies may have been prevented if the European countries had implemented fortification at the level adopted by the USA in 1998 and 25% of women took folic acid supplements. An estimated 19,500 NTD pregnancies would have been prevented if no women took folic acid supplements. Conclusions: This study suggests that failure to implement mandatory folic acid fortification in the 28 European countries has caused, and continues to cause, neural tube defects to occur in almost 1,000 pregnancies every year., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Morris, Addor, Ballardini, Barisic, Barrachina-Bonet, Braz, Cavero-Carbonell, Den Hond, Garne, Gatt, Haeusler, Khoshnood, Lelong, Kinsner-Ovaskainen, Kiuru-Kuhlefelt, Klungsoyr, Latos-Bielenska, Limb, O'Mahony, Perthus, Pierini, Rankin, Rissmann, Rouget, Sayers, Sipek, Stevens, Tucker, Verellen-Dumoulin, de Walle, Wellesley, Wertelecki and Bermejo-Sanchez.)

Background and Objectives: Congenital heart defects (CHD) and growth restriction at birth are two major causes of childhood and adult morbidity and mortality. The aim of this study was to assess the overall risk of growth restriction at birth, as measured by its imperfect proxy small (< 10th percentile) for gestational age (SGA), for newborns with CHD. Methods: Using data from a population-based cohort of children born with CHD, we assessed the risk of growth restriction at birth using SGA and severe SGA (3rd percentile). To compare the odds of SGA and severe SGA across five specific major CHD, we used ordinal logistic regression using isolated, minor (non-operated) ventricular septal defect (VSD) as the control group. Results: The overall proportion of SGA for "isolated" CHD (i.e., those not associated with other anomalies) was 13% (95% CI, 12-15%), which is 30% higher than what would be expected in the general population (i.e., 10%). The risk of severe SGA was 5% (95% CI, 4-6%) as compared with the expected 3% in the general population. There were substantial differences in the risk of overall SGA and more so severe SGA across the different CHD. The highest risk of SGA occurred for Tetralogy of Fallot (adjusted OR 2.7, 95% CI, 1.3-5.8) and operated VSD (adjusted OR 2.1, 95% CI, 1.1-3.8) as compared with the control group of minor (non-operated) VSD. Conclusion: The overall risks of both SGA and severe SGA were higher in isolated CHD than what would be expected in the general population with substantial differences across the subtypes of CHD. These results may provide a clue for understanding the underlying mechanisms of the relation between alterations in fetal circulation associated with different types of CHD and their effects on fetal growth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ghanchi, Rahshenas, Bonnet, Derridj, LeLong, Salomon, Goffinet and Khoshnood.)

Background: Whereas no global severity score exists for congenital heart defects (CHD), risk (Risk Adjusted Cardiac Heart Surgery-1: RACHS-1) and/or complexity (Aristotle Basic Complexity: ABC) scores have been developed for those who undergo surgery. Population-based studies for assessing the predictive ability of these scores are lacking., Objective: To assess the predictive ability of RACHS-1 and ABC scores for the risk of infant mortality using population-based cohort (EPICARD) data for newborns with structural CHD., Methods: The study population comprised 443 newborns who underwent curative surgery. We assessed the predictive ability of each score alone and in conjunction with an a priori selected set of predictors of infant mortality. Statistical analysis included logistic regression models for which we computed model calibration, discrimination (ROC), and a rarely used but clinically meaningful measure of variance explained (Tjur's coefficient of discrimination)., Results: The risk of mortality increased with increasing RACHS-1 and the ABC scores and models based on both scores had adequate calibration. Model discrimination was higher for the RACHS-1-based model (ROC 0.68, 95% CI, 0.58-0.79) than the ABC-based one (ROC 0.59, 95% CI, 0.49-0.69), P  = 0.03. Neither score had the good predictive ability when this was assessed using Tjur's coefficient., Conclusions: Even if the RACHS-1 score had better predictive ability, both scores had low predictive ability using a variance-explained measure. Because of this limitation and the fact that neither score can be used for newborns with CHD who do not undergo surgery, it is important to develop new predictive models that comprise all newborns with structural CHD., Competing Interests: The authors have no competing interests to disclose., (© 2021 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Purpose: This study determined the prevalence, mortality, and time trends of children with congenital diaphragmatic hernia (CDH)., Methods: Twenty-five hospital- and population-based surveillance programs in 19 International Clearinghouse for Birth Defects Surveillance and Research member countries provided birth defects mortality data between 1974 and 2015. CDH cases included live births, stillbirths, or elective termination of pregnancy for fetal anomalies. Prevalence, cumulative mortality rates, and 95% confidence intervals (CIs) were calculated using Poisson regression and a Kaplan-Meier product-limit method. Joinpoint regression analyses were conducted to assess time trends., Results: The prevalence of CDH was 2.6 per 10,000 total births (95% CI: 2.5-2.7), slightly increasing between 2001 and 2012 (average annual percent change = 0.5%; 95% CI:-0.6 to 1.6). The total percent mortality of CDH was 37.7%, with hospital-based registries having more deaths among live births than population-based registries (45.1% vs. 33.8%). Mortality rates decreased over time (average annual percent change = -2.4%; 95% CI: -3.8 to 1.1). Most deaths due to CDH occurred among 2- to 6-day-old infants for both registry types (36.3%, hospital-based; 12.1%, population-based)., Conclusions: The mortality of CDH has decreased over time. Mortality remains high during the first week and varied by registry type., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Following an alert on neural tube defects and dolutegravir, we sought to evaluate if the exposure integrase strand transfer inhibitors (INSTIs) at conception was associated with birth defects or other adverse pregnancy outcomes., Methods: In the prospective national French Perinatal Cohort (EPF), we studied birth defects and other perinatal outcomes by matching each pregnant woman exposed to INSTIs with a pregnant woman exposed to darunavir/ritonavir receiving the same backbone of nucleoside reverse transcriptase inhibitors and matched for other characteristics such as age, geographic origin, centre and year of delivery., Results: Among 808 women exposed to INSTIs during pregnancy (raltegravir = 703, dolutegravir = 57 and elvitegravir = 48), we reported a slightly higher rate of birth defects in infants exposed at conception to raltegravir (6.7%) vs. infants exposed to raltegravir later in pregnancy: 2.9% if initiated during pregnancy as first-line, and 2.5% as second-line treatment,  P =0.04. When compared with matched controls, raltegravir exposure at conception was not significantly associated with birth defects: 6.4 vs. 2.3%, P = 0.08. There was no cluster of birth defect type and no neural tube defects were observed. Other perinatal outcomes, such as preterm birth and stillbirths, did not differ significantly between raltegravir-exposed women and matched counterparts. No difference in any outcome was observed for elvitegravir/cobicistat or dolutegravir., Conclusion: We found a nonsignificant trend for an association between exposure to raltegravir at conception and birth defects, which needs to be evaluated by larger prospective surveillance data, as these drugs are increasingly prescribed in women living with HIV., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Omphalocele is the second most common abdominal birth defect and often occurs with other structural and genetic defects. The objective of this study was to determine omphalocele prevalence, time trends, and mortality during early childhood, by geographical region, and the presence of associated anomalies., Methods: We conducted a retrospective study with 23 birth defect surveillance systems in 18 countries who are members of the International Clearinghouse for Birth Defects Surveillance and Research that submitted data on cases ascertained from 2000 through 2012, approximately 16 million pregnancies were surveyed that resulted in live births, stillbirths, or elective terminations of pregnancy for fetal anomalies (ETOPFA) and cases with omphalocele were included. Overall prevalence and mortality rates for specific ages were calculated (day of birth, neonatal, infant, and early childhood). We used Kaplan-Meier estimates with 95% confidence intervals (CI) to calculate cumulative mortality and joinpoint regression for time trend analyses., Results: The prevalence of omphalocele was 2.6 per 10,000 births (95% CI: 2.5, 2.7) and showed no temporal change from 2000-2012 (average annual percent change = -0.19%, p = .52). The overall mortality rate was 32.1% (95% CI: 30.2, 34.0). Most deaths occurred during the neonatal period and among children with multiple anomalies or syndromic omphalocele. Prevalence and mortality varied by registry type (e.g., hospital- vs. population-based) and inclusion or exclusion of ETOPFA., Conclusions: The prevalence of omphalocele showed no temporal change from 2000-2012. Approximately one-third of children with omphalocele did not survive early childhood with most deaths occurring in the neonatal period., (© 2020 Wiley Periodicals LLC.)

Purpose: Human chorionic gonadotropin stimulates fetal testosterone production and contributes to normal development of male genitalia. Using population based data we hypothesized that differences in maternal free beta human chorionic gonadotropin may be associated with hypospadias., Materials and Methods: Data were obtained from the Paris Registry of Congenital Malformations (REMAPAR) (2011 to 2016). The initial study population included 3,172 pregnant women who gave birth to a singleton live born male infant with a congenital malformation. After exclusion of cases with unknown beta human chorionic gonadotropin and those with chromosomal or genetic abnormalities, the study population included 194 boys with isolated hypospadias and 1,075 controls. For cases with operative notes (125) we obtained data on type (proximal/distal) of hypospadias. Using quantile regression we compared median values of multiple of median beta human chorionic gonadotropin measured for first trimester Down syndrome screening (10th to 13th gestational weeks) for overall as well as by type of hypospadias vs controls. We also considered possible effects of placental dysfunction (maternal age, intrauterine growth retardation and preterm births) as potential confounding factors., Results: Overall the median beta human chorionic gonadotropin multiple of median was comparable for women who had an infant with hypospadias vs controls (0.99 vs 0.95, p=0.3). However, proximal hypospadias was associated with a statistically significant higher median multiple of median than distal hypospadias or unspecified (1.49 vs 0.92 vs 1.05, p=0.02). The estimates were comparable after adjustment for placental dysfunction., Conclusions: Our findings support the hypothesis that an alteration in maternal beta human chorionic gonadotropin levels is associated with hypospadias. However, this association appears to be limited to proximal hypospadias.

Background: Public health organisations use public health indicators to guide health policy. Joint analysis of multiple public health indicators can provide a more comprehensive understanding of what they are intended to evaluate., Objective: To analyse variaitons in the prevalence of congenital anomaly-related perinatal mortality attributable to termination of pregnancy for foetal anomaly (TOPFA) and prenatal diagnosis of congenital anomaly prevalence., Methods: We included 55 363 cases of congenital anomalies notified to 18 EUROCAT registers in 10 countries during 2008-12. Incidence rate ratios (IRR) representing the risk of congenital anomaly-related perinatal mortality according to TOPFA and prenatal diagnosis prevalence were estimated using multilevel Poisson regression with country as a random effect. Between-country variation in congenital anomaly-related perinatal mortality was measured using random effects and compared between the null and adjusted models to estimate the percentage of variation in congenital anomaly-related perinatal mortality accounted for by TOPFA and prenatal diagnosis., Results: The risk of congenital anomaly-related perinatal mortality decreased as TOPFA and prenatal diagnosis prevalence increased (IRR 0.79, 95% confidence interval [CI] 0.72, 0.86; and IRR 0.88, 95% CI 0.79, 0.97). Modelling TOPFA and prenatal diagnosis together, the association between congenital anomaly-related perinatal mortality and TOPFA prevalence became stronger (RR 0.70, 95% CI 0.61, 0.81). The prevalence of TOPFA and prenatal diagnosis accounted for 75.5% and 37.7% of the between-country variation in perinatal mortality, respectively., Conclusion: We demonstrated an approach for analysing inter-linked public health indicators. In this example, as TOPFA and prenatal diagnosis of congenital anomaly prevalence decreased, the risk of congenital anomaly-related perinatal mortality increased. Much of the between-country variation in congenital anomaly-related perinatal mortality was accounted for by TOPFA, with a smaller proportion accounted for by prenatal diagnosis., (© 2020 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

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., (© 2019 Wiley Periodicals, Inc.)

Background: 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., Methods: 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., Results: 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)., Conclusions: 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., (© 2019 Wiley Periodicals, Inc.)

Objectives: To describe the epidemiology and geographical differences in prevalence of congenital cerebral anomalies in Europe., Design and Setting: Congenital cerebral anomalies (International Classification of Diseases, 10th Revision code Q04) recorded in 29 population-based EUROCAT registries conducting surveillance of 1.7 million births per annum (29% of all European births)., Participants: All birth outcomes (live births, fetal deaths from 20 weeks gestation and terminations of pregnancy after prenatal diagnosis of a fetal anomaly (TOPFA)) from 2005 to 2014., Main Outcome Measures: Prevalence, proportion of associated non-cerebral anomalies, prenatal detection rate., Results: 4927 cases with congenital cerebral anomalies were identified; a prevalence (adjusted for under-reporting) of 9.8 (95% CI: 8.5 to 11.2) per 10 000 births. There was a sixfold difference in prevalence across the registries. Registries with higher proportions of prenatal diagnoses had higher prevalence. Overall, 55% of all cases were liveborn, 3% were fetal deaths and 41% resulted in TOPFA. Forty-eight per cent of all cases were an isolated cerebral anomaly, 25% had associated non-cerebral anomalies and 27% were chromosomal or part of a syndrome (genetic or teratogenic). The prevalence excluding genetic or chromosomal conditions increased by 2.4% per annum (95% CI: 1.3% to 3.5%), with the increases occurring only for congenital malformations of the corpus callosum (3.0% per annum) and 'other reduction deformities of the brain' (2.8% per annum)., Conclusions: Only half of the cases were isolated cerebral anomalies. Improved prenatal and postnatal diagnosis may account for the increase in prevalence of congenital cerebral anomalies from 2005 to 2014. However, major differences in prevalence remain between regions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Medical advancements have resulted in better survival and life expectancy among those with spina bifida, but a significantly increased risk of perinatal and postnatal mortality for individuals with spina bifida remains., Objectives: To examine stillbirth and infant and child mortality among those affected by spina bifida using data from multiple countries., Methods: We conducted an observational study, using data from 24 population- and hospital-based surveillance registries in 18 countries contributing as members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). Cases of spina bifida that resulted in livebirths or stillbirths from 20 weeks' gestation or elective termination of pregnancy for fetal anomaly (ETOPFA) were included. Among liveborn spina bifida cases, we calculated mortality at different ages as number of deaths among liveborn cases divided by total number of liveborn cases with spina bifida. As a secondary outcome measure, we estimated the prevalence of spina bifida per 10 000 total births. The 95% confidence interval for the prevalence estimate was estimated using the Poisson approximation of binomial distribution., Results: Between years 2001 and 2012, the overall first-week mortality proportion was 6.9% (95% CI 6.3, 7.7) and was lower in programmes operating in countries with policies that allowed ETOPFA compared with their counterparts (5.9% vs. 8.4%). The majority of first-week mortality occurred on the first day of life. In programmes where information on long-term mortality was available through linkage to administrative databases, survival at 5 years of age was 90%-96% in Europe, and 86%-96% in North America., Conclusions: Our multi-country study showed a high proportion of stillbirth and infant and child deaths among those with spina bifida. Effective folic acid interventions could prevent many cases of spina bifida, thereby preventing associated childhood morbidity and mortality., (© 2019 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Objectives: To assess prenatal changes in the volume of congenital pulmonary malformations (CPM) and examine whether these changes differ in lesions that appear cystic on ultrasound compared with hyperechoic lesions, and to study the relationship between CPM volume and risk of fetal compression., Methods: We conducted a nationally representative, multicenter, prospective cohort study, which included 579 ultrasound examinations in 176 pregnant women with a diagnosis of fetal CPM, between March 2015 and November 2016. Several ultrasound examinations were performed between diagnosis and delivery, including measurement of CPM volume. We modeled changes in CPM volume ratio (CVR) as a function of gestational age, overall and for cystic/mixed vs hyperechoic malformations, and examined the association between CVR and signs of compression during pregnancy., Results: When modeling CVR changes over time, there was a statistically significant decrease in CVR with increasing gestational age (P < 0.001), but the pattern of change differed according to CPM phenotype at first ultrasound examination: cystic/mixed CPM were characterized by a monotonic decrease in CVR with increasing gestational age (P = 0.002), whereas hyperechoic CPM showed an initial increase in CVR up to 27 weeks of gestation, followed by a decrease thereafter (P < 0.001). Peak CVR values were predicted as early as 21-22 weeks for cystic/mixed CPMs compared with 25-26 weeks for hyperechoic malformations. Regardless of CPM phenotype, fetuses that showed no sign of compression at any point had substantially lower CVR at first CVR measurement, and the CVR remained relatively constant thereafter. Among the subpopulation of fetuses with no sign of compression at first CVR measurement, the odds of a subsequent compression was 7-fold higher (adjusted odds ratio, 7.0; 95% CI, 1.6-29.9) if initial CVR was > 0.4 vs CVR ≤ 0.4 cm 2 ., Conclusions: Predicted changes in CVR during pregnancy differ between cystic and hyperechoic malformations. This may be the result of different pathophysiological mechanisms or differences in the timing of occurrence of these different types of CPM. CVR measured at the initial diagnostic ultrasound examination was strongly associated with the odds of subsequent compression. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

Achondroplasia is a rare genetic disorder resulting in short-limb skeletal dysplasia. We present the largest European population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. All cases of achondroplasia notified to 28 EUROCAT registries (1991-2015) were included in the study. Prevalence, birth outcomes, prenatal diagnosis, associated anomalies, and the impact of paternal and maternal age on de novo achondroplasia were presented. The study population consisted of 434 achondroplasia cases with a prevalence of 3.72 per 100,000 births (95%CIs: 3.14-4.39). There were 350 live births, 82 terminations of pregnancy after prenatal diagnosis, and two fetal deaths. The prenatal detection rate was significantly higher in recent years (71% in 2011-2015 vs. 36% in 1991-1995). Major associated congenital anomalies were present in 10% of cases. About 20% of cases were familial. After adjusting for maternal age, fathers >34 years had a significantly higher risk of having infants with de novo achondroplasia than younger fathers. Prevalence was stable over time, but regional differences were observed. All pregnancy outcomes were included in the prevalence estimate with 80.6% being live born. The study confirmed the increased risk for older fathers of having infants with de novo achondroplasia., (© 2019 Wiley Periodicals, Inc.)

Objective: To estimate the prevalence and indications of terminations of pregnancy (TOP) between 22 +0 and 31 +6 weeks of gestational age in France and to examine the characteristics of women by indication of TOP., Study Design: From the EPIPAGE 2 population-based cohort study of preterm births in France in 2011, we selected 5009 singleton live births, stillbirths and TOP that occurred between 22 and 31 weeks. We estimated the proportion of TOP by gestational age. We then classified terminations by indications into 4 categories: fetal anomalies (TOPFA), preterm premature rupture of the membranes (PPROM), maternal conditions and fetal growth restriction (FGR). We also classified TOPFA by type of anomaly. Maternal characteristics were compared between TOPFA and TOP for maternal or fetal conditions without congenital anomaly., Results: 23.1% of all births and 54.3% of stillbirths were terminations. The proportion of terminations was 36.9% of all births at 22 weeks, 50.2% at 24 weeks and <10% at 30-31 weeks. 85.8% of terminations were for fetal anomaly, 4.4% for PPROM, 6.1% for maternal complications and 3.7% for severe FGR. Compared to women with a TOPFA, those with a termination for maternal or fetal conditions were more often nulliparous, single, African, obese, smokers and covered by non-standard insurance for women in socially deprived circumstances., Conclusion: In France, there is a high proportion of TOP of which 14% are for indications other than congenital anomalies. Because rates of terminations have an impact on very preterm birth and perinatal mortality rates, studies on pregnancy outcome should report all terminations, not only those for congenital anomalies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (© 2019 S. Karger AG, Basel.)

Objectives: To quantify the risk of preterm birth (PTB) for newborns with congenital heart defects (CHDs) conceived following infertility treatments, and to examine the role of multiple pregnancies in the association between infertility treatments and PTB for newborns with CHD., Methods: We used data from a population-based, prospective cohort study (EPICARD EPIdémiologie des CARDiopathies congénitales) including 2190 newborns with CHD and excluding cases with atrial septal defects born to women living in the Greater Paris area between May 2005 and April 2008. Statistical analysis included logistic regression to take into account potential confounders (maternal characteristics, invasive prenatal testing, CHD prenatal diagnosis, medically induced labour/caesarean section before labour, birth year). The role of multiple pregnancies was assessed using a path-analysis approach, allowing decomposition of the total effect of infertility treatments on the risk of PTB into its indirect (mediated by the association between infertility treatments and multiple pregnancies) and direct (mediated by mechanisms other than multiple pregnancies) effects., Results: PTB occurred for 40.6% (95% CI 28.7 to 52.5) of newborns with CHD conceived following infertility treatments vs 12.7% (95% CI 11.3 to 14.2) for spontaneously conceived newborns (p<0.001). After taking into account potentially confounding factors, infertility treatments were associated with a 5.0-fold higher odds of PTB (adjusted OR=5.0, 95% CI 2.9 to 8.6). Approximately two-thirds of this higher risk of PTB associated with infertility treatments was an indirect effect (ie, due to multiple pregnancies) and one-third was a direct effect (ie, not mediated by multiple pregnancies)., Conclusion: Newborns with CHD conceived following infertility treatments are at a particularly high risk of PTB, exposing over 40% of them to the 'double jeopardy' of CHD and PTB., Competing Interests: Competing interests: None declared.

Septo-optic nerve dysplasia is a rare congenital anomaly with optic nerve hypoplasia, pituitary hormone deficiencies and midline developmental defects of the brain. The clinical findings are visual impairment, hypopituitarism and developmental delays. The aim of this study was to report prevalence, associated anomalies, maternal age and other epidemiological factors from a large European population based network of congenital anomaly registries (EUROCAT). Data from 29 full member registries for the years 2005-2014 were included, covering 6.4 million births. There were 99 cases with a diagnosis of septo-optic dysplasia. The prevalence of septo-optic dysplasia in Europe was calculated to lie between 1.9 and 2.5 per 100,000 births after adjusting for potential under-reporting in some registries. The prevalence was highest in babies of mothers aged 20-24 years of age and was significantly higher in UK registries compared with other EUROCAT registries (P = 0.021 in the multilevel model) and the additional risk for younger mothers was significantly greater in the UK compared to the rest of Europe (P = 0.027). The majority of septo-optic dysplasia cases were classified as an isolated cerebral anomaly (N = 76, 77%). Forty percent of diagnoses occurred in fetuses with a prenatal diagnosis. The anomaly may not be visible at birth, which is reflected in that 57% of the postnatal diagnoses occurred over 1 month after birth. This is the first population based study to describe the prevalence of septo-optic dysplasia in Europe. Septo-optic dysplasia shares epidemiological patterns with gastroschisis and this strengthens the hypothesis of vascular disruption being an aetiological factor for septo-optic dysplasia., (Copyright © 2018. Published by Elsevier Masson SAS.)

Introduction: The prevalence of chronic hypertension is increasing in pregnant women. Beta-blockers are among the most prevalent anti-hypertensive agents used in early pregnancy., Objective: The objective of this study was to investigate whether first-trimester use of beta-blockers increases the risk of specific congenital anomalies in offspring., Methods: A population-based case-malformed control study was conducted in 117,122 registrations of congenital anomalies from 17 European Concerted Action on Congenital Anomalies and Twins (EUROCAT) registries participating in EUROmediCAT with data for all or part of the period between 1995 and 2013. Associations previously reported in the literature (signals) were tested and an exploratory analysis was performed to identify new signals. Odds ratios of exposure to any beta-blocker or to a beta-blocker subgroup were calculated for each signal anomaly compared with two control groups (non-chromosomal, non-signal anomalies and chromosomal anomalies). The exploratory analyses were performed for each non-signal anomaly compared with all the other non-signal anomalies., Results: The signals from the literature (congenital heart defects, oral clefts, neural tube defects and hypospadias) were not confirmed. Our exploratory analysis revealed that multi-cystic renal dysplasia had significantly increased odds of occurring after maternal exposure to combined alpha- and beta-blockers (adjusted odds ratio 3.8; 95% confidence interval 1.3-11.0)., Conclusion: Beta-blocker use in the first trimester of pregnancy was not found to be associated with a higher risk of specific congenital anomalies in the offspring, but a new signal between alpha- and beta-blockers and multi-cystic renal dysplasia was found. Future large epidemiological studies are needed to confirm or refute our findings.

Objectives: Glycol ethers (GE) are oxygenated solvents frequently found in occupational and consumer products. Some of them are well-known testicular and developmental animal toxicants. This study aims to evaluate the risk of male genital anomalies in association with prenatal exposure to GE using urinary biomarkers of exposure., Methods: We conducted a case-control study nested in two joint mother-child cohorts (5303 pregnant women). Cases of cryptorchidism and hypospadias were identified at birth and confirmed during a 2-year follow-up period (n=14 cryptorchidism and n=15 hypospadias). Each case was matched to three randomly selected controls within the cohorts for region of inclusion and gestational age at urine sampling. Concentrations of five GE acidic metabolites were measured in spot maternal urine samples collected during pregnancy. ORs were estimated with multivariate conditional logistic regressions including a Firth's penalisation., Results: Detection rates of urinary GE metabolites ranged from 8% to 93% and only two were sufficiently detected (>33%) in each cohort to be studied: methoxyacetic acid (MAA) and phenoxyacetic acid (PhAA). A significantly higher risk of hypospadias was associated with the highest tertile of exposure to MAA: OR (95% CI) 4.5(1.4 to 23.4). No association were observed with urinary concentration of PhAA, nor with the risk of cryptorchidism., Conclusions: In view of the toxicological plausibility of our results, this study, despite its small sample size, raises concern about the potential developmental toxicity of MAA on the male genital system and calls for thorough identification of current sources of exposure to MAA., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To characterise and compare cognitive outcomes in children with operated (open-heart surgery) and non-operated (catheter-based interventions only or no intervention) congenital heart defects (CHD) and to determine associated risk factors., Design: This prospective population-based study reports outcomes of 3-year-old children with CHD with or without open-heart surgery., Main Outcome Measures: Standardised cognitive scores (mean scores and proportions below normative values) were assessed with the Kaufman Assessment Battery for Children II. We analysed demographic, perinatal and operative variables as predictors of cognitive outcomes., Results: 419 children participated (154 with open-heart surgery; 265 without surgery). Global cognitive scores did not differ between the groups. Compared with the non-operated group, children who underwent surgery obtained lower scores in expressive language (p=0.03) and logical reasoning (p=0.05). When compared with test norms, the frequency of global cognitive scores >1 SDs below the expected mean was higher in the surgical group (25% vs 16% in the general population) (p=0.03). A higher-than-expected proportion of children in the non-operated group scored >2 SDs below the expected mean (7% vs 2%) (p=0.05). Being small for gestational age (SGA) significantly increased the risk of cognitive impairment in the surgical group, after adjustments for multiple covariates including maternal education, complexity of the CHD and operative-related variables (adjusted OR=5.9; 95% CI (1.7 to 20.1))., Conclusions: Despite mean scores within the normative range, a high proportion of preschool children with CHD with or without surgery are at early cognitive risk. SGA is a strong predictor of the neurodevelopmental prognosis in CHD., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: (1) Assess the population-level probability of prenatal diagnosis and termination of pregnancy for fetal anomaly for four major congenital heart defects; (2) Examine, using population-based data, the relation between timing of (prenatal vs postnatal) diagnosis and risk of infant (ie, < 1 year) mortality for four major congenital heart defects (CHDs)., Design: Population-based cohort (the EPIdémiologie des CARDiopathies congénitales) study., Setting: Greater Paris area (Paris and its surrounding suburbs)., Patients: Three hundred and fifty-four cases of four major CHDs, including functionally univentricular heart (FUH, N=132), d-transposition of great arteries (d-TGA, N=85), tetralogy of Fallot (TOF, N=60) and coarctation of aorta (CoA, N=77). Statistical analysis included the Mantel-Haenszel method and a test of homogeneity of risk ratios., Results: Approximately 95% of FUH, more than two-thirds of d-TGA and TOF, and 40% of CoA were prenatally diagnosed. Overall, we did not find any statistically significant association between timing of (prenatal vs postnatal) diagnosis of CHD and risk of infant mortality (Mantel-Haenszel risk ratio 1.1, 95% CI 0.5 - 2.7); and the differences between the risk ratios of the association between prenatal diagnosis and infant mortality across the four CHDs was not statistically significant., Conclusion: These results imply that at least in the settings where specialised services are readily available, survival may no longer be the most relevant outcome, or the best criterion, for evaluating the impact of prenatal diagnosis on the outcome of CHD. The beneficial effects of prenatal diagnosis may be better sought by looking at more 'subtle' or long-term neurodevelopmental outcomes., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Congenital heart defects (CHD) and preterm birth (PTB) are major causes of infant mortality. However, limited data exist on risk of mortality associated with PTB for newborns with CHD. Our objective was to assess impact of PTB on risk of infant mortality for newborns with CHD, while taking into account the role of associated anomalies and other potentially confounding factors., Methods: We used data on 2172 live births from a prospective population-based cohort study of CHD (the EPICARD Study) and compared neonatal, post-neonatal and overall infant mortality for infants born at <32, 32-34 and 35-36 weeks vs. those born at term (37-41 weeks)., Results: Preterm newborns had a 3.8-fold higher risk of infant death (17.9%) than term newborns (4.7%), RR 3.8, 95%CI 2.7-5.2; the risk associated with PTB was more than four-fold higher for neonatal (RR 4.3, 95% CI 2.9-6.6) and three-fold higher for post-neonatal deaths (RR 3.0, 95% CI 1.7-5.2). Survival analysis showed that newborns <35 weeks had a higher risk of mortality, which decreased but persisted after exclusion of associated anomalies and adjustment for potential confounders., Conclusions: Preterm birth is associated with an approximately four-fold higher risk of infant mortality for newborns with CHD. This excess risk appears to be mostly limited to newborns <35 weeks of gestation and is disproportionately due to early deaths.

Introduction: We have developed a new knowledge base intelligent system for obstetrics and gynecology ultrasound imaging, based on an ontology and a reference image collection. This study evaluates the new system to support accurate annotations of ultrasound images. We have used the early ultrasound diagnosis of ectopic pregnancies as a model clinical issue., Material and Methods: The ectopic pregnancy ontology was derived from medical texts (4260 ultrasound reports of ectopic pregnancy from a specialist center in the UK and 2795 Pubmed abstracts indexed with the MeSH term "Pregnancy, Ectopic") and the reference image collection was built on a selection from 106 publications. We conducted a retrospective analysis of the signs in 35 scans of ectopic pregnancy by six observers using the new system., Results: The resulting ectopic pregnancy ontology consisted of 1395 terms, and 80 images were collected for the reference collection. The observers used the knowledge base intelligent system to provide a total of 1486 sign annotations. The precision, recall and F-measure for the annotations were 0.83, 0.62 and 0.71, respectively. The global proportion of agreement was 40.35% 95% CI [38.64-42.05]., Discussion: The ontology-based intelligent system provides accurate annotations of ultrasound images and suggests that it may benefit non-expert operators. The precision rate is appropriate for accurate input of a computer-based clinical decision support and could be used to support medical imaging diagnosis of complex conditions in obstetrics and gynecology., (Copyright © 2017. Published by Elsevier Masson SAS.)

Objectives: The aim of this study was to describe the epidemiology of Ebstein's anomaly in Europe and its association with maternal health and medication exposure during pregnancy., Design: We carried out a descriptive epidemiological analysis of population-based data., Setting: We included data from 15 European Surveillance of Congenital Anomalies Congenital Anomaly Registries in 12 European countries, with a population of 5.6 million births during 1982-2011. Participants Cases included live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly. Main outcome measures We estimated total prevalence per 10,000 births. Odds ratios for exposure to maternal illnesses/medications in the first trimester of pregnancy were calculated by comparing Ebstein's anomaly cases with cardiac and non-cardiac malformed controls, excluding cases with genetic syndromes and adjusting for time period and country., Results: In total, 264 Ebstein's anomaly cases were recorded; 81% were live births, 2% of which were diagnosed after the 1st year of life; 54% of cases with Ebstein's anomaly or a co-existing congenital anomaly were prenatally diagnosed. Total prevalence rose over time from 0.29 (95% confidence interval (CI) 0.20-0.41) to 0.48 (95% CI 0.40-0.57) (p<0.01). In all, nine cases were exposed to maternal mental health conditions/medications (adjusted odds ratio (adjOR) 2.64, 95% CI 1.33-5.21) compared with cardiac controls. Cases were more likely to be exposed to maternal β-thalassemia (adjOR 10.5, 95% CI 3.13-35.3, n=3) and haemorrhage in early pregnancy (adjOR 1.77, 95% CI 0.93-3.38, n=11) compared with cardiac controls., Conclusions: The increasing prevalence of Ebstein's anomaly may be related to better and earlier diagnosis. Our data suggest that Ebstein's anomaly is associated with maternal mental health problems generally rather than lithium or benzodiazepines specifically; therefore, changing or stopping medications may not be preventative. We found new associations requiring confirmation.

Background: Ectopic pregnancy is a frequent early complication of pregnancy associated with significant rates of morbidly and mortality. The positive diagnosis of this condition is established through transvaginal ultrasound scanning. The timing of diagnosis depends on the operator expertise in identifying the signs of ectopic pregnancy, which varies dramatically among medical staff with heterogeneous training. Developing decision support systems in this context is expected to improve the identification of these signs and subsequently improve the quality of care. In this article, we present a new knowledge base for ectopic pregnancy, and we demonstrate its use on the annotation of clinical images., Results: The knowledge base is supported by an application ontology, which provides the taxonomy, the vocabulary and definitions for 24 types and 81 signs of ectopic pregnancy, 484 anatomical structures and 32 technical elements for image acquisition. The knowledge base provides a sign-centric model of the domain, with the relations of signs to ectopic pregnancy types, anatomical structures and the technical elements. The evaluation of the ontology and knowledge base demonstrated a positive feedback from a panel of 17 medical users. Leveraging these semantic resources, we developed an application for the annotation of ultrasound images. Using this application, 6 operators achieved a precision of 0.83 for the identification of signs in 208 ultrasound images corresponding to 35 clinical cases of ectopic pregnancy., Conclusions: We developed a new ectopic pregnancy knowledge base for the annotation of ultrasound images. The use of this knowledge base for the annotation of ultrasound images of ectopic pregnancy showed promising results from the perspective of clinical decision support system development. Other gynecological disorders and fetal anomalies may benefit from our approach.

Methods for analysing dental caries and associated risk indicators have evolved considerably in recent decades. The use of zero-inflated or hurdle models is increasing so as to take account of the decayed, missing, and filled teeth (DMFT) distribution, which is positively skewed and has a high proportion of zero scores. However, there is a need to develop new statistical models that involve pragmatic biological considerations on dental caries in epidemiological surveys. In this paper, we show that the zero-inflated and the hurdle models can both be expressed as a compound sum. Using the same compound sum, we then present the generalized negative binomial (GNB) distribution for dental caries count data, and provide a numerical application using the data of the EPIPAP study. The GNB model generates the best score functions while handling the lifetime dental caries disease process better. In conclusion, the GNB model suits the nature of some count data, in particular when structural zeros are unlikely to occur and when several latent spells can lead to new countable events. For these reasons, the use of the GNB distribution appears to be relevant for the modelling of dental caries count data., (© 2016 S. Karger AG, Basel.)