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Background Objectives Methods Results Conclusions Globally, 240,000 babies die in the neonatal period annually due to congenital anomalies (CA). Malta reports the highest neonatal mortality rate (NMR) among EU (European Union) Countries, constituting a public health concern.This study describes the contribution of CA to NMR in Malta, investigating possible associations with known maternal risk factors of maternal age, nationality, and education. Additionally, it provides an update on the contribution of CA to neonatal deaths in Malta and other EU countries.Anonymous data for births and neonatal deaths were obtained for 2006–2020 from the National Obstetrics Information System (NOIS) in Malta. Regression analyses adjusting for maternal risk factors were run on this data to explore possible associations with NMR. NMRs published by EUROSTAT 2011–2020 were used to compare mortality by underlying cause of death (CA or non‐CA causes) for Malta and other EU countries.Between 2006 and 2020, 63,890 live births with 283 neonatal deaths were registered in Malta, (NMR 4.4 per 1000 live births). CA accounted for 39.6% of neonatal deaths. No time trends were observed in either total NMR, NMR attributed to CA or mortality due to non‐CA causes. Adjusted variables revealed associations for women hailing from non‐EU, low‐income countries. Malta registered high NMRs compared to EU countries, most marked for deaths attributed to CA.Between 2006 and 2020, Malta's NMR remained stable. Maternal Nationality, from non‐EU low‐income countries, was associated with higher neonatal mortality. The influx of such migrants may play a partial role in the high NMRs experienced. Malta's high NMR was primarily driven by early neonatal deaths, which included high proportions of deaths due to CA and is linked to the fact that termination of pregnancy is illegal in Malta. [ABSTRACT FROM AUTHOR]

Objective: To analyse the accuracy of antenatal ultrasound screening in Malta, comparing detection rates within the private and public sectors, and with the rest of Europe. To assess local trends in accuracy for each organ system. Material and methods: Ethics approval was obtained to gather routinely collected data from the national congenital anomalies registry between 2016 and 2018. This was analysed to determine local antenatal ultrasound accuracy rates and trends. Electronic medical appointment record data was also used to indirectly determine whether a significant difference existed in the detection of antenatal anomalies in mothers scanned privately and those scanned within the public sector. χ²-for-trend was used to analyse changes in the accuracy rates. European Surveillance of Congenital Anomalies (EUROCAT) data was used to compare scanning accuracy in Malta and other EUROCAT centres. Results: The local rate of undetected congenital anomalies was 62.0% for public scans and 83.9% for private scans. Local trends over the three-year period showed an improvement in accuracy rates in detecting isolated syndromes (p=0.05), anomalies of the renal system (p=0.02) and craniofacial anomalies (p=0.05). Malta's overall performance was similar to other EUROCAT centres. Conclusion: Scans carried out within the public sector are more accurate than private scans, and Malta's overall performance was similar to other EUROCAT centres. [ABSTRACT FROM AUTHOR]

Folate is essential for normal cell division and as intrauterine fetal growth involves a process of rapidly dividing cells, there is a consequent increased requirement for folate at this time. Folate, and the synthetic form folic acid, is thus vital for the early development process of a healthy fetus and there is indisputable evidence that it can significantly reduce the risk of neural tube defects (NTDs). Further ongoing research suggests that folic acid supplementation in pregnancy is also associated with a decreased risk of other birth defects. This review gives an overview of the current literature related to the use of folic acid in the peri-conceptional period and prevention of birth defects, in particular NTDs. [ABSTRACT FROM AUTHOR]

Background Neonatal mortality is a public health concern, and congenital anomalies contribute significantly to this mortality. This paper describes trends in neonatal mortality in Malta separately for congenital anomaly and non-congenital anomaly causes. Methods Data for neonatal deaths of 22-week gestation onwards registered between 1994-2013 were obtained from the National Mortality Register. Chi-square tests were used to analyse 5-year time trends and differences in proportions of causes of neonatal deaths. Neonatal mortality was compared with other European countries. Results Between 1994 and 2013, 441 neonatal deaths and 84 821 livebirths were registered, giving a neonatal mortality of 5.2 per 1000 livebirths. Congenital anomalies accounted for 36.7% ( n = 162) of the neonatal deaths, while the remaining 63.3% ( n = 279) were attributed to non-congenital causes. During the 20-year period, neonatal mortality due to non-congenital causes decreased from 4.6 per 1000 livebirths in 1994-98 to 2.5 per 1000 in 2009-13, while that due to congenital anomalies remained stable (2.0 per 1000 livebirths in 1994-98 and 2.2 per 1000 in 2009-13). This has resulted in comparatively higher proportions of neonatal deaths attributed to congenital anomalies in recent years (45.9% in 2009-13 vs. 29.9% in 1994-98). Comparing neonatal mortality reported from European countries, Malta has a high rate most marked for deaths due to congenital anomalies. Conclusions During 1994-2013, neonatal mortality has decreased due to a decline of non-congenital causes of death, possibly related to improved health care. The proportionate neonatal mortality attributed to congenital anomalies has increased and is the highest reported from Europe. This may be explained by the fact that termination of pregnancy is illegal in Malta. [ABSTRACT FROM AUTHOR]

Aim: This study reviews the clinical workload in paediatrics in Malta over a 16-year period. Methods: National statistics for live birth rates were obtained from the Directorate of Health Information and Research. Data for paediatric (birth to 14 completed years) and neonatal admissions, day cases, outpatient visits, attendance at Paediatric Accident and Emergency and the Community-based Developmental Unit were obtained from the Annual Reports, Department of Paediatrics, for the period 1996-2011. Results: During the study period, live births fell by 11% from 4,349 in 1996 to 3,857 in 2005, and recovered to 4,283 in 2011. Whereas neonatal admissions to NPICU remained constant at around 340(±22) per annum, inpatient admissions to the general Paediatric wards decreased by 19% (from 3,151 to 2,550), and casualty reviews dropped by 35% (11,831 to 7,773). In contrast, day care reviews increased by 66% (1,347 to 3,928), the total outpatient workload increased by 70% (13,500 to 22,998), and cases reviewed in the Community-based Child Developmental Unit increased by 184% from 413 to 1174. Changes observed in the clinical activity in Gozo General Hospital were similar but less marked. Conclusion: Over a 16 year period, there has been a significant shift in the paediatric workload in Malta from an in-patient bias in 1996 to increased day care and outpatient reviews in 2011. This shift is largely the result of improved hospital and community day health care services, and can be increased further with augmented community care. Health resources and future paediatric health care programmes will need to take heed of these trends. [ABSTRACT FROM AUTHOR]

Unlabelled: Diabetes mellitus is generally associated with a higher incidence of early pregnancy loss and congenital anomalies, though this relationship should be strictly restricted to patients with previously existing diabetes. In gestational diabetes mellitus, which often develops during the third trimester, no such relationship should exist, though the birth of a previous infant with a congenital anomaly is often assumed to be a risk factor for gestational diabetes.Objective: The study attempts to analyse the congenital anomaly rate in women with gestational diabetes and compare this to the rates in women known to have normal glucose tolerance.Results: The prevalence of infants/fetuses with congenital anomalies born to women with gestational diabetes amounted to 4.48%, a rate similar to that recorded in women with normal glucose tolerance (4.54%).Conclusions: The development of gestational diabetes, in contrast to pre-existing diabetes, does not appear to be associated with an increased risk for teratogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Assisted reproductive technology (ART) is increasingly used to overcome growing rates of infertility and subfertility. Perinatal and maternal morbidity and mortality are elevated in ART conceptions even in vaginally delivered singletons. Malta is a small archipelago with comprehensive national data. This study was carried out in order to investigate ART rates in Maltese deliveries for 2000-2019 inclusive.Methods: Anonymous data was obtained from the Malta National Obstetric Information System (NOIS). For this study all ART methods were aggregated into one group. Deliveries refer to single pregnancies. A p value ≤0.05 was taken to represent statistically significance.Results: This study analysed 82,356 deliveries over the period with overall 2% ART. There was a significant rising trend in all deliveries (ART plus non-ART) with time (p = 0.012). Of these, 1262 were twin deliveries (18% ART) and 56 were triplet deliveries (66% ART). Multiple deliveries (ART plus non-ART) also rose significantly (p = 0. 00035). The proportion of ART deliveries rose significantly overall and individually, for singletons (3.4-4.6%) since 2018, and over a quarter of such deliveries since 2013 for twin and further multiples.Discussion: The Maltese rate of twins and triplets plateaued before reaching the peaks experienced by other countries and it may be that more infertile couples were and are only having one embryo transferred. In smaller countries with only one neonatal unit, ART services should strive to produce a smooth throughput so as to minimize surges and strains on downstream neonatal services which may have deleterious effects on outcomes, especially neonatal. [ABSTRACT FROM AUTHOR]

Background Despite concerns about worsening pregnancy outcomes resulting from healthcare restrictions, economic difficulties and increased stress during the COVID-19 pandemic, preterm birth (PTB) rates declined in some countries in 2020, while stillbirth rates appeared stable. Like other shocks, the pandemic may have exacerbated existing socioeconomic disparities in pregnancy, but this remains to be established. Our objective was to investigate changes in PTB and stillbirth by socioeconomic status (SES) in European countries. Methods The Euro-Peristat network implemented this study within the Population Health Information Research Infrastructure (PHIRI) project. A common data model was developed to collect aggregated tables from routine birth data for 2015–2020. SES was based on mother's educational level or area-level deprivation/maternal occupation if education was unavailable and harmonized into low, medium and high SES. Country-specific relative risks (RRs) of PTB and stillbirth for March to December 2020, adjusted for linear trends from 2015 to 2019, by SES group were pooled using random effects meta-analysis. Results Twenty-one countries provided data on perinatal outcomes by SES. PTB declined by an average 4% in 2020 {pooled RR: 0.96 [95% confidence intervals (CIs): 0.94–0.97]} with similar estimates across all SES groups. Stillbirths rose by 5% [RR: 1.05 (95% CI: 0.99–1.10)], with increases of between 3 and 6% across the three SES groups, with overlapping confidence limits. Conclusions PTB decreases were similar regardless of SES group, while stillbirth rates rose without marked differences between groups. [ABSTRACT FROM AUTHOR]

Background: Preterm birth and young maternal age are known risk factors for infant and childhood mortality. There is limited knowledge of the impact of these risk factors in children born with major congenital anomalies (CAs), who have inherently higher risks of death compared with other children. Objectives: To investigate the risk factors for mortality up to age 10 years in children born with specific major CAs. Methods: This population-based cohort study involved 150,198 livebirths from 1995 to 2014 in 13 European CA registries linked to mortality data. Cox proportional hazards models estimated the association of gestational age, maternal age and child's sex with death <1 year and 1-9 years for the whole cohort and by CA subgroup. Hazard ratios (HR) from each registry were pooled using multivariate meta-analysis. Results: Preterm birth had a dose-response association with mortality; compared with infants born at 37+ weeks gestation, those born at <28, 28-31 and 32-36 weeks had 14.88 (95% CI 12.57, 17.62), 8.39 (95% CI 7.16, 9.85) and 3.88 (95% CI 3.40, 4.43) times higher risk of death <1 year, respectively. The corresponding risks at 1-9 years were 4.99 (95% CI 2.94, 8.48), 3.09 (95% CI 2.28, 4.18) and 2.04 (95% CI 1.69, 2.46) times higher, respectively. Maternal age <20 years (versus 20-34 years) was a risk factor for death <1 year (HR 1.30, 95% CI 1.09, 1.54) and 1-9 years (HR 1.58, 95% CI 1.19, 2.10). Females had 1.22 (95% CI 1.07, 1.39) times higher risk of death between 1 and 9 years than males. Conclusion: Preterm birth was associated with considerably higher infant and childhood mortality in children with CAs, comparable to estimates reported elsewhere for the background population. Additional risk factors included young maternal age and female sex. Information on risk factors could benefit clinical care and guide counselling of parents following CA diagnoses. [ABSTRACT FROM AUTHOR]

Introduction: The trend towards delayed motherhood has accelerated in developed countries over the last few decades. Advanced maternal age (AMA) is defined as age 35 years and older at the estimated date of delivery. Objective: The aim of this large retrospective cohort study is to assess for the association between AMA and adverse maternal outcomes after adjustment for confounding factors in maternal characteristics and in the obstetric history. Study Design: Mothers of 20 years and older, who delivered singleton babies in Malta and Gozo between 1st January 2000 and 31st December 2014 were studied. All data was derived from the National Obstetric Information System. Results: The study population included 55,943 singleton births. 12.2% (6,838) of mothers were between 35 - 39 years and 2.4% (1,325) were 40 years and older. Significant difference was found between maternal age and BMI (p<0.0001), maternal smoking status (p<0.0001), noninsulin dependent diabetes mellitus (p=0.004), history of stillbirth (p<0.0001), gestational diabetes (p<0.0001), pregnancy - induced - hypertension (p=0.008) and preeclampsia (p=0.008). Significant difference was also found between maternal age and mode of delivery (p<0.0001). Regression analysis revealed persistent significant differences between maternal age and different maternal outcomes. Conclusion: This study demonstrates that AMA in Malta significantly increases the risk for hypertension in pregnancy, gestational diabetes and caesarean delivery. Care providers need to be aware of these increased risks and adjust their obstetric management according to the individual to ensure optimal maternal outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Males are usually born in excess of females and the ratio of male births to female births is conventionally referred to as M/F. Many factors, including stress, privation and natural disasters are associated with a lowering of M/F. Malta has a North-South divide, with a more affluent North as opposed to a more industrialised and less prosperous South. This study was carried out in order to ascertain whether regional economic differences influenced M/F in Malta. Methods: Births by gender, year of birth and locality from 1999 to 2013 were subdivided into ten regions in a geographic distribution devised by the Department of Health Information and Research. Regions were also amalgamated into two groups of five which represented North-West and South-East Malta. The island of Gozo was considered separately. Results: There were no statistically significant differences in M/F between the ten regions nor between North-West, South-East and Gozo regions. There were no significant secular trends in M/F in these regions. Discussion: M/F declines under adverse environmental factors (including economic stress) but despite the overall poorer economic circumstances in the South of the Island, this study failed to show a significant difference in M/F by region. This may be due at least in part to the relatively small numbers involved. Alternatively, the purported socio-economic differences may not have been sufficiently large so as to skew M/F to statistically significant levels. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

African women delivering in the Maltese Islands are either regular or irregular migrants. The latter group presents significant socio-economic problems. Objective: This study sets out to compare the obstetric outcomes of African-nationals delivering in Malta to the general population. Study design: The obstetric data of three subgroups of women – those from the Maghreb region; the sub-Saharan and Horn of Africa; and the overall population registered for the Maltese Islands were obtained using the computerised National Obstetrics Information System. Results: Women from the sub-Saharan regions were statistically younger than those from the Maghreb region or the general population. African women from both regions were more likely to be multiparous; and were more likely to have experienced a previous perinatal loss. The multiple pregnancy rates were significantly higher in both African groups. Women from the sub-Saharan region were more likely to suffer from sexual and blood-borne infections. African women had lower obstetric intervention rates but higher operative deliveries. Infants born to African women were more likely to be premature and of low birth weight. Conclusion: Women originating from the African continent particularly from the sub-Saharan regions present socio-biological and cultural differences which can contribute towards adverse obstetric and perinatal outcomes. [ABSTRACT FROM AUTHOR]

Objective: To compare the prospective risk of stillbirth between women with and without a stillbirth in their first pregnancy.Methods: We conducted a cohort study using perinatal data from Finland, Malta, and Scotland. Women who had at least two singleton deliveries were included. The exposed and unexposed cohorts comprised women with a stillbirth and live birth in their first pregnancy, respectively. The risk of stillbirth in any subsequent pregnancy was assessed using a Cox proportional hazards model. Time-to-event analyses were conducted to investigate whether first pregnancy outcome had an effect on time to or the number of pregnancies preceding subsequent stillbirth.Results: The pooled data set included 1,064,564 women, 6,288 (0.59%) with a stillbirth and 1,058,276 with a live birth in a first pregnancy. Compared with women with a live birth, women with a stillbirth in the first pregnancy were more likely to have a subsequent stillbirth (adjusted hazard ratio [aHR] 2.25, 95% CI 1.86-2.72). For women with more than two pregnancies, the difference in risk of subsequent stillbirth between the two groups increased with the number of subsequent pregnancies. Maternal age younger than 25 years or 40 years and older, smoking, low socioeconomic status, not having a partner, pre-existing diabetes, preeclampsia, placental abruption, or delivery of a growth-restricted neonate in a first pregnancy were independently associated with subsequent stillbirth. Compared with women with a live birth in the first pregnancy, women with a stillbirth were more likely to have another pregnancy within 1 year. The absolute risk of stillbirth in a subsequent pregnancy for women with stillbirth and live birth in a first pregnancy were 2.5% and 0.5%, respectively.Conclusion: Compared with women with a live birth in a first pregnancy, women with a stillbirth have a higher risk of subsequent stillbirth irrespective of the number and sequence of the pregnancies. Despite high relative risk, the absolute risk of recurrence was low. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In Malta, the health system is hybrid, with similarities to both UK system and the US system, where the National Health Service is supplemented by private practice. This is widely performed either as a primary job or as a supplement to a government salary. This article reviews unfavourable secular trends in Maltese fertility, births, marriages, separations, single parenthood and loans incurred after marriage, and relates them to (equally unfavourable in terms of private practice) escalating numbers of paediatricians working in private practice. Overall, future prospects appear bleak for private practice in this branch of medicine, with a dwindling patient pool being shared by an ever-increasing number of paediatricians. The only identifiable factor that may mitigate is the potential for more private health insurance uptake. This must be coupled with a movement to improve the perception of a substantial proportion of the public that facilities are poorer in the private health sector than in the NHS service. Since Malta is a developed, EU country, these results may (cautiously) be extrapolated to other, larger developed countries. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of changes in risk factors between the first two pregnancies on the occurrence of placental abruption (PA) in the same woman. Methods: Routinely collected obstetric data from Aberdeen Maternity and Neonatal Databank, the Maltese National Obstetric Information System and the Finnish Medical Birth Register were aggregated. Records of the first two singleton pregnancies from women who had PA in one pregnancy but not the other, were identified from this pooled dataset. A case-crossover study design was used; cases were pregnancies with abruption and matched controls were pregnancies without abruption in the same woman. Conditional logistic regression was used to investigate changes in risk factors for placental abruption in pregnancies with and without abruption. Results: A total of 2,991 women were included in the study. Of these 1,506 (50.4%) had PA in their first pregnancy and 1,485 (49.6%) in a second pregnancy. Pregnancies complicated by preeclampsia {194 (6.5%) versus 115 (3.8%) adj OR 1.69; (95% CI 1.23–2.33)}, antepartum haemorrhage of unknown origin {556 (18.6%) versus 69 (2.3%) adjOR 27.05; 95% CI 16.61–44.03)} and placenta praevia {80 (2.7%) versus 21 (0.7%) (adjOR 3.05; 95% CI 1.74–5.36)} were associated with PA. Compared to 20 to 25 years, maternal age of 35–39 years {365 (12.2) versus 323 (10.8) (adjOR 1.32; 95% CI 1.01–1.73) and single marital status (adjOR 1.36; 95% CI 1.04–1.76) were independently associated with PA. Maternal smoking, BMI and fetal gender were not associated with PA. Conclusion: Advanced maternal age, pregnancies complicated with unexplained bleeding in pregnancy, placenta praevia and preeclampsia were independently associated with a higher risk of placental abruption. [ABSTRACT FROM AUTHOR]

Background: Variations in intervention rates, without subsequent reductions in adverse outcomes, can indicate overuse. We studied variations in and associations between commonly used childbirth interventions and adverse outcomes, adjusted for population characteristics. Methods and findings: In this multinational cross-sectional study, existing data on 4,729,307 singleton births at ≥37 weeks in 2013 from Finland, Sweden, Norway, Denmark, Iceland, Ireland, England, the Netherlands, Belgium, Germany (Hesse), Malta, the United States, and Chile were used to describe variations in childbirth interventions and outcomes. Numbers of births ranged from 3,987 for Iceland to 3,500,397 for the USA. Crude data were analysed in the Netherlands, or analysed data were shared with the principal investigator. Strict variable definitions were used and information on data quality was collected. Intervention rates were described for each country and stratified by parity. Uni- and multivariable analyses were performed, adjusted for population characteristics, and associations between rates of interventions, population characteristics, and outcomes were assessed using Spearman's rank correlation coefficients. Considerable intercountry variations were found for all interventions, despite adjustments for population characteristics. Adjustments for ethnicity and body mass index changed odds ratios for augmentation of labour and episiotomy. Largest variations were found for augmentation of labour, pain relief, episiotomy, instrumental birth, and cesarean section (CS). Percentages of births at ≥42 weeks varied from 0.1% to 6.7%. Rates among nulliparous versus multiparous women varied from 56% to 80% versus 51% to 82% for spontaneous onset of labour; 14% to 36% versus 8% to 28% for induction of labour; 3% to 13% versus 7% to 26% for prelabour CS; 16% to 48% versus 12% to 50% for overall CS; 22% to 71% versus 7% to 38% for augmentation of labour; 50% to 93% versus 25% to 86% for any intrapartum pain relief, 19% to 83% versus 10% to 64% for epidural anaesthesia; 6% to 68% versus 2% to 30% for episiotomy in vaginal births; 3% to 30% versus 1% to 7% for instrumental vaginal births; and 42% to 70% versus 50% to 84% for spontaneous vaginal births. Countries with higher rates of births at ≥42 weeks had higher rates of births with a spontaneous onset (rho = 0.82 for nulliparous/rho = 0.83 for multiparous women) and instrumental (rho = 0.67) and spontaneous (rho = 0.66) vaginal births among multiparous women and lower rates of induction of labour (rho = −0.71/−0.66), prelabour CS (rho = −0.61/−0.65), overall CS (rho = −0.61/−0.67), and episiotomy (multiparous: rho = −0.67). Variation in CS rates was mainly due to prelabour CS (rho = 0.96). Countries with higher rates of births with a spontaneous onset had lower rates of emergency CS (nulliparous: rho = −0.62) and higher rates of spontaneous vaginal births (multiparous: rho = 0.70). Prelabour and emergency CS were positively correlated (nulliparous: rho = 0.74). Higher rates of obstetric anal sphincter injury following vaginal birth were found in countries with higher rates of spontaneous birth (nulliparous: rho = 0.65). In countries with higher rates of epidural anaesthesia (nulliparous) and spontaneous births (multiparous), higher rates of Apgar score < 7 were found (rhos = 0.64). No statistically significant variation was found for perinatal mortality. Main limitations were varying quality of data and missing information. Conclusions: Considerable intercountry variations were found for all interventions, even after adjusting for population characteristics, indicating overuse of interventions in some countries. Multivariable analyses are essential when comparing intercountry rates. Implementation of evidence-based guidelines is crucial in optimising intervention use and improving quality of maternity care worldwide. Anna Seijmonsbergen-Schermers and co-authors report on use of childbirth interventions and associated outcomes in high-income countries. Author summary: Why was this study done?: Interventions during childbirth are important to prevent adverse outcomes in mothers and children. However, large variations in childbirth interventions are indicators of over- or underuse. Variations in childbirth interventions rates have been studied before, but these studies did not account for differences in population characteristics, such as maternal age and body mass index. We conducted this study, including data of 13 countries, to describe variations adjusted for population characteristics; to examine correlations between interventions and between interventions and adverse outcomes; and to describe the quality of data. What did the researchers do and find?: We included data from 4,729,307 singleton births at ≥37 weeks in 13 countries in 2013. We found large variations in the use of childbirth interventions between these countries, without a significant difference in perinatal mortality rates. Largest variations were found for augmentation of labour, pain relief, episiotomy, instrumental vaginal birth, and cesarean section. Variations remained after adjustments for differences in population characteristics. We found several correlations between interventions and a few correlations between interventions and adverse outcomes. For instance, countries with higher rates of prelabour cesarean section had also higher rates of emergency cesarean section. Quality of data, methods of data collection, and definition of variables varied across countries. What do these findings mean?: The findings suggest that some childbirth interventions are frequently overused in many countries. Quality of maternity care needs to be improved, for instance, through implementation of international guidelines. Adjusting for population characteristics is important in order to make valid comparisons between countries. The findings on quality of the data warrant improvement of data quality, including uniformly recorded country-level data being freely available for research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hypospadias is a common male birth defect that has shown widespread variation in reported prevalence estimates. Many countries have reported increasing trends over recent decades. To analyze the prevalence and trends of hypospadias for 27 international programs over a 31-yr period. The study population included live births, stillbirths, and elective terminations of pregnancy diagnosed with hypospadias during 1980–2010 from 27 surveillance programs around the world. We used joinpoint regression to analyze changes over time in international total prevalence of hypospadias across programs, prevalence for each specific program, and prevalence across different degrees of severity of hypospadias. The international total prevalence of hypospadias for all years was 20.9 (95% confidence interval: 19.2–22.6) per 10 000 births. The prevalence for each program ranged from 2.1 to 39.1 per 10 000 births. The international total prevalence increased 1.6 times during the study period, by 0.25 cases per 10 000 births per year (p < 0.05). When analyzed separately, there were increasing trends for first-, second-, and third-degree hypospadias during the early 1990s to mid-2000s. The majority of programs (61.9%) had a significantly increasing trend during many of the years evaluated. Limitations include known differences in data collection methods across programs. Although there have been changes in clinical practice and registry ascertainment over time in some countries, the consistency in the observed increasing trends across many programs and by degrees of severity suggests that the total prevalence of hypospadias may be increasing in many countries. This observation is contrary to some previous reports that suggested that the total prevalence of hypospadias was no longer increasing in recent decades. We report on the prevalence and trends of hypospadias among 27 birth defect surveillance systems, which indicate that the prevalence of hypospadias continues to increase internationally. We report on prevalence and trends of hypospadias among 27 birth defect surveillance systems (1980–2010), which indicate that the prevalence of hypospadias continues to increase internationally. [ABSTRACT FROM AUTHOR]

Abstract Women with epilepsy need to continue to take anticonvulsants during their pregnancies to prevent seizures from occurring. Since the 1980's, it has been known that the use of valproate (an anticonvulsant) in the first trimester of pregnancy is associated with an increased risk of spina bifida. Recent studies have also demonstrated increased risks of other congenital anomalies as well as a risk of cognitive impairment. Doctors in the EU are now advised not to prescribe valproate in pregnant women, in women who can become pregnant or in girls unless other treatments are ineffective or not tolerated. This study aimed to determine if there has been a reduction in the numbers of babies born with valproate syndrome in Europe from 2005 to 2014. Data from 15 European congenital anomaly registries, who are members of EUROCAT (A European network of population-based registries for the epidemiologic surveillance of congenital anomalies), identified 28 cases of valproate syndrome in 2.74 million births from 2005 to 2014. The prevalence of valproate syndrome in Europe significantly decreased from 0.22 per 10,000 births in 2005/6 to 0.03 per 10,000 births in 2013/14. One registry, Ile de la Reunion, had the majority of cases (17). After excluding these cases there still remained a decreasing trend even though it no longer reached statistical significance due to the small number of cases. This study emphasises the continued need for European collaboration in analysing rare exposures and rare anomalies. [ABSTRACT FROM AUTHOR]

Abstract 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. [ABSTRACT FROM AUTHOR]

Background: Surveillance of congenital anomalies is important to identify potential teratogens. Methods: This study analysed the prevalence of 61 congenital anomaly subgroups (excluding chromosomal) in 25 population-based EUROCAT registries (1980–2012). Live births, fetal deaths and terminations of pregnancy for fetal anomaly were analysed with multilevel random-effects Poisson regression models. Results: Seventeen anomaly subgroups had statistically significant trends from 2003–2012; 12 increasing and 5 decreasing. Conclusions: The annual increasing prevalence of severe congenital heart defects, single ventricle, atrioventricular septal defects and tetralogy of Fallot of 1.4% (95% CI: 0.7% to 2.0%), 4.6% (1.0% to 8.2%), 3.4% (1.3% to 5.5%) and 4.1% (2.4% to 5.7%) respectively may reflect increases in maternal obesity and diabetes (known risk factors). The increased prevalence of cystic adenomatous malformation of the lung [6.5% (3.5% to 9.4%)] and decreased prevalence of limb reduction defects [-2.8% (-4.2% to -1.5%)] are unexplained. For renal dysplasia and maternal infections, increasing trends may be explained by increased screening, and deceases in patent ductus arteriosus at term and increases in craniosynostosis, by improved follow up period after birth and improved diagnosis. For oesophageal atresia, duodenal atresia/stenosis and ano-rectal atresia/stenosis recent changes in prevalence appeared incidental when compared with larger long term fluctuations. For microcephaly and congenital hydronephrosis trends could not be interpreted due to discrepancies in diagnostic criteria. The trends for club foot and syndactyly disappeared once registries with disparate results were excluded. No decrease in neural tube defects was detected, despite efforts at prevention through folic acid supplementation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation. Methods Data from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity. Results Thirteen out of 27 CA-medication exposure signals, based on 389 exposed cases, passed data validation. There was some prior evidence in the literature to support six signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99-14.20/OR 28.20, 95% CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining six signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists. Conclusion Signals which strengthened prior evidence should be prioritized for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible. [ABSTRACT FROM AUTHOR]

Aims Information about medication safety in pregnancy is inadequate. We aimed to develop a signal detection methodology to routinely identify unusual associations between medications and congenital anomalies using data collected by 15 European congenital anomaly registries. Methods EUROmediCAT database data for 14 950 malformed foetuses/babies with first trimester medication exposures in 1995-2011 were analyzed. The odds of a specific medication exposure (coded according to chemical substance or subgroup) for a specific anomaly were compared with the odds of that exposure for all other anomalies for 40 385 medication anomaly combinations in the data. Simes multiple testing procedure with a 50% false discovery rate (FDR) identified associations least likely to be due to chance and those associations with more than two cases with the exposure and the anomaly were selected for further investigation. The methodology was evaluated by considering the detection of well-known teratogens. Results The most common exposures were genitourinary system medications and sex hormones (35.2%), nervous system medications (28.0%) and anti-infectives for systemic use (25.7%). Fifty-two specific medication anomaly associations were identified. After discarding 10 overlapping and three protective associations, 39 associations were selected for further investigation. These associations included 16 which concerned well established teratogens, valproic acid (2) and maternal diabetes represented by use of insulin (14). Conclusions Medication exposure data in the EUROmediCAT central database can be analyzed systematically to determine a manageable set of associations for validation and then testing in independent datasets. Detection of teratogens depends on frequency of exposure, level of risk and teratogenic specificity. [ABSTRACT FROM AUTHOR]

Background: Hypospadias is a common congenital malformation. The prevalence of hypospadias has a large geographical variation, and recent studies have reported both increasing and decreasing temporal trends. It is unclear whether hypospadias prevalence is associated with maternal age. Aim: To analyze the prevalence and trends of total hypospadias, isolated hypospadias, hypospadias with multiple congenital anomalies, hypospadias with a known cause, and hypospadias severity subtypes in Europe over a 10-year period and to investigate whether maternal age is associated with hypospadias. Methods: We included all children with hypospadias born from 2001 to 2010 who were registered in 23 EUROCAT registries. Information on the total number of births and maternal age distribution for the registry population was also provided. We analyzed the total prevalence of hypospadias and relative risks by maternal age. Results: From 2001 to 2010, 10,929 hypospadias cases were registered in 5,871,855 births, yielding a total prevalence of 18.61 per 10,000 births. Prevalence varied considerably between different registries, probably due to differences in ascertainment of hypospadias cases. No significant temporal trends were observed with the exceptions of an increasing trend for anterior and posterior hypospadias and a decreasing trend for unspecified hypospadias. After adjusting for registry effects, maternal age was not significantly associated with hypospadias. Conclusions: Total hypospadias prevalence was stable in 23 EUROCAT registries from 2001 to 2010 and was not significantly influenced by maternal age. [ABSTRACT FROM AUTHOR]

Introduction Published prevalence rates of congenital diaphragmatic hernia (CDH) vary. This study aims to describe the epidemiology of CDH using data from highquality, population-based registers belonging to the European Surveillance of Congenital Anomalies (EUROCAT). Methods Cases of CDH delivered between 1980 and 2009 notified to 31 EUROCAT registers formed the population-based case series. Prevalence over time was estimated using multilevel Poisson regression, and heterogeneity between registers was evaluated from the random component of the intercept. Results There were 3373 CDH cases reported among 12 155 491 registered births. Of 3131 singleton cases, 353 (10.4%) were associated with a chromosomal anomaly, genetic syndrome or microdeletion, 784 (28.2%) were associated with other major structural anomalies. The male to female ratio of CDH cases overall was 1:0.69. Total prevalence was 2.3 (95% CI 2.2 to 2.4) per 10 000 births and 1.6 (95% CI 1.6 to 1.7) for isolated CDH cases. There was a small but significant increase (relative risk (per year)= 1.01, 95% credible interval 1.00-1.01; p=0.030) in the prevalence of total CDH over time but there was no significant increase for isolated cases (ie, CDH cases that did not occur with any other congenital anomaly). There was significant variation in total and isolated CDH prevalence between registers. The proportion of cases that survived to 1 week was 69.3% (1392 cases) for total CDH cases and 72.7% (1107) for isolated cases. Conclusions This large population-based study found an increase in total CDH prevalence over time. CDH prevalence also varied significantly according to geographical location. No significant association was found with maternal age. [ABSTRACT FROM AUTHOR]

Background Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterised by upper limb anomalies and congenital heart defects. We present epidemiological and clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. Methods The study was based on data collected during 1990-2011 by 34 registries. The registries are population-based and use multiple sources of information to collect data on all types of birth using standardized definitions, methodology and coding. Diagnostic criteria for inclusion in the study were the presence of radial ray abnormalities and congenital heart disease (CHD), or the presence of either radial ray anomaly or CHD, with family history of HOS. Results A total of 73 cases of HOS were identified, including 11 (15.1%) TOPFA and 62 (84.9%) LB. Out of 73 HOS cases, 30.8% (20/65) were suspected prenatally, 55.4% (36/65) at birth, 10.7% (7/65) in the first week of life, and 3.1% (2/65) in the first year of life. The prenatal detection rate was 39.2% (20/51), with no significant change over the study period. In 55% (11/20) of prenatally detected cases, parents decided to terminate pregnancy. Thumb anomalies were reported in all cases. Agenesis/hypoplasia of radius was present in 49.2% (30/61), ulnar aplasia/hypoplasia in 24.6% (15/61) and humerus hypoplasia/phocomelia in 42.6% (26/61) of patients. Congenital heart defects (CHD) were recorded in 78.7% (48/61) of patients. Isolated septal defects were present in 54.2 (26/48), while 25% (12/48) of patients had complex/severe CHD. The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births. Conclusions HOS is a rare genetic condition showing regional variation in its prevalence. It is often missed prenatally, in spite of the existence of major structural anomalies. When discovered, parents in 45% (9/20) of cases opt for the continuation of pregnancy. Although a quarter of patients have severe CHD, the overall first week survival is very good, which is important information for counselling purposes. [ABSTRACT FROM AUTHOR]

Congenital anomalies (CA) are the paradigm example of rare diseases liable to primary prevention actions due to the multifactorial etiology of many of them, involving a number of environmental factors together with genetic predispositions. Yet despite the preventive potential, lack of attention to an integrated preventive strategy has led to the prevalence of CA remaining relatively stable in recent decades. The 2 European projects, EUROCAT and EUROPLAN, have joined efforts to provide the first science-based and comprehensive set of recommendations for the primary prevention of CA in the European Union. The resulting EUROCAT-EUROPLAN 'Recommendations on Policies to Be Considered for the Primary Prevention of Congenital Anomalies in National Plans and Strategies on Rare Diseases' were issued in 2012 and endorsed by EUCERD (European Union Committee of Experts on Rare Diseases) in 2013. The recommendations exploit interdisciplinary expertise encompassing drugs, diet, lifestyles, maternal health status, and the environment. The recommendations include evidence-based actions aimed at reducing risk factors and at increasing protective factors and behaviors at both individual and population level. Moreover, consideration is given to topics specifically related to CA (e.g. folate status, teratogens) as well as of broad public health impact (e.g. obesity, smoking) which call for specific attention to their relevance in the pre- and periconceptional period. The recommendations, reported entirely in this paper, are a comprehensive tool to implement primary prevention into national policies on rare diseases in Europe. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study examines trends and geographical differences in total and live birth prevalence of trisomies 21, 18 and 13 with regard to increasing maternal age and prenatal diagnosis in Europe. Twenty-one population-based EUROCAT registries covering 6.1 million births between 1990 and 2009 participated. Trisomy cases included live births, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly. We present correction to 20 weeks gestational age (ie, correcting early terminations for the probability of fetal survival to 20 weeks) to allow for artefactual screening-related differences in total prevalence. Poisson regression was used. The proportion of births in the population to mothers aged 35+ years in the participating registries increased from 13% in 1990 to 19% in 2009. Total prevalence per 10 000 births was 22.0 (95% CI 21.7-22.4) for trisomy 21, 5.0 (95% CI 4.8-5.1) for trisomy 18 and 2.0 (95% CI 1.9-2.2) for trisomy 13; live birth prevalence was 11.2 (95% CI 10.9-11.5) for trisomy 21, 1.04 (95% CI 0.96-1.12) for trisomy 18 and 0.48 (95% CI 0.43-0.54) for trisomy 13. There was an increase in total and total corrected prevalence of all three trisomies over time, mainly explained by increasing maternal age. Live birth prevalence remained stable over time. For trisomy 21, there was a three-fold variation in live birth prevalence between countries. The rise in maternal age has led to an increase in the number of trisomy-affected pregnancies in Europe. Live birth prevalence has remained stable overall. Differences in prenatal screening and termination between countries lead to wide variation in live birth prevalence. [ABSTRACT FROM AUTHOR]

Background The epidemiology of congenital small intestinal atresia (SIA) has not been well studied. This study describes the presence of additional anomalies, pregnancy outcomes, total prevalence and association with maternal age in SIA cases in Europe. Methods Cases of SIA delivered during January 1990 to December 2006 notifi ed to 20 EUROCAT registers formed the population-based case series. Prevalence over time was estimated using multilevel Poisson regression, and heterogeneity between registers was evaluated from the random component of the intercept. Results In total 1133 SIA cases were reported among 5126, 164 registered births. Of 1044 singleton cases, 215 (20.6%) cases were associated with a chromosomal anomaly. Of 829 singleton SIA cases with normal karyotype, 221 (26.7%) were associated with other structural anomalies. Considering cases with normal karyotype, the total prevalence per 10 000 births was 1.6 (95% CI 1.5 to 1.7) for SIA, 0.9 (95% CI 0.8 to 1.0) for duodenal atresia and 0.7 (95% CI 0.7 to 0.8) for jejunoileal atresia (JIA). There was no signifi cant trend in SIA, duodenal atresia or JIA prevalence over time (RR=1.0, 95% credible interval (CrI): 1.0 to 1.0 for each), but SIA and duodenal atresia prevalence varied by geographical location (p=0.03 and p=0.04, respectively). There was weak evidence of an increased risk of SIA in mothers aged less than 20 years compared with mothers aged 20 to 29 years (RR=1.3, 95% CrI: 1.0 to 1.8). Conclusion This study found no evidence of a temporal trend in the prevalence of SIA, duodenal atresia or JIA, although SIA and duodenal atresia prevalence varied signifi cantly between registers. INSETS: What is known about the topic;What this study adds. [ABSTRACT FROM AUTHOR]

Data about deliveries, births, mothers and newborn babies are collected extensively to monitor the health and care of mothers and babies during pregnancy, delivery and the post-partum period, but there is no common approach in Europe. We analysed the problems related to using the European data for international comparisons of perinatal health. We made an inventory of relevant data sources in 25 European Union (EU) member states and Norway, and collected perinatal data using a previously defined indicator list. The main sources were civil registration based on birth and death certificates, medical birth registers, hospital discharge systems, congenital anomaly registers, confidential enquiries and audits. A few countries provided data from routine perinatal surveys or from aggregated data collection systems. The main methodological problems were related to differences in registration criteria and definitions, coverage of data collection, problems in combining information from different sources, missing data and random variation for rare events. Collection of European perinatal health information is feasible, but the national health information systems need improvements to fill gaps. To improve international comparisons, stillbirth definitions should be standardised and a short list of causes of fetal and infant deaths should be developed. [ABSTRACT FROM AUTHOR]

Prematurity remains one of the main causes of neonatal mortality and morbidity even in countries that have well-developed comprehensive maternity and neonatal services. Objective: A review of the epidemiology and the short-term complications arising from natural or iatrogenic prematurity in modern practice is necessary to assess the true import of this obstetric complication. Methodology: All deliveries with known gestational age at delivery in the Maltese Islands during the period 1999–2006 were included in the study (23,073 maternities with a total of 23,422 births). These maternities included a total of 1279 delivered at a documented 36 or less completed weeks of gestation. Results: During the period under review the prematurity rate amounted to 6.2% of all maternities. Iatrogrenic-induced births accounted for 33.9% of the total. A premature birth was statistically more likely to occur in women at their extremes of reproductive life (≤17 years: OR=1.16; or ≥30 years: OR=1.44: p<0.0001), or who gave a history of multiparity (Para 3+: OR=1.56: p=0.008) or previous recurrent miscarriage (OR=1.79: p=0.008) or fetal loss (OR=3.17: p<0.0001). The current pregnancy was statistically more likely to be a multiple pregnancy (OR=13.52: p<0.0001) or be complicated by hypertension (OR=2.62: p<0.0001), pre-existing (OR=7.50: p<0.0001) or gestational (OR=2.4: p<0.0001) diabetes, or antenatal bleeding (OR=9.22: p<0.0001). Premature births were statistically more likely to deliver by Caesarean section (OR=2.13: p<0.0001). The stillbirth and neonatal mortality is significantly higher (OR=73.0: p<0.0001) in premature births; while the premature infant is very much more likely to require resuscitation and life support interventions (low 5 min Apgar score: OR=36.5: p<0.0001). The neonatal period of the premature infant is fraught with risks of significant serious complications such as respiratory distress syndrome (OR=9.14: p<0.0001), hyperbilirubinaemia (OR=16.0: p<0.0001) and sepsis (OR=16.0: p<0.0001). Conclusions: The short-term morto-morbidity and the long-term morbidity associated with preterm births necessitates a determined drive to identify those pregnant women at risk so that proactive intervention management can be instituted. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Variations in intervention rates, without subsequent reductions in adverse outcomes, can indicate overuse. We studied variations in and associations between commonly used childbirth interventions and adverse outcomes, adjusted for population characteristics.Methods and Findings: In this multinational cross-sectional study, existing data on 4,729,307 singleton births at ≥37 weeks in 2013 from Finland, Sweden, Norway, Denmark, Iceland, Ireland, England, the Netherlands, Belgium, Germany (Hesse), Malta, the United States, and Chile were used to describe variations in childbirth interventions and outcomes. Numbers of births ranged from 3,987 for Iceland to 3,500,397 for the USA. Crude data were analysed in the Netherlands, or analysed data were shared with the principal investigator. Strict variable definitions were used and information on data quality was collected. Intervention rates were described for each country and stratified by parity. Uni- and multivariable analyses were performed, adjusted for population characteristics, and associations between rates of interventions, population characteristics, and outcomes were assessed using Spearman's rank correlation coefficients. Considerable intercountry variations were found for all interventions, despite adjustments for population characteristics. Adjustments for ethnicity and body mass index changed odds ratios for augmentation of labour and episiotomy. Largest variations were found for augmentation of labour, pain relief, episiotomy, instrumental birth, and cesarean section (CS). Percentages of births at ≥42 weeks varied from 0.1% to 6.7%. Rates among nulliparous versus multiparous women varied from 56% to 80% versus 51% to 82% for spontaneous onset of labour; 14% to 36% versus 8% to 28% for induction of labour; 3% to 13% versus 7% to 26% for prelabour CS; 16% to 48% versus 12% to 50% for overall CS; 22% to 71% versus 7% to 38% for augmentation of labour; 50% to 93% versus 25% to 86% for any intrapartum pain relief, 19% to 83% versus 10% to 64% for epidural anaesthesia; 6% to 68% versus 2% to 30% for episiotomy in vaginal births; 3% to 30% versus 1% to 7% for instrumental vaginal births; and 42% to 70% versus 50% to 84% for spontaneous vaginal births. Countries with higher rates of births at ≥42 weeks had higher rates of births with a spontaneous onset (rho = 0.82 for nulliparous/rho = 0.83 for multiparous women) and instrumental (rho = 0.67) and spontaneous (rho = 0.66) vaginal births among multiparous women and lower rates of induction of labour (rho = -0.71/-0.66), prelabour CS (rho = -0.61/-0.65), overall CS (rho = -0.61/-0.67), and episiotomy (multiparous: rho = -0.67). Variation in CS rates was mainly due to prelabour CS (rho = 0.96). Countries with higher rates of births with a spontaneous onset had lower rates of emergency CS (nulliparous: rho = -0.62) and higher rates of spontaneous vaginal births (multiparous: rho = 0.70). Prelabour and emergency CS were positively correlated (nulliparous: rho = 0.74). Higher rates of obstetric anal sphincter injury following vaginal birth were found in countries with higher rates of spontaneous birth (nulliparous: rho = 0.65). In countries with higher rates of epidural anaesthesia (nulliparous) and spontaneous births (multiparous), higher rates of Apgar score < 7 were found (rhos = 0.64). No statistically significant variation was found for perinatal mortality. Main limitations were varying quality of data and missing information.Conclusions: Considerable intercountry variations were found for all interventions, even after adjusting for population characteristics, indicating overuse of interventions in some countries. Multivariable analyses are essential when comparing intercountry rates. Implementation of evidence-based guidelines is crucial in optimising intervention use and improving quality of maternity care worldwide. [ABSTRACT FROM AUTHOR]

Presents a survey of informed consent for registration of congenital anomalies in Europe. Description of the survey's participants; Methods and results of the survey; Statistics related to the survey; Reports that the primary concern of most patients is not the use of their data for research but inappropriate access to medical data.