Accuracy of congenital anomaly coding in live birth children recorded in European health care databases, a EUROlinkCAT study.

Electronic health care databases are increasingly being used to investigate the epidemiology of congenital anomalies (CAs) although there are concerns about their accuracy. The EUROlinkCAT project linked data from eleven EUROCAT registries to electronic hospital databases. The coding of CAs in electronic hospital databases was compared to the (gold standard) codes in the EUROCAT registries. For birth years 2010-2014 all linked live birth CA cases and all children identified in the hospital databases with a CA code were analysed. Registries calculated sensitivity and Positive Predictive Value (PPV) for 17 selected CAs. Pooled estimates for sensitivity and PPV were then calculated for each anomaly using random effects meta-analyses. Most registries linked more than 85% of their cases to hospital data. Gastroschisis, cleft lip with or without cleft palate and Down syndrome were recorded in hospital databases with high accuracy (sensitivity and PPV ≥ 85%). Hypoplastic left heart syndrome, spina bifida, Hirschsprung's disease, omphalocele and cleft palate showed high sensitivity (≥ 85%), but low or heterogeneous PPV, indicating that hospital data was complete but may contain false positives. The remaining anomaly subgroups in our study, showed low or heterogeneous sensitivity and PPV, indicating that the information in the hospital database was incomplete and of variable validity. Electronic health care databases cannot replace CA registries, although they can be used as an additional ascertainment source for CA registries. CA registries are still the most appropriate data source to study the epidemiology of CAs.

Prenatal diagnosis and pregnancy outcome of major structural anomalies detectable in the first trimester: A population-based cohort study in the Netherlands.

BACKGROUND: Prenatal diagnosis of several major congenital anomalies can be achieved in the first trimester of pregnancy. OBJECTIVE: This study investigates the timing of diagnosis and pregnancy outcome of foetuses and neonates with selected structural anomalies in the Northern Netherlands over a 10-year period when the prenatal screening programme changed significantly, but no first-trimester anatomical screening was implemented. METHODS: We performed a population-based retrospective cohort study with data from the EUROCAT Northern Netherlands database on pregnancies with delivery or termination of pregnancy for fetal anomaly (TOPFA) date between 2010 and 2019. The analysis was restricted to anomalies potentially detectable in the first trimester of pregnancy in at least 50% of cases, based on previously published data. These included: anencephaly, encephalocele, spina bifida, holoprosencephaly, tricuspid/pulmonary valve atresia, hypoplastic left heart, abdominal wall and limb reduction defects, lethal skeletal dysplasia, megacystis, multiple congenital anomalies. The primary outcome was the timing of diagnosis of each structural anomaly. Information on additional investigations, genetic testing and pregnancy outcome (live birth, TOPFA and foetal/neonatal death) was also collected. RESULTS: A total of 478 foetuses were included; 95.0% (n = 454) of anomalies were detected prenatally and 5.0% (n = 24) postpartum. Among the prenatally detected cases, 31% (n = 141) were diagnosed before 14 weeks of gestation, 65.6% (n = 298) between 14-22 weeks and 3.3% (n = 15) after 22 weeks. Prenatal genetic testing was performed in 80.4% (n = 365) of cases with prenatally diagnosed anomalies, and the results were abnormal in 26% (n = 95). Twenty-one% (n = 102) of pregnancies resulted in live births and 62.8% (n = 300) in TOPFA. Spontaneous death occurred in 15.9% (n = 76) of cases: in-utero (6.1%, n = 29), at delivery (7.7%, n = 37) or in neonatal life (2.1%, n = 10). CONCLUSION: Major structural anomalies amenable to early diagnosis in the first trimester of pregnancy are mostly diagnosed during the second trimester in the absence of a regulated first-trimester anatomical screening programme in the Netherlands and are associated with TOPFA and spontaneous death, especially in cases with underlying genetic anomalies.

Timing of diagnosis of fetal structural abnormalities after the introduction of universal cell-free DNA in the absence of first-trimester anatomical screening.

INTRODUCTION: Since 2021, first-trimester anatomical screening (FTAS) is offered in the Netherlands alongside genome-wide cell-free DNA (cfDNA). Previously, only second-trimester anatomical screening (STAS) was offered. This study identifies structural abnormalities amenable to first-trimester diagnosis detected at/after STAS in the period following cfDNA implementation and preceding FTAS introduction. METHODS: This retrospective cohort includes 547 fetuses referred between 2017 and 2020 because of suspected structural abnormalities before/at/after STAS. Additional prenatal investigations and postnatal follow-up were searched. Abnormalities were classified into "always", "sometimes", and "never" detectable in the first-trimester based on a previously suggested classification. RESULTS: Of the 547 pregnancies, 13 (2.6%) received FTAS and 534 (97.6%) received a dating ultrasound and STAS. In 492/534 (92.1%) anomalies were confirmed; 66 (13.4%) belonged to the "always detectable" group in the first trimester, 303 (61.6%) to the "sometimes detectable", and 123 (25.0%) to the never detectable. Of the "always detectable" anomalies 29/66 (44%) were diagnosed during dating ultrasounds and 37 (56%) during STAS. The rate of termination of pregnancy for anomalies detected during FTAS and at/after STAS was 84.6% (n = 11/13) and 29.3% (n = 144/492) (p < 0.01). CONCLUSION: When FTAS is not part of screening paradigms, most fetal anomalies remain undetected until the second trimester or later in pregnancy, including 56% of anomalies "always detectable" in the first trimester.

A Multicountry Analysis of Prevalence and Mortality among Neonates and Children with Bladder Exstrophy.

OBJECTIVE: Bladder exstrophy (BE) is a rare but severe birth defect affecting the lower abdominal wall and genitourinary system. The objective of the study is to examine the total prevalence, trends in prevalence, and age-specific mortality among individuals with BE. STUDY DESIGN: We conducted a retrospective cohort study. Data were analyzed from 20 birth defects surveillance programs, members of the International Clearinghouse for Birth Defects Surveillance and Research in 16 countries. Live births, stillbirths, and elective terminations of pregnancy for fetal anomaly (ETOPFA) diagnosed with BE from 1974 to 2014. Pooled and program-specific prevalence of BE per 100,000 total births was calculated. The 95% confidence intervals (CI) for prevalence were estimated using Poisson approximation of binomial distribution. Time trends in prevalence of BE from 2000 to 2014 were examined using Poisson regression. Proportion of deaths among BE cases was calculated on the day of birth, day 2 to 6, day 7 to 27, day 28 to 364, 1 to 4 years, and ≥5 years. Mortality analysis was stratified by isolated, multiple, and syndromic case status. RESULTS: The pooled total prevalence of BE was 2.58 per 100,000 total births (95% CI = 2.40, 2.78) for study years 1974 to 2014. Prevalence varied over time with a decreasing trend from 2000 to 2014. The first-week mortality proportion was 3.5, 17.3, and 14.6% among isolated, multiple, and syndromic BE cases, respectively. The majority of first-week mortality occurred on the first day of life among isolated, multiple, and syndromic BE cases. The proportion of first-week deaths was higher among cases reported from programs in Latin America where ETOPFA services were not available. CONCLUSIONS: Prevalence of BE varied by program and showed a decreasing trend from 2000 to -2014. Mortality is a concern among multiple and syndromic cases, and a high proportion of deaths among cases occurred during the first week of life. KEY POINTS: · Total prevalence of BE was 2.58 per 100,000 births.. · Prevalence decreased from 2000 to 2014.. · The first-week mortality was 9.3%..

Effect of prenatal screening on trends in perinatal mortality associated with congenital anomalies before and after the introduction of prenatal screening: A population-based study in the Northern Netherlands.

BACKGROUND: Perinatal mortality in foetuses/children with congenital anomalies remains high. Prenatal diagnosis, essential for risk assessment and organisation of perinatal/postnatal care, offers parents the opportunity to consider the termination of pregnancy. In times of quick changes in prenatal screening programmes, it is relevant to evaluate the effect of prenatal screening on perinatal mortality rates. OBJECTIVES: The objective of this study was to study trends in early foetal and perinatal mortality associated with congenital anomalies before/after the introduction of the Dutch prenatal screening programme. METHODS: This population-based cohort study included 8535 foetuses/neonates with congenital anomalies born in the Northern Netherlands between 2001 and 2017. Total deaths were defined as sum of early foetal (before 24 weeks' gestation) and perinatal deaths (from 24 weeks' gestation till day 7 post-partum). Foetal deaths were categorised into spontaneous or elective termination of pregnancy for foetal anomalies (TOPFA). Trends in total mortality as well as early foetal and perinatal mortality were studied. Joinpoint regression was used to calculate the average annual percentage chance (AAPC) and identify linear trends in mortality within subperiods. RESULTS: Total and perinatal mortality were 17% and 4%. Total mortality was higher in abnormal karyotype and central nervous system anomalies. We observed an increase in total mortality over time: 11.9% in 2001 versus 21.9% in 2017 (AAPC 2.6, 95% confidence interval [CI] 1.5, 3.7), caused by an increase in early foetal mortality from 5.5% to 19.2% (AAPC 8.7, 95% CI 4.7, 12.9) and a decrease in perinatal mortality from 6.4% to 2.7% (AAPC -5.6, 95% CI -10.0, -1.0). The increase in early foetal mortality reflects an increase in TOPFA from 3.6% to 16.9% (AAPC 8.3, 95% CI 4.2, 12.7), mostly occurring at 13-14 and 20-23 weeks' gestation. CONCLUSIONS: The introduction of the prenatal screening programme led to a decrease in perinatal mortality among foetuses and neonates with congenital anomalies and a marked increase in early foetal mortality before 24 weeks' gestation due to higher rates of TOPFA.

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

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

Analysis of Mortality among Neonates and Children with Spina Bifida: An International Registry-Based Study, 2001-2012.

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.

Prenatal diagnosis of urinary tract anomalies, a cohort study in the Northern Netherlands.

OBJECTIVE: To describe prevalence, time of diagnosis, and type of birth in children and fetuses with urinary tract (UT) anomalies after the introduction of the anomaly scan in the Netherlands in 2007. METHODS: We selected, from a population-based congenital anomaly registry, children and fetuses with UT anomalies born between 2008 and 2014. Cases were defined according to type of UT anomaly and whether isolated or with associated anomalies. Information was collected on time of diagnosis and type of birth. RESULTS: We included 487 cases. Total prevalence increased from 34.0 in 2008 to 42.3 per 10 000 births in 2014, mainly by an increase in anomalies of the collecting system. Almost 70% presented as isolated. Anomalies of the renal parenchyma were more often associated with genetic or other anomalies (47.3%) than anomalies of the collecting system (19.0%). The proportion of prenatally diagnosed cases increased from 59.3% in 2008 to 80.9% in 2014. Termination of pregnancy occurred in 14.8%, of which the majority were UT anomalies associated with a genetic disorder or other anomalies. CONCLUSION: In the period after the introduction of the anomaly scan, we observed an increasing prevalence of anomalies of the collecting system, but no increase in termination of pregnancies.

Gastroschisis in Europe - A Case-malformed-Control Study of Medication and Maternal Illness during Pregnancy as Risk Factors.

BACKGROUND: Gastroschisis, a congenital anomaly of the abdomen, is associated with young maternal age and has increased in prevalence in many countries. Maternal illness and medication exposure are among environmental risk factors implicated in its aetiology. METHODS: A population-based case-malformed control study was conducted using data from 18 European congenital anomaly registries, with information on first trimester medication use, covering 8 million births 1995-2012. 1577 gastroschisis cases (of which 4% stillbirths, 11% terminations of pregnancy) were compared to 153 357 non-chromosomal/monogenic controls. Literature review identified previous associations concerning maternal illness and medication exposure to be tested as signals. Logistic regression adjusted for maternal age group, registry, and time period was used to evaluate associations. RESULTS: Comparing gastroschisis to other congenital anomalies, the data supported signals concerning maternal depression (aOR 2.52, 95% CI 1.45, 4.39), antidepressant use (aOR 2.03, 95% CI 1.22, 3.38), postnatal depression/psychosis following a previous pregnancy (aOR 8.32, 95% CI 2.56, 27.01), sexually transmitted infections (aOR 2.85, 95% CI 1.13, 7.24), topical antivirals (aOR 5.31, 95% CI 1.63, 17.33), and continuation of oral contraceptives in early pregnancy (aOR 2.17, 95% CI 1.13, 4.18). Exploratory analyses suggested associations with a wider range of maternal infections and medications, including tonsillitis and the expectorant bromhexine. CONCLUSIONS: While it is difficult to disentangle the effects of the medication and underlying indication, our results add to the evidence base on preventable risk factors for gastroschisis. These risk factors may contribute to the higher risk among young mothers, and geographical and temporal variation in prevalence.

Prevalence, timing of diagnosis and pregnancy outcome of abdominal wall defects after the introduction of a national prenatal screening program.

OBJECTIVE: To examine prevalence, time of diagnosis and outcome of fetuses with an exomphalos or gastroschisis, diagnosed since the introduction of a national prenatal screening program in 2007. METHODS: A prospective cohort study was undertaken in two fetal medicine units in the Netherlands. Cases were included if the estimated due date was between 2009 and 2013. Outcome measures were gestational age at diagnosis, presence of additional anomalies and pregnancy outcome. RESULTS: A total of 141 exomphalos and 44 gastroschisis cases were included in the study, of which, respectively, 96 and 95% were diagnosed prenatally. The majority of the cases are visualized prior to the 20-week scan. In the exomphalos group, 83% had additional anomalies of which 57% had a chromosomal anomaly. Additional anomalies were present in 11% of the gastroschisis cases of which 40% had a chromosomal anomaly. The pregnancy termination rate was 61% (exomphalos) and 14% (gastroschisis). CONCLUSION: Almost all exomphalos and gastroschisis cases are diagnosed prenatally, the majority in the first trimester. Associated anomalies are far more common in exomphalos with a fourfold lower survival rate than gastroschisis. In the exomphalos group, the pregnancy termination rate doubled, while in the gastroschisis group the rate remained low. © 2017 John Wiley & Sons, Ltd.

The impact of national prenatal screening on the time of diagnosis and outcome of pregnancies affected with common trisomies, a cohort study in the Northern Netherlands.

BACKGROUND: To evaluate the impact of the introduction of prenatal screening on time of detection and pregnancy outcome for trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13). METHODS: We performed a retrospective, population-based cohort study in the Northern Netherlands including 503 trisomy cases born between 2005 and 2012. Screening tests and invasive procedures, timing of diagnosis and pregnancy outcome were compared between the period before (2005-2006) and after introduction (2007-2012) using X 2 tests. RESULTS: There was an increase in proportion of women who had a prenatal screening and/or invasive test, from 62% in 2005-2006 to 84% in 2010-2012 (p < 0.01), while the proportion of prenatally diagnosed cases did not change (60% overall). In women < =35 years 47% of the cases were diagnosed prenatally vs 73% in women >35 years (p < 0.01). More T13/T18 cases were diagnosed <24 weeks after introduction (62% vs 84%; p < 0.01). In T13/T18 intra-uterine death decreased (26% vs 15%), while terminations increased: 55% vs 72%. CONCLUSION: The introduction of prenatal screening had limited impact on the time of detection and outcome of the most common trisomies. The introduction of the 20-week anomaly scan has resulted in more trisomy cases diagnosed <24 weeks and a shift from fetal death to terminations.

EUROmediCAT signal detection: a systematic method for identifying potential teratogenic medication.

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.

Epidemiology of hypospadias in Europe: a registry-based study.

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.

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study.

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

Early pregnancy exposure to antihistamines and risk of congenital heart defects: results of two case-control studies.

UNLABELLED: We aimed to study the association between use of antihistamines in early pregnancy and congenital heart defects (CHD) in the offspring. DESIGN: Two case-control studies. SETTING: HAVEN study, Erasmus MC, University Medical Centre, Rotterdam, and Eurocat Northern Netherlands (NNL), University Medical Center Groningen, Groningen, the Netherlands. We studied 361 children with CHD and 410 controls without congenital malformations from the HAVEN study and replicated the analyses in 445 children with CHD and 530 controls from the Eurocat NNL registry. Information about antihistamine use in early pregnancy and potential confounders was obtained from questionnaires postpartum. We calculated the association between antihistamines and CHD risk by multivariable logistic regression analysis. MAIN OUTCOME MEASURES: Odds ratios (OR) with 95% confidence intervals (CI). In the HAVEN study, 25 of 771 mothers used antihistamines that were associated with an increased CHD risk (OR 3.0, 95% CI 1.2-7.3), particularly atrioventricular septal defects (AVSD) (OR 5.1, 95 % CI 1.3-20.5) and perimembranous ventricular septal defects (pVSD) (OR 5.1, 95% CI 1.8-14.4). Mothers with severe nausea who did not use antihistamines had a reduced risk (OR 0.7, 95% CI 0.5-0.98), whereas nauseous mothers using antihistamines showed an almost fivefold increased risk of pVSD (OR 4.8, 95% CI 1.1-21.8). The association between antihistamines and AVSD was confirmed in the Eurocat cohort (OR 3.5, 95% CI 1.4-8.7), but we could not replicate the association with overall CHD risk. We found a positive association between antihistamine use in early pregnancy and CHD risk, particularly AVSD, which seemed to be independent of nausea/vomiting.

Antibiotics prescribed before, during and after pregnancy in the Netherlands: a drug utilization study.

PURPOSE: To describe the prescription of antibiotics before, during and after pregnancy, and the trends over a 16-year period in the Netherlands, and to determine whether they were prescribed according to national guidelines. METHODS: The IADB (http://iadb.nl) contains prescriptions dispensed by community pharmacies in the Netherlands. We extracted information on 18,873 pregnancies for 14,969 women between 1994 and 2009, focusing on antibiotics dispensed in the four trimesters before conception to two trimesters after birth (nine trimesters in total). We calculated trends in prescription rates during pregnancy and over time, and also compared the prescription of antibiotics in the Netherlands with safety category based on the Australian Drug Evaluation Committee. RESULTS: During pregnancy 20.8% of the women were prescribed at least one antibiotic. The 'beta-lactam antibacterials/penicillins' group and the specific antibiotic amoxicillin were most commonly prescribed in the nine trimesters covered. The prescription rate of the 'other antibacterials' group during pregnancy increased over the years, in contrast to that of the 'sulphonamides/trimethoprim' group, which decreased. In total, 2.0% of pregnancies were exposed to a 'potentially harmful' antibiotic and 0.8% to a 'harmful' antibiotic. Compared with the period before conception, 'safe' antibiotics were prescribed more often during pregnancy than the other groups. CONCLUSIONS: One in five women was prescribed at least one antibiotic during pregnancy in the Netherlands, which is comparable with rates in other European countries. Our results suggest that antibiotics appear to be prescribed to pregnant women generally in accordance with national recommendations.

Prenatal diagnosis and epidemiology of multicystic kidney dysplasia in Europe.

OBJECTIVES: The aim of this study is to describe the prenatal diagnosis and epidemiology of multicystic kidney dysplasia (MCKD). METHODS: The study is based on routinely collected data from a European database of major congenital anomalies including 13 registries with cases born in 1997-2006 and covering 1 458 552 births. RESULTS: There were 601 MCKD cases giving an overall prevalence of 4.12 per 10 000 births with regional variation. In live births, 87% of cases had an isolated renal anomaly and 13% had associated major nonrenal anomalies (chromosomal, syndrome or other major anomalies). For the cases with isolated renal anomalies, 51/386 (11%) and 7/386 (2%) choose to terminate the pregnancy or resulted in an intrauterine fetal death, respectively. The prenatal detection rate was 88% in both unilateral and bilateral cases. Birth outcome differed with 92% of unilateral MCKD cases being liveborn compared with 33% of bilateral MCKD cases. For unilateral MCKD cases, 84% had an isolated renal anomaly compared with 51% of bilateral MCKD cases (p < 0.001). CONCLUSIONS: Cases with unilateral MCKD are mainly liveborn, and only 16% have associated major malformations or a syndrome. Cases with bilateral MCKD are often associated with nonrenal major congenital anomalies or part of a syndrome, and only one third of bilateral MCKD cases in this study were liveborn. Prenatal detection rate of MCKD was high for both unilateral and bilateral cases. © 2014 John Wiley & Sons, Ltd.

The role of maternal-fetal cholesterol transport in early fetal life: current insights.

The importance of maternal cholesterol as an exogenous cholesterol source for the growing embryo was first reported in studies of Smith-Lemli-Opitz syndrome. Although most of the fetus's cholesterol is synthesized by the fetus itself, there is now growing evidence that during the first weeks of life, when most organs develop, the fetus largely depends on maternal cholesterol as its cholesterol source. The maternal-fetal cholesterol transport mechanism, by transporters in both the yolk sac and placenta, is becoming better understood. This minireview summarizes current insights on maternal-fetal cholesterol transport based on in vitro and in vivo studies. As the prevalence of maternal diseases, such as diabetes, obesity, and the metabolic syndrome that adversely affect maternal cholesterol levels, is now rapidly reaching epidemic proportions, we urgently need to determine the impact of these maternal conditions on the developing human fetus.

Recent decrease in the prevalence of congenital heart defects in Europe.

OBJECTIVES: To examine trends in the prevalence of congenital heart defects (CHDs) in Europe and to compare these trends with the recent decrease in the prevalence of CHDs in Canada (Quebec) that was attributed to the policy of mandatory folic acid fortification. STUDY DESIGN: We used data for the period 1990-2007 for 47 508 cases of CHD not associated with a chromosomal anomaly from 29 population-based European Surveillance of Congenital Anomalies registries in 16 countries covering 7.3 million births. We estimated trends for all CHDs combined and separately for 3 severity groups using random-effects Poisson regression models with splines. RESULTS: We found that the total prevalence of CHDs increased during the 1990s and the early 2000s until 2004 and decreased thereafter. We found essentially no trend in total prevalence of the most severe group (group I), whereas the prevalence of severity group II increased until about 2000 and decreased thereafter. Trends for severity group III (the most prevalent group) paralleled those for all CHDs combined. CONCLUSIONS: The prevalence of CHDs decreased in recent years in Europe in the absence of a policy for mandatory folic acid fortification. One possible explanation for this decrease may be an as-yet-undocumented increase in folic acid intake of women in Europe following recommendations for folic acid supplementation and/or voluntary fortification. However, alternative hypotheses, including reductions in risk factors of CHDs (eg, maternal smoking) and improved management of maternal chronic health conditions (eg, diabetes), must also be considered for explaining the observed decrease in the prevalence of CHDs in Europe or elsewhere.

Periconceptional folic acid associated with an increased risk of oral clefts relative to non-folate related malformations in the Northern Netherlands: a population based case-control study.

Periconceptional folic acid has been associated with a reduced risk of neural tube defects, but findings on its effect in oral clefts are largely inconclusive. This case-control study assesses the effects of periconceptional folic acid on cleft risk, using complementary data from the Dutch Oral Cleft Registry and a population-based birth defects registry (Eurocat) of children and foetuses born in the Northern Netherlands between 1997 and 2009. Cases were live-born infants with non-syndromic clefts (n = 367) and controls were infants or foetuses with chromosomal/syndromal (n = 924) or non-folate related anomalies (n = 2,021). We analyzed type/timing/duration of supplement use related to traditional cleft categories as well as to their timing (early/late embryonic periods) and underlying embryological processes (fusion/differentiation defects). Consistent supplement use during the aetiologically relevant period (weeks 0-12 postconception) was associated with an increased risk of clefts (adjusted odds ratio 1.72, 95% confidence interval 1.19-2.49), especially of cleft lip/alveolus (3.16, 1.69-5.91). Further analysis systematically showed twofold to threefold increased risks for late differentiation defects-mainly clefts of the lip/alveolus-with no significant associations for early/late fusion defects. Effects were attributable to folic acid and not to other multivitamin components, and inclusion of partial use (not covering the complete aetiologically relevant period) generally weakened associations. In conclusion, this study presents several lines of evidence indicating that periconceptional folic acid in the Northern Netherlands is associated with an increased risk of clefts, in particular of cleft lip/alveolus. This association is strengthened by the specificity, consistency, systematic pattern, and duration of exposure-response relationship of our findings, underlining the need to evaluate public health strategies regarding folic acid and to further investigate potential adverse effects.