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

Background: 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.Objective: To analyze the prevalence and trends of hypospadias for 27 international programs over a 31-yr period.Design, setting, and participants: 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.Outcome measurements and statistical analysis: 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.Results and limitations: 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 Conclusions: 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.Patient summary: 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. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Background Esophageal atresia (EA) affects around 2.3-2.6 per 10,000 births world-wide. Infants born with this condition require surgical correction soon after birth. Most survival studies of infants with EA are locally or regionally based. We aimed to describe survival across multiple world regions.Methods We included infants diagnosed with EA between 1980 and 2015 from 24 birth defects surveillance programs that are members of the International Clearinghouse for Birth Defects Surveillance and Research. We calculated survival as the proportion of liveborn infants alive at 1 month, 1- and 5-years, among all infants with EA, those with isolated EA, those with EA and additional anomalies or EA and a chromosomal anomaly or genetic syndrome. We also investigated trends in survival over the decades, 1980s-2010s.Results We included 6,466 liveborn infants with EA. Survival was 89.4% (95% CI 88.1-90.5) at 1-month, 84.5% (95% CI 83.0-85.9) at 1-year and 82.7% (95% CI 81.2-84.2) at 5-years. One-month survival for infants with isolated EA (97.1%) was higher than for infants with additional anomalies (89.7%) or infants with chromosomal or genetic syndrome diagnoses (57.3%) with little change at 1- and 5-years. Survival at 1 month improved from the 1980s to the 2010s, by 6.5% for infants with isolated EA and by 21.5% for infants with EA and additional anomalies.Conclusions Almost all infants with isolated EA survived to 5 years. Mortality was higher for infants with EA and an additional anomaly, including chromosomal or genetic syndromes. Survival improved from the 1980s, particularly for those with additional anomalies.

Preeclampsia (PE) is a common obstetric disorder typically affecting 2–8% of all pregnancies and can lead to several adverse obstetric outcomes for both mother and fetus with the greatest burden of severe outcomes in low middle-income countries (LMICs), therefore, screening for PE is vital. Globally, screening is based on maternal characteristics and medical history which are nonspecific for the disorder. In 2004, the World Health Organization acknowledged that no clinically useful test was able to predict the onset of PE, which prompted a universal search for alternative means of screening. Over the past decade or so, emphasis has been placed on the use of maternal characteristics in conjunction with biomarkers of disease combined into predictive algorithms, however these are yet to transition into the clinic and are cost prohibitive in LMICs. As a result, the screening paradigm for PE remains unchanged. It is evident that novel approaches are needed. Vibrational spectroscopy, specifically Raman spectroscopy and Fourier-transform infrared spectroscopy (FTIR), could provide better alternatives suited for implementation in low resource settings as no specialized reagents are required for conventional approaches and there is a drive to portable platforms usable in both urban and rual community settings. These techniques are based on light scattering and absorption, respectively, allowing detailed molecular analysis of samples to produce a unique molecular fingerprint of diseased states. The specificity of vibrational spectroscopy might well make it suited for application in other obstetric disorders such as gestational diabetes mellitus and obstetric cholestasis. In this review, we summarize current approaches sought as alternatives to current screening methodologies and introduce how vibrational spectroscopy could offer superior screening and diagnostic paradigms in obstetric care. Additionally, we propose a real benefit of such tools in LMICs where limited resources battle the higher prevalence of obstetric disorders.

Aims/hypothesis: The aim of this prospective nationwide study was to examine antenatal pregnancy care and pregnancy outcomes in women with type 1 and type 2 diabetes, and to describe changes since 2002/2003. Methods: This national population-based cohort included 3036 pregnant women with diabetes from 155 maternity clinics in England and Wales who delivered during 2015. The main outcome measures were maternal glycaemic control, preterm delivery (before 37 weeks), infant large for gestational age (LGA), and rates of congenital anomaly, stillbirth and neonatal death. Results: Of 3036 women, 1563 (51%) had type 1, 1386 (46%) had type 2 and 87 (3%) had other types of diabetes. The percentage of women achieving HbA1c < 6.5% (48 mmol/mol) in early pregnancy varied greatly between clinics (median [interquartile range] 14.3% [7.7–22.2] for type 1, 37.0% [27.3–46.2] for type 2). The number of infants born preterm (21.7% vs 39.7%) and LGA (23.9% vs 46.4%) were lower for women with type 2 compared with type 1 diabetes (both p < 0.001). The prevalence rates for congenital anomaly (46.2/1000 births for type 1, 34.6/1000 births for type 2) and neonatal death (8.1/1000 births for type 1, 11.4/1000 births for type 2) were unchanged since 2002/2003. Stillbirth rates are almost 2.5 times lower than in 2002/2003 (10.7 vs 25.8/1000 births for type 1, p = 0.0012; 10.5 vs 29.2/1000 births for type 2, p = 0.0091). Conclusions/interpretation: Stillbirth rates among women with type 1 and type 2 diabetes have decreased since 2002/2003. Rates of preterm delivery and LGA infants are lower in women with type 2 compared with type 1 diabetes. In women with type 1 diabetes, suboptimal glucose control and high rates of perinatal morbidity persist with substantial variations between clinics. Data availability: Further details of the data collection methodology, individual clinic data and the full audit reports for healthcare professionals and service users are available from http://content.digital.nhs.uk/npid.

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.

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. Fil: Bakker, Marian K.. University of Groningen; Países Bajos Fil: Kancherla, Vijaya. University of Emory; Estados Unidos Fil: Canfield, Mark A.. No especifíca; Fil: Bermejo-Sanchez, Eva. Instituto de Salud Carlos Iii (isciii); España Fil: Cragan, Janet D.. Centers for Disease Control and Prevention; Estados Unidos Fil: Dastgiri, Saeed. University Of Medical Sciences Tabriz; Irán Fil: De Walle, Hermien E. K.. Pontificia Universidad Javeriana; Colombia Fil: Feldkamp, Marcia L.. No especifíca; Fil: Groisman, Boris. Dirección Nacional de Instituto de Investigación.Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gatt, Miriam. Pontificia Universidad Javeriana; Colombia Fil: Hurtado Villa, Paula. Lund University; Suecia Fil: Kallen, Karin. No especifíca; Fil: Landau, Daniella. Sorbonne University; Francia Fil: Lelong, Nathalie. No especifíca; Fil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Martínez, Laura. Singleton Hospital; Reino Unido Fil: Morgan, Margery. No especifíca; Fil: Mutchinick, Osvaldo M.. No especifíca; Fil: Nembhard, Wendy N.. No especifíca; Fil: Pierini, Anna. No especifíca; Fil: Rissmann, Anke. Otto-von-Guericke-Universität Magdeburg; Alemania Fil: Sipek, Antonin. No especifíca; Fil: Szabova, Elena. No especifíca; Fil: Tagliabue, Giovanna. No especifíca; Fil: Wertelecki, Wladimir. No especifíca; Fil: Zarante, Ignacio. Pontificia Universidad Javeriana; Colombia Fil: Mastroiacovo, Pierpaolo. No especifíca

OBJECTIVE: To investigate whether exposure to metformin during the first trimester of pregnancy, for diabetes or other indications, increases the risk of all or specific congenital anomalies.DESIGN: Population based exploratory case-control study using malformed controls. Cases of 29 specific subgroups of non-genetic anomalies, and all non-genetic anomalies combined, were compared with controls (all other non-genetic anomalies or genetic syndromes).SETTING: 11 EUROmediCAT European congenital anomaly registries surveying 1 892 482 births in Europe between 2006 and 2013.PARTICIPANTS: 50 167 babies affected by congenital anomaly (41 242 non-genetic and 8925 genetic) including live births, fetal deaths from 20 weeks' gestation, and terminations of pregnancy for fetal anomaly.MAIN OUTCOME MEASURE: Odds ratios adjusted for maternal age, registry, multiple birth, and maternal diabetes status.RESULTS: 168 babies affected by congenital anomaly (141 non-genetic and 27 genetic) were exposed to metformin, 3.3 per 1000 births. No evidence was found for a higher proportion of exposure to metformin during the first trimester among babies with all non-genetic anomalies combined compared with genetic controls (adjusted odds ratio 0.84, 95% confidence interval 0.55 to 1.30). The only significant result was for pulmonary valve atresia (adjusted odds ratio 3.54, 1.05 to 12.00, compared with non-genetic controls; 2.86, 0.79 to 10.30, compared with genetic controls).CONCLUSIONS: No evidence was found for an increased risk of all non-genetic congenital anomalies combined following exposure to metformin during the first trimester, and the one significant association was no more than would be expected by chance. Further surveillance is needed to increase sample size and follow up the cardiac signal, but these findings are reassuring given the increasing use of metformin in pregnancy.

ObjectivesTo evaluate the risk of major congenital anomaly associated with first-trimester exposure to insulin analogues compared with human insulin in offspring of women with pregestational diabetes.Design and settingA population-based cohort of women with pregestational diabetes (n=1661) who delivered between 1996 and 2012 was established retrospectively from seven European regions covered bythe European Surveillance of Congenital Anomalies (EUROCAT) congenital anomaly registries.Primary outcome measuresThe risk of non-chromosomal major congenital anomaly in live births, fetal deaths and terminations for a fetal anomaly exposed to insulin analogues in the first trimester of pregnancy was compared with the risk in those exposed to human insulin only.ResultsDuring the first trimester, 870 fetuses (52.4%) were exposed to human insulin only, 397 fetuses (23.9%) to insulin analogues only and 394 fetuses (23.7%) to both human insulin and insulin analogues. The risk of major congenital anomaly in fetuses exposed to insulin analogues only was lower than those exposed to human insulin only; the relative risk adjusted for glycaemic control and region was 0.56 (95% CI 0.29 to 1.06). The significantly lower risk related to exposure of insulin analogues only was observed in congenital heart defects: adjusted relative risk 0.14 (95% CI 0.03 to 0.62).ConclusionsIn this retrospective population-based cohort study across Europe, first-trimester exposure to insulin analogues did not increase the risk of major congenital anomaly compared with exposure to human insulin. A possible lower risk of congenital heart defects among fetuses exposed to insulin analogues only deserves further investigation.

Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin. We performed a literature search for studies of pregnant women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analysed to compare the congenital anomaly rate among foetuses of mothers using insulin analogues with foetuses of mothers using human insulin. Of 29 studies, we included 1286 foetuses of mothers using short-acting insulin analogues with 1089 references of mothers using human insulin and 768 foetuses of mothers using long-acting insulin analogues with 685 references of mothers using long-acting human insulin (Neutral Protamine Hagedorn). The congenital anomaly rate was 4.84% and 4.29% among the foetuses of mothers using lispro and aspart. For glargine and detemir, the congenital anomaly rate was 2.86% and 3.47%, respectively. No studies on the use of insulin glulisine and degludec in pregnancy were found. There was no statistically significant difference in the congenital anomaly rate among foetuses exposed to insulin analogues (lispro, aspart, glargine or detemir) compared with those exposed to human insulin or Neutral Protamine Hagedorn insulin. The total prevalence of congenital anomalies was not increased for foetuses exposed to insulin analogues. The small samples in the included studies provided insufficient statistical power to identify a moderate increased risk of specific congenital anomalies.

Background Trisomy 13 is one of the three autosomal trisomies compatible with viability. It is associated with structural anomalies, learning disability and poor survival. Advanced maternal age is the most frequently suggested risk factor. This is a population based register study to investigate the temporal trends of trisomy 13. Methods Chromosomal trisomies were reviewed by the Welsh Congenital Anomaly Register using data from 1998-2012. All pregnancy outcomes were included. Prevalence rates and trends for all cases and for cases with mothers aged below 35 years and those aged 35 years and older were plotted for trisomy 13, 18 and 21. Possible risk factors contributing to the trend in older mothers were compared in the early and late period of the study. Results There were 124 cases of trisomy 13 over the 15 year period with 55 mothers aged 35 years and older. Overall prevalence was 2.5 per 10,000 total births. A significant declining trend in the prevalence of trisomy 13 in mothers aged 35 and older (χ(2) trend = 4.98, p=0.026) was noted. Rates for younger mothers were lower and remained stable. Prevalence of trisomy 18 and 21 in older mothers remained stable. Conclusion The unexpected declining trend in trisomy 13 in older mothers could not be explained by the risk factors examined in this study. There have been no other reports of trends in the prevalence of trisomy 13 in older mothers in recent years. There is further need for surveillance of trends in future and in other populations.

Metformin affects stem cell function and has been shown to cross the human placenta at term, exposing the fetus to concentrations approaching those in the maternal circulation. Limited evidence from3 meta-analyses and a cohort study suggests that the rate of all major congenital anomalies combined is not significantly increased after exposure to metformin. As teratogens tend to increase the risk of specific, rather than all, congenital anomalies, an increased risk of specific congenital anomalies after first trimester metformin exposure cannot be ruled out. The researchers designed a population-based exploratory case-control study using malformed controls. Cases of 29 specific subgroups of nongenetic anomalies, and all nongenetic anomalies combined, were compared with controls (all other nongenetic anomalies or genetic syndromes). Eleven EUROmediCAT European congenital anomaly registries surveying 1,892,482 births in Europe between 2006 and 2013 were used. There were 50,167 babies affected by congenital anomaly (41,242 nongenetic and 8925 genetic) including live births, fetal deaths from 20 weeks' gestation, and terminations of pregnancy for fetal anomaly. EUROCAT population-based registries record all major congenital anomalies among live births, fetal deaths at 20 weeks' gestation or later, and terminations of pregnancy for fetal anomaly, using ICD-10 (International Classification of Diseases, 10th Revision) codes. Detailed descriptions of registries and the methods used have been published previously. The EUROmediCAT database includes data, since 1995, from those EUROCAT registries that record first trimester drug exposure either directly or through linkage with healthcare databases with information on prescribing and dispensing of drugs. Exposure to metformin in the first trimester was rare before 2006, so this study was based on data from 2006 onwards. Registries with less than 3 exposures were excluded. The researchers recorded 53,689 babies affected by congenital anomaly in the EUROmediCAT database (2006-2013), of 1,892,482 births surveyed, across the 11 registries that were eligible to take part in this study. After exclusions, 50,167 babies with congenital anomaly were left for analysis, consisting of 41,242 with a nongenetic anomaly and 8925 with a genetic syndrome. In all, 168 babies affected by congenital anomaly (141 nongenetic and 27 genetic)were exposed to metformin (3.3 per 1000 babies affected by congenital anomaly), of which 2 had a combined preparation (A10BD02 metformin and sulfonylureas). Overall, metformin exposure among fetuses with all nongenetic anomalies combined compared with controls was not statistically significantly different (adjusted odds ratio, 0.84; 95% confidence interval, 0.55-1.30). The only significant result was for pulmonary valve atresia (adjusted odds ratio, 3.54; 1.05-12.00, compared with nongenetic controls; 2.86, 0.79-10.30, compared with genetic controls). This one significant association was no more than would be expected by chance given the number of comparisons that were made. Further surveillance is needed to increase the sample size and follow up the signal related to the cardiac anomaly seen, but these findings are reassuring given the increasing use of metformin in pregnancy.

Aim: To explore antidiabetic medicine prescribing to women before, during and after pregnancy in different regions of Europe.Methods: A common protocol was implemented across seven databases in Denmark, Norway, The Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the rest of the UK. Women with a pregnancy starting and ending between 2004 and 2010, (Denmark, 2004-2009; Norway, 2005-2010; Emilia Romagna, 2008-2010), which ended in a live or stillbirth, were identified. Prescriptions for antidiabetic medicines issued (UK) or dispensed (non-UK) during pregnancy and/or the year before or year after pregnancy were identified. Prescribing patterns were compared across databases and over calendar time.Results: 1,082,673 live/stillbirths were identified. Pregestational insulin prescribing during the year before pregnancy ranged from 0.27% (CI95 0.25-0.30) in Tuscany to 0.45% (CI95 0.43-0.47) in Norway, and increased between 2004 and 2009 in all countries. During pregnancy, insulin prescribing peaked during the third trimester and increased over time; third trimester prescribing was highest in Tuscany (2.2%) and lowest in Denmark (0.5%). Of those prescribed an insulin during pregnancy, between 50.5% in Denmark and 88.8% in the Netherlands received an insulin analogue alone or in combination with human insulin, this proportion increasing over time. Oral products were mainly metformin and prescribing was highest in the 3 months before pregnancy. Metformin use during pregnancy increased in some countries. Conclusion: Pregestational diabetes is increasing in many areas of Europe. There is considerable variation between and within countries in the choice of medication for treating pregestational diabetes in pregnancy, including choice of insulin analogues and oral antidiabetics, and very large variation in the diagnosis and treatment of gestational diabetes despite international guidelines.

This is the protocol for a review and there is no abstract. The objectives are as follows: To compare the effects (see outcomes below) of different total* doses (in terms of boluses, concentration, volume and timeframe) of opioid epidural (excluding combined-spinal epidural and intrathecal) analgesia administered (alone or as adjunctive) during labour on the woman and the infant. To compare the safety (see outcomes below) of different total* doses (as above) of opioid epidural analgesia administered during labour for the woman and the infant. *We define ‘total’ as the sum of all boluses and infusions (concentration, volume and timeframe) administered between onset of labour (as defined by authors) and delivery. If analgesia post-delivery is reported, we shall describe this separately. We shall undertake secondary analyses of drug concentrations and volumes, see Types of interventions. However, since opioids pass into the fetus, and may accumulate, total dose is an important consideration for infant adverse events, such as drowsiness. (see Why it is important to do this review).

BACKGROUND: Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP).METHODS AND FINDINGS: Three population-based EUROCAT congenital anomaly registries- Norway (2004-2010), Wales (2000-2010) and Funen, Denmark (2000-2010)-were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06-2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03-1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99-1.21). Adjusting for socio-economic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12-1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression.CONCLUSION: The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.

BACKGROUND: The prevalence of esophageal atresia (EA) has been shown to vary across different geographical settings. Investigation of geographical differences may provide an insight into the underlying etiology of EA. METHODS: The study population comprised infants diagnosed with EA during 1998 to 2007 from 18 of the 46 birth defects surveillance programs, members of the International Clearinghouse for Birth Defects Surveillance and Research. Total prevalence per 10,000 births for EA was defined as the total number of cases in live births, stillbirths, and elective termination of pregnancy for fetal anomaly (ETOPFA) divided by the total number of all births in the population. RESULTS: Among the participating programs, a total of 2943 cases of EA were diagnosed with an average prevalence of 2.44 (95% confidence interval [CI], 2.352.53) per 10,000 births, ranging between 1.77 and 3.68 per 10,000 births. Of all infants diagnosed with EA, 2761 (93.8%) were live births, 82 (2.8%) stillbirths, 89 (3.0%) ETOPFA, and 11 (0.4%) had unknown outcomes. The majority of cases (2020, 68.6%), had a reported EA with fistula, 749 (25.5%) were without fistula, and 174 (5.9%) were registered with an unspecified code. CONCLUSIONS: On average, EA affected 1 in 4099 births (95% CI, 1 in 39544251 births) with prevalence varying across different geographical settings, but relatively consistent over time and comparable between surveillance programs. Findings suggest that differences in the prevalence observed among programs are likely to be attributable to variability in population ethnic compositions or issues in reporting or registration procedures of EA, rather than a real risk occurrence difference. Birth Defects Research (Part A), 2012. (c) 2012 Wiley Periodicals, Inc.

Acardia is a severe, complex malformation of monozygotic twinning, but beyond clinical case series, very few epidemiologic data are available. The goals of this study were to assess the epidemiologic characteristics of acardia from birth defect registries in the International Clearinghouse for Birth Defects Surveillance and Research (Clearinghouse), and compare these findings to current literature. The study included 17 surveillance programs of the Clearinghouse representing 23 countries from North and South America, Europe, China, and Australia. Anonymized individual records with clinical and demographic data were reviewed centrally by clinical geneticists. A literature search was performed. A total of 164 cases of acardia were reported from an underlying cohort of 21.2 million births. Of these, 23% were elective pregnancy terminations. Rates did not vary significantly by maternal age. For many cases, information on pregnancy exposures and genetic testing was missing. However, these limited data did not suggest high rates of chronic illnesses (diabetes, seizure disorders) or lifestyle factors such as smoking. One case had trisomy 13. Major malformations were reported in 2.4% of co-twins. With some basic assumptions, the total prevalence of acardia was estimated at 1 in 50,000-70,000 births, and 1 in 200-280 monozygotic twins. In summary, acardia is a dramatic, probably underreported, and incompletely understood malformation. Studies on its epidemiology and etiology are challenging and still rare. An international collaboration of epidemiologists, clinicians, and geneticists is necessary to understand the etiology, pathogenesis, and occurrence of this severe malformation complex. (C) 2011 Wiley Periodicals, Inc.

Cyclopia is characterized by the presence of a single eye, with varying degrees of doubling of the intrinsic ocular structures, located in the middle of the face. It is the severest facial expression of the holoprosencephaly (HPE) spectrum. This study describes the prevalence, associated malformations, and maternal characteristics among cases with cyclopia. Data originated in 20 Clearinghouse (ICBDSR) affiliated birth defect surveillance systems, reported according to a single pre-established protocol. A total of 257 infants with cyclopia were identified. Overall prevalence was 1 in 100,000 births (95% CI: 0.89-1.14), with only one program being out of range. Across sites, there was no correlation between cyclopia prevalence and number of births (r = 0.08; P = 0.75) or proportion of elective termination of pregnancy (r = -0.01; P = 0.97). The higher prevalence of cyclopia among older mothers (older than 34) was not statistically significant. The majority of cases were liveborn (122/200; 61%) and females predominated (male/total: 42%). A substantial proportion of cyclopias (31%) were caused by chromosomal anomalies, mainly trisomy 13. Another 31% of the cases of cyclopias were associated with defects not typically related to HPE, with more hydrocephalus, heterotaxia defects, neural tube defects, and preaxial reduction defects than the chromosomal group, suggesting the presence of ciliopathies or other unrecognized syndromes. Cyclopia is a very rare defect without much variability in prevalence by geographic location. The heterogeneous etiology with a high prevalence of chromosomal abnormalities, and female predominance in HPE, were confirmed, but no effect of increased maternal age or association with twinning was observed. (C) 2011 Wiley Periodicals, Inc.

Bladder exstrophy (BE) is a complex congenital anomaly characterized by a defect in the closure of the lower abdominal wall and bladder. We aimed to provide an overview of the literature and conduct an epidemiologic study to describe the prevalence, and maternal and case characteristics of BE. We used data from 22 participating member programs of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). All cases were reviewed and classified as isolated, syndrome, and multiple congenital anomalies. We estimated the total prevalence of BE and calculated the frequency and odds ratios for various maternal and case characteristics. A total of 546 cases with BE were identified among 26,355,094 births. The total prevalence of BE was 2.07 per 100,000 births (95% CI: 1.90-2.25) and varied between 0.52 and 4.63 among surveillance programs participating in the study. BE was nearly twice as common among male as among female cases. The proportion of isolated cases was 71%. Prevalence appeared to increase with increasing categories of maternal age, particularly among isolated cases. The total prevalence of BE showed some variations by geographical region, which is most likely attributable to differences in registration of cases. The higher total prevalence among male cases and older mothers, especially among isolated cases, warrants further attention. (C) 2011 Wiley Periodicals, Inc.

Conjoined twins (CT) are a very rare developmental accident of uncertain etiology. Prevalence has been previously estimated to be 1 in 50,000 to 1 in 100,000 births. The process by which monozygotic twins do not fully separate but form CT is not well understood. The purpose of the present study was to analyze diverse epidemiological aspects of CT, including the different variables listed in the Introduction Section of this issue of the Journal. The study was made possible using the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) structure. This multicenter worldwide research includes the largest sample of CT ever studied. A total of 383 carefully reviewed sets of CT obtained from 26,138,837 births reported by 21 Clearinghouse Surveillance Programs (SP) were included in the analysis. Total prevalence was 1.47 per 100,000 births (95% CI: 1.32-1.62). Salient findings including an evident variation in prevalence among SPs: a marked variation in the type of pregnancy outcome, a similarity in the proportion of CT types among programs: a significant female predominance in CT: particularly of the thoracopagus type and a significant male predominance in parapagus and parasitic types: significant differences in prevalence by ethnicity and an apparent increasing prevalence trend in South American countries. No genetic, environmental or demographic significant associated factors were identified. Further work in epidemiology and molecular research is necessary to understand the etiology and pathogenesis involved in the development of this fascinating phenomenon of nature. (C) 2011 Wiley Periodicals, Inc.

To describe the characteristics and outcome of fetuses with Turner syndrome reported to a national congenital anomalies register.All cases with a diagnosis of Turner syndrome reported to Congenital Anomaly Register and Information Service for Wales (CARIS) between 1 January 1998 and 31 December 2007 were included. The cases were grouped in five categories based on their outcomes: fetal loss (FL), termination of pregnancy (TOP), live birth (LB), and postnatal (PN) detection and comparison was undertaken between the groups.One hundred twenty-four cases were reported during the study period. The prevalence of Turner syndrome was 1 in 4901 live female births. Seventy-four percent had 45 X karyotype while the rest had some form of Mosaic Turner karyotype. Pregnancy was terminated in 66% of antenatally diagnosed cases. FL and TOP groups had 92% and 87%, respectively, of 45 X karyotype - far greater than in the LB and PN groups. Increased nuchal thickness was the commonest anomaly noted in antenatal ultrasound and was a predictor for 45 X karyotype, FL, and termination.Termination was the most common outcome of fetuses diagnosed antenatally with Turner syndrome. This has modified the natural history of Turner syndrome particularly in cases with Mosaic karyotype.

Aim This paper outlines research into the causes of congenital anomalies, and introduces a pan-European study. The potential roles of nurses and midwives in this area are illustrated by a case report. Background Since the thalidomide disaster, use of drugs in pregnancy has been carefully monitored to prevent anything similar happening again. However, monitoring is incomplete and questions remain unanswered. Key issues Many medicines are essential for the health of pregnant women. However, drug use in pregnancy requires surveillance. Methods include spontaneous reporting of adverse events, cohort studies and case control studies. It is hoped that a Europe-wide study, combining data from several congenital anomaly registers, will provide a sufficiently large population to assess the impact of selected drugs on congenital anomalies. However, this work depends on the consistency of reporting by nurses and midwives. Conclusion Drug safety in pregnancy remains undetermined. Collaboration across Europe has the potential to provide a framework for safety evaluation. Implications for nursing management Prescribers should consider the possibility of pregnancy in women of child-bearing age. Careful review of maternal drug use in early pregnancy is essential. Midwives and nurses should be aware of adverse event drug reporting systems, including congenital anomaly registers.

Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin. We performed a literature search for studies of pregnant women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analysed to compare the congenital anomaly rate among foetuses of mothers using insulin analogues with foetuses of mothers using human insulin. Of 29 studies, we included 1286 foetuses of mothers using short-acting insulin analogues with 1089 references of mothers using human insulin and 768 foetuses of mothers using long-acting insulin analogues with 685 references of mothers using long-acting human insulin (Neutral Protamine Hagedorn). The congenital anomaly rate was 4.84% and 4.29% among the foetuses of mothers using lispro and aspart. For glargine and detemir, the congenital anomaly rate was 2.86% and 3.47%, respectively. No studies on the use of insulin glulisine and degludec in pregnancy were found. There was no statistically significant difference in the congenital anomaly rate among foetuses exposed to insulin analogues (lispro, aspart, glargine or detemir) compared with those exposed to human insulin or Neutral Protamine Hagedorn insulin. The total prevalence of congenital anomalies was not increased for foetuses exposed to insulin analogues. The small samples in the included studies provided insufficient statistical power to identify a moderate increased risk of specific congenital anomalies.

Trisomy 13 is one of the three autosomal trisomies compatible with viability. It is associated with structural anomalies, learning disability and poor survival. Advanced maternal age is the most frequently suggested risk factor. This is a population based register study to investigate the temporal trends of trisomy 13.Chromosomal trisomies were reviewed by the Welsh Congenital Anomaly Register using data from 1998-2012. All pregnancy outcomes were included. Prevalence rates and trends for all cases and for cases with mothers aged below 35 years and those aged 35 years and older were plotted for trisomy 13, 18 and 21. Possible risk factors contributing to the trend in older mothers were compared in the early and late period of the study.There were 124 cases of trisomy 13 over the 15 year period with 55 mothers aged 35 years and older. Overall prevalence was 2.5 per 10,000 total births. A significant declining trend in the prevalence of trisomy 13 in mothers aged 35 and older (χ(2) trend = 4.98, p=0.026) was noted. Rates for younger mothers were lower and remained stable. Prevalence of trisomy 18 and 21 in older mothers remained stable.The unexpected declining trend in trisomy 13 in older mothers could not be explained by the risk factors examined in this study. There have been no other reports of trends in the prevalence of trisomy 13 in older mothers in recent years. There is further need for surveillance of trends in future and in other populations.

Cloacal exstrophy presents as a complex abdominal wall defect thought to result from a mesodermal abnormality. Anatomically, its main components are Omphalocele, bladder Exstrophy and Imperforate anus. Other associated malformations include renal malformations and Spine defects (OEIS complex). Historically, the prevalence ranges from 1 in 200,000 to 400,000 births, with higher rates in females. Cloacal exstrophy is likely etiologically heterogeneous as suggested by its recurrence in families and occurrence in monozygotic twins. The defect has been described in infants with limb-body wall, with trisomy 18, and in one pregnancy exposed to Dilantin and diazepam. Due to its rarity, the use of a nonspecific diagnostic code for case identification, and lack of validation of the clinical findings, cloacal exstrophy remains an epidemiologic challenge. The purpose of this study was to describe the prevalence, associated anomalies and maternal characteristics among infants born with cloacal exstrophy. We used data from the International Clearinghouse for Birth Defects Surveillance and Research submitted from 18 birth defect surveillance programs representing 24 countries. Cases were clinically evaluated locally and reviewed centrally by two authors. Cases of persistent cloaca were excluded. A total of 186 cases of cloacal exstrophy were identified. Overall prevalence was 1 in 131,579 births: ranging from 1 in 44,444 births in Wales to 1 in 269,464 births in South America. Live birth prevalence was 1 in 184,195 births. Prevalence ratios did not vary by maternal age. Forty-two (22.6%) cases met the criteria for the OEIS complex, whereas 60 (32.3%) were classified as OEI and 18 (9.7%) as EIS (one with suspected VATER (0.5%)). Other findings included two cases with trisomy 13 (one without a karyotype confirmation), one with mosaic trisomy 12 (0.5%), one with mosaic 45, X (0.5%) and one classified as having amnion band sequence (0.5%). Twenty-seven (14.5%) infants had other anomalies unrelated to cloacal exstrophy. Cloacal exstrophy is a rare anomaly with variability in prevalence by geographic location. The proportion of cases classified as OEIS complex was lower in this study than previously reported. Among all cases, 54.8% were reported to have an omphalocele. (C) 2011 Wiley Periodicals, Inc.

Sirenomelia is a very rare limb anomaly in which the normally paired lower limbs are replaced by a single midline limb. This study describes the prevalence, associated malformations, and maternal characteristics among cases with sirenomelia. Data originated from 19 birth defect surveillance system members of the International Clearinghouse for Birth Defects Surveillance and Research, and were reported according to a single preestablished protocol. Cases were clinically evaluated locally and reviewed centrally. A total of 249 cases with sirenomelia were identified among 25,290,172 births, for a prevalence of 0.98 per 100,000, with higher prevalence in the Mexican registry. An increase of sirenomelia prevalence with maternal age less than 20 years was statistically significant. The proportion of twinning was 9%, higher than the 1% expected. Sex was ambiguous in 47% of cases, and no different from expectation in the rest. The proportion of cases born alive, premature, and weighting less than 2,500 g were 47%, 71.2%, and 88.2%, respectively. Half of the cases with sirenomelia also presented with genital, large bowel, and urinary defects. About 10-15% of the cases had lower spinal column defects, single or anomalous umbilical artery, upper limb, cardiac, and central nervous system defects. There was a greater than expected association of sirenomelia with other very rare defects such as bladder exstrophy, cyclopia/holoprosencephaly, and acardia-acephalus. The application of the new biological network analysis approach, including molecular results, to these associated very rare diseases is suggested for future studies. (C) 2011 Wiley Periodicals, Inc.

Rates of Down syndrome (DS) show considerable international variation, but a systematic assessment of this variation is lacking. The goal of this study was to develop and test a method to assess the validity of DS rates in surveillance programs, as an indicator of quality of ascertainment. The proposed method compares the observed number of cases with DS (livebirths plus elective pregnancy terminations, adjusted for spontaneous fetal losses that would have occurred if the pregnancy had been allowed to continue) in each single year of maternal age, with the expected number of cases based on the best-published data on rates by year of maternal age. To test this method we used data from birth years 2000 to 2005 from 32 surveillance programs of the International Clearinghouse for Birth Defects Surveillance and Research. We computed the adjusted observed versus expected ratio (aOE) of DS birth prevalence among women 25-44 years old. The aOE ratio was close to unity in 13 programs (the 95% confidence interval included 1), above 1 in 2 programs and below 1 in 18 programs (P

BACKGROUND: Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incomplete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly and single median rnaxillary central incisor. Information on the epidemiology of HPE is limited, both because few population-based studies have been reported, and because small Studies must observe a greater number of years in order to accumulate sufficient numbers of births for a reliable estimate. METHODS: We collected data from 2000 through 2004 from 24 of the 46 Birth Defects Registry Members of the International Clearinghouse for Birth Defects Surveillance and Research. This Study is based on more than 7 million births in various areas from North and South America, Europe, and Australia. RESULTS: A total of 963 HPE cases were registered, yielding an overall prevalence of 1.31 per 10,000 births. Because the estimate was heterogeneous, possible causes of variations among populations were analyzed: random variation, Under-reporting and over-reporting bias, variation in proportion of termination of pregnancies among all registered cases and real differences among populations. CONCLUSIONS: The data do not suggest large differences in total prevalence of HPE among the studied Populations that would be useful to generate etiological hypotheses.

Background: Liver dysfunction in pregnancy has serious consequences. Its frequency and characteristics have not been systematically documented in Britain. We have prospectively determined incidence, causes, and outcome of liver dysfunction in pregnancy in an obstetric unit in Southwest Wales, UK. Methods: A central laboratory identified all abnormal liver tests (bilirubin >25 μmol/l, aspartate transaminase >40 U/l, or γ glutamyl transpeptidase >35 U/l) from patients in antenatal clinics and wards of an obstetric unit serving a population of 250 000. Patients with abnormal liver tests were assessed and followed through after pregnancy. Medical advice was provided to obstetric teams. Findings: There were 4377 deliveries during the 15 month study. A total of 142 patients had abnormal liver tests. There were 206 contributing diagnoses, the great majority being pregnancy specific. Among the most important were pre-eclampsia (68), HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome (30), obstetric cholestasis (23), hyperemesis gravidarum (11), acute fatty liver of pregnancy (five), and hepatic infarct (one). Sepsis, postoperative factors, and placental pathology (51) were not uncommonly responsible but incidental or pre-existing hepatobiliary disease was infrequent (17). Sixty five patients were delivered early by induction or caesarean section because of liver dysfunction. Despite substantial liver related morbidity, there were no maternal deaths and only two intrauterine deaths. Conclusions: Liver dysfunction was seen in 3% of deliveries during a 15 month prospective study and was usually directly related to pregnancy with spontaneous recovery in the puerperium. Incidence of the most serious conditions, acute fatty liver of pregnancy and HELLP syndrome, was much greater than previously reported. Profound effects on maternal and infant health were observed but close medical and obstetric collaboration ensured low mortality.

The aim of this study was to evaluate the usefulness of estimating bladder volume with a dedicated portable ultrasound device immediately prior to gynaecological laparoscopy. Catheterisation was performed if the estimated volume was greater than 100 ml. Forty consecutive women were studied prospectively. Twenty-six women did not require catheterisation. The procedure was quick and effective in safely reducing the frequency of pre-operative catheterisation.