The circadian rhythm of the perinatal mortality rate in Switzerland.

The authors examine the relation between the perinatal mortality rate (PMR), birth weight in four categories, and hour of birth throughout the week in Switzerland, using data on 672,013 births and 5,764 perinatal deaths recorded between 1979 and 1987. From Monday to Friday, the PMR follows a circadian rhythm with a regular increase from early morning to evening, with a peak for babies born between 7 and 8 p.m. This pattern of variation has two main components: The circadian rhythms for the proportion of births in the four weight categories and the PMR circadian rhythm for babies weighing more than 2.5 kg. According to a cosinor model, which describes about 40% of the total variation in the PMR, the most important determinants are changes in the proportions of births: Low birth weight increases toward the afternoon and night. Mechanisms underlying the weight-specific timing of birth are discussed, including time selection of birth according to obstetric risks, the direct effect of neonatal and obstetric care, and chronobiologic behavior.

Starting a Family at Your Parent's House: Multigenerational Households and Below Replacement Fertility in urban Bulgaria

In societies with strong multigenerational links, economic uncertainty results in choosing to stay with one child, sometimes in association with postponement of first births (i.e. Italy) and sometimes in early childbearing (i.e. Bulgaria). The interaction between intergenerational family practices in lowest-low fertility contexts is likely to play a role on differences timing to parenthood. In this paper, we focus on the phenomenon of women who have one child in their early twenties in Bulgaria and do not intend to have a second child. We argue that the key to this process is the persistence of extended multigenerational households in the Bulgarian context and their effect on young couples' fertility decision making. We use semi-structured interview data from the project Fertility Choices in Central and Eastern Europe and ethnographic fieldnotes. The interviews were collected from a sample of 22 couples resident in Sofia and representing different permutations of educational level, marital status and number of children (0 or 1). The four-year ethnographic fieldwork was conducted in both rural and urban Bulgaria between 1997 and 2009. Results suggest that as long as the economic situation remains dire, and young Bulgarians hopes for the future remain cynical, multigenerational households represent the accepted practice of entering into parenthood for young families.

Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.

OBJECTIVE: This contribution addresses the risk associated with exposure to statins during pregnancy. DESIGN: Multicentre observational prospective controlled study. SETTING: European Network of Teratology Information Services. POPULATION: Pregnant women who contacted one of 11 participating centres, seeking advice about exposure to statins during pregnancy, or to agents known to be nonteratogenic. METHODS: Pregnancies exposed during first trimester to statins were followed up prospectively, and their outcomes were compared with a matched control group. MAIN OUTCOME MEASURES: Rates of major birth defects, live births, miscarriages, elective terminations, preterm deliveries and gestational age and birthweight at delivery. RESULTS: We collected observations from 249 exposed pregnancies and 249 controls. The difference in the rate of major birth defects between the statin-exposed and the control groups was small and statistically nonsignificant (4.1% versus 2.7% odds ratio [OR] 1.5; 95% confidence interval [95% CI] 0.5-4.5, P = 0.43). In an adjusted Cox model, the difference between miscarriage rates was also small and not significant (hazard ratio 1.36, 95% CI 0.63-2.93, P = 0.43). Premature birth was more frequent in exposed pregnancies (16.1% versus 8.5%; OR 2.1, 95% CI 1.1-3.8, P = 0.019). Nonetheless, median gestational age at birth (39 weeks, interquartile range [IQR] 37-40 versus 39 weeks, IQR 38-40, P = 0.27) and birth weight (3280 g, IQR 2835-3590 versus 3250 g, IQR 2880-3630, P = 0.95) did not differ between exposed and non-exposed pregnancies. CONCLUSIONS: This study did not detect a teratogenic effect of statins. Its statistical power remains insufficient to challenge current recommendations of treatment discontinuation during pregnancy.

Increasing prevalence of gastroschisis in Europe 1980-2002: a phenomenon restricted to younger mothers?

Gastroschisis is an abdominal wall defect more prevalent in offspring of young mothers. It is known to be increasing in prevalence despite the general decrease in the proportion of births to young European women. We investigated whether the increase in prevalence was restricted to the high-risk younger mothers. We analysed 936 cases of gastroschisis from 25 population-based registries in 15 European countries, 1980-2002. We fitted a Bayesian Hierarchical Model which allowed us to estimate trend, to estimate which registries were significantly different from the common distribution, and to adjust simultaneously for maternal age, time (in grouped years) and the random variation between registries. The maternal age-standardised prevalence (standardised to the year 2000 European maternal age structure) increased almost fourfold from 0.54 [95% Credible Interval (CrI) 0.37, 0.75] per 10,000 births in 1980-84 to 2.12 [95% CrI 1.85, 2.40] per 10,000 births in 2000-02. The relative risk of gastroschisis for mothers <20 years of age in 1995-2002 was 7.0 [95% CrI 5.6, 8.7]. There were geographical differences within Europe, with higher rates of gastroschisis in the UK, and lower rates in Italy after adjusting for maternal age. After standardising for regional variation, our results showed that the increase in risk over time was the same for mothers of all ages--the increase for mothers <20 years was 3.96-fold compared with an increase of 3.95-fold for mothers in the other age groups. These findings indicate that the phenomenon of increasing gastroschisis prevalence is not restricted to younger mothers only.

Contribution of ultrasonographic examination to the prenatal detection of chromosomal abnormalities in 19 centres across Europe.

The objective of this study was to evaluate the prenatal detection of chromosomal abnormalities by fetal ultrasonographic examination in a large database provided by 19 Registries of Congenital Anomalies from 11 European countries. This study included 1738 cases of chromosomal abnormalities, liveborn, stillborn or termination of pregnancy regardless of maternal age from a population of 664,340 births during the period 1996 - 1998. The most frequent chromosomal anomalies were Down syndrome (n=1050), trisomy 18 (n=191), Turner syndrome (n=125), trisomy 13 (n=86), and triploidy (n=56). Fetal ultrasonographic examination resulted in the prenatal detection of 37.7% of the chromosomal abnormalities, thereby resulting in a reduction of 28.6% in their prevalence at birth due to terminations of pregnancy. The detection rate by ultrasound examination varied according to local policies of prenatal diagnosis : it was lower in countries where routine scan were not performed and higher in countries in which at least one routine anomaly scan during the second trimester of pregnancy was performed. The ultrasound detection varied according to the specific chromosomal anomaly and was lowest for Klinefelter syndrome (5.7%) and highest for triploidy (78.6%). For Down syndrome it was 26.4%. Termination of pregnancy was performed in 75.9% of the cases. Among the 655 cases detected by ultrasound, the most frequent ultrasound signs by category of chromosomal abnormalities were analysed. This study shows that ultrasound screening is an important tool in the prenatal detection of chromosomal abnormalities in Europe, leading to a significant reduction in the prevalence of livebirth children with chromosomal anomalies.

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.

Do Agglomeration Economies Reduce the Sensitivity of Firm Location to Tax Differentials?

Recent theoretical work in economic geography has shown that agglomeration forces can mitigate 'race-to-the-bottom' tax competition, by partly or fully offsetting firms' sensitivity to tax differentials. We test this proposition using data on firm births across Swiss municipalities. We find that corporate taxes deter firm births less in more spatially concentrated sectors. Firms in sectors with an agglomeration intensity in the top quintile are less than half as responsive to differences in corporate tax burdens as firms in sectors with an agglomeration intensity in the bottom quintile. Hence, agglomeration economies do appear to attenuate the impact of tax differentials on firms' location choices.

Atrioventricular septal defects among infants in Europe: a population-based study of prevalence, associated anomalies, and survival.

OBJECTIVE: To describe the epidemiology of chromosomal and non-chromosomal cases of atrioventricular septal defects in Europe. METHODS: Data were obtained from EUROCAT, a European network of population-based registries collecting data on congenital anomalies. Data from 13 registries for the period 2000-2008 were included. RESULTS: There was a total of 993 cases of atrioventricular septal defects, with a total prevalence of 5.3 per 10,000 births (95% confidence interval 4.1 to 6.5). Of the total cases, 250 were isolated cardiac lesions, 583 were chromosomal cases, 79 had multiple anomalies, 58 had heterotaxia sequence, and 23 had a monogenic syndrome. The total prevalence of chromosomal cases was 3.1 per 10,000 (95% confidence interval 1.9 to 4.3), with a large variation between registers. Of the 993 cases, 639 cases were live births, 45 were stillbirths, and 309 were terminations of pregnancy owing to foetal anomaly. Among the groups, additional associated cardiac anomalies were most frequent in heterotaxia cases (38%) and least frequent in chromosomal cases (8%). Coarctation of the aorta was the most common associated cardiac defect. The 1-week survival rate for live births was 94%. CONCLUSION: Of all cases, three-quarters were associated with other anomalies, both chromosomal and non-chromosomal. For infants with atrioventricular septal defects and no chromosomal anomalies, cardiac defects were often more complex compared with infants with atrioventricular septal defects and a chromosomal anomaly. Clinical outcomes for atrioventricular septal defects varied between regions. The proportion of termination of pregnancy for foetal anomaly was higher for cases with multiple anomalies, chromosomal anomalies, and heterotaxia sequence.

Paper 4: EUROCAT statistical monitoring: identification and investigation of ten year trends of congenital anomalies in Europe.

BACKGROUND: As part of EUROCAT's surveillance of congenital anomalies in Europe, a statistical monitoring system has been developed to detect recent clusters or long-term (10 year) time trends. The purpose of this article is to describe the system for the identification and investigation of 10-year time trends, conceived as a "screening" tool ultimately leading to the identification of trends which may be due to changing teratogenic factors.METHODS: The EUROCAT database consists of all cases of congenital anomalies including livebirths, fetal deaths from 20 weeks gestational age, and terminations of pregnancy for fetal anomaly. Monitoring of 10-year trends is performed for each registry for each of 96 non-independent EUROCAT congenital anomaly subgroups, while Pan-Europe analysis combines data from all registries. The monitoring results are reviewed, prioritized according to a prioritization strategy, and communicated to registries for investigation. Twenty-one registries covering over 4 million births, from 1999 to 2008, were included in monitoring in 2010.CONCLUSIONS: Significant increasing trends were detected for abdominal wall anomalies, gastroschisis, hypospadias, Trisomy 18 and renal dysplasia in the Pan-Europe analysis while 68 increasing trends were identified in individual registries. A decreasing trend was detected in over one-third of anomaly subgroups in the Pan-Europe analysis, and 16.9% of individual registry tests. Registry preliminary investigations indicated that many trends are due to changes in data quality, ascertainment, screening, or diagnostic methods. Some trends are inevitably chance phenomena related to multiple testing, while others seem to represent real and continuing change needing further investigation and response by regional/national public health authorities.

Prevention of vitamin K deficiency bleeding with three oral mixed micellar phylloquinone doses: results of a 6-year (2005-2011) surveillance in Switzerland.

In 2003, the Swiss guidelines to prevent vitamin K deficiency bleeding (VKDB) were adapted. As two oral doses (2 mg, hour/day 4) of mixed micellar VK preparation had failed to abolish late VKDB, a third dose (week 4) was introduced. This report summarizes the new guidelines acceptance by Swiss pediatricians and the results of a prospective 6-year surveillance to study their influence on the incidence of VKDB. The new guidelines acceptance by Swiss pediatricians was evaluated by a questionnaire sent to all pediatricians of the Swiss Society of Paediatrics. With the help of the Swiss Paediatric Surveillance Unit, the incidence of VKDB was monitored prospectively from July 1, 2005 until June 30, 2011. Over a 6-year period (458,184 live births), there was one case of early and four cases of late VKDB. Overall incidence was 1.09/10(5) (95 % confidence intervals (CI) 0.4-2.6). Late VKDB incidence was 0.87/10(5) (95 % CI 0.24-2.24). All four infants with late VKDB had an undiagnosed cholestasis at the time of bleeding; parents of 3/4 had refused VK prophylaxis, and in 1/4, the third VK dose had been forgotten. Compared with historical control who had received only two oral doses of mixed micellar VK (18 cases for 475,372 live births), the incidence of late VKDB was significantly lower with three oral doses (Chi(2),Yates correction, P = 0.007). CONCLUSION: VKDB prophylaxis with 3 × 2 mg oral doses of mixed micellar VK seems to prevent adequately infants from VKDB. The main risk factors for VKDB in breast-fed infants are parental VK prophylaxis refusal or an unknown cholestasis.

Biliary atresia: Swiss national study, 1994-2004.

OBJECTIVES: To determine the epidemiology of biliary atresia (BA) in Switzerland, the outcome of the children from diagnosis, and the prognostic factors. PATIENTS AND METHODS: The records of all patients with BA born in Switzerland between January 1994 and December 2004 were analyzed. Survival rates were calculated with the Kaplan-Meier method, and prognostic factors evaluated with the log rank test. Median follow up was 58 months (range, 5-124). RESULTS: BA was diagnosed in 48 children. Incidence was 1 in 17,800 live births (95% confidence interval 1/13,900-1/24,800), without significant regional, annual, or seasonal variation. Forty-three children underwent a Kasai portoenterostomy (PE) in 5 different Swiss pediatric surgery units. Median age at Kasai PE was 68 days (range, 30-126). Four-year survival with native liver after Kasai PE was 37.4%. Liver transplantation (LT) was needed in 31 in 48 children with BA, including 5 patients without previous Kasai PE. Four patients (8%, all born before 2001) died while waiting for LT, and 29 LT were performed in 27 patients (28 in Geneva and 1 in Paris). All of the transplanted patients are alive. Four-year overall BA patient survival was 91.7%. Four-year survival with native liver was 75% in patients who underwent Kasai PE before 46 days, 33% in patients operated on between 46 and 75 days, and 11% in patients operated on after 75 days (P = 0.02). CONCLUSIONS: Overall survival of patients with BA in Switzerland compares favorably with current international standards, whereas results of the Kasai operation could be improved to reduce the need for LTs in infancy and early childhood.

Descriptive epidemiology of Cornelia de Lange syndrome in Europe.

Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly/mental retardation syndrome consisting of characteristic dysmorphic features, microcephaly, hypertrichosis, upper limb defects, growth retardation, developmental delay, and a variety of associated malformations. We present a population-based epidemiological study of the classical form of CdLS. The data were extracted from the database of European Surveillance of Congenital Anomalies (EUROCAT) database, a European network of birth defect registries which follow a standard methodology. Based on 23 years of epidemiologic monitoring (8,558,346 births in the 1980-2002 period), we found the prevalence of the classical form of CdLS to be 1.24/100,000 births or 1:81,000 births and estimated the overall CdLS prevalence at 1.6-2.2/100,000. Live born children accounted for 91.5% (97/106) of cases, fetal deaths 2.8% (3/106), and terminations of pregnancy following prenatal diagnosis 5.7% (6/106). The most frequent associated congenital malformations were limb defects (73.1%), congenital heart defects (45.6%), central nervous system malformations (40.2%), and cleft palate (21.7%). In the last 11 years, as much as 68% of cases with major malformations were not detected by routine prenatal US. Live born infants with CdLS have a high first week survival (91.4%). All patients were sporadic. Maternal and paternal age did not seem to be risk factors for CdLS. Almost 70% of patients, born after the 37th week of gestation, weighed <or=2,500 g. Low birth weight correlated with a more severe phenotype. Severe limb anomalies were significantly more often present in males.

Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice.

Cleft palate is a common congenital disorder that affects up to 1 in 2,500 live human births and results in considerable morbidity to affected individuals and their families. The etiology of cleft palate is complex, with both genetic and environmental factors implicated. Mutations in the transcription factor-encoding genes p63 and interferon regulatory factor 6 (IRF6) have individually been identified as causes of cleft palate; however, a relationship between the key transcription factors p63 and IRF6 has not been determined. Here, we used both mouse models and human primary keratinocytes from patients with cleft palate to demonstrate that IRF6 and p63 interact epistatically during development of the secondary palate. Mice simultaneously carrying a heterozygous deletion of p63 and the Irf6 knockin mutation R84C, which causes cleft palate in humans, displayed ectodermal abnormalities that led to cleft palate. Furthermore, we showed that p63 transactivated IRF6 by binding to an upstream enhancer element; genetic variation within this enhancer element is associated with increased susceptibility to cleft lip. Our findings therefore identify p63 as a key regulatory molecule during palate development and provide a mechanism for the cooperative role of p63 and IRF6 in orofacial development in mice and humans.

Holt Oram syndrome: a registry-based study in Europe.

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.

Risk of a Down syndrome live birth in women 45 years of age and older.

OBJECTIVES: To determine the risk of a Down syndrome (DS) live birth for women 45 years of age and over. METHODS: A meta-analysis of data from five published articles, 13 EUROCAT congenital anomaly population registers and two unpublished sources. RESULTS: Information was available on the number of DS live births occurring amongst 13,745 live births to women 45 years of age and over. Information was also available on DS pregnancies diagnosed prenatally that were subsequently terminated. These pregnancies were adjusted for expected fetal loss to estimate the number of live births that would have occurred in the absence of prenatal diagnoses, when a total of 471 DS live births were estimated to have occurred. The risk of a DS birth did not increase for women 45 years of age and over. The average risk was 34 per 1000 births (95% CI: 31-37). CONCLUSION: The risk of a DS live birth for women 45 years of age and over is considerably lower than has often been previously assumed. The most likely explanation is that women of this age are more likely to miscarry DS pregnancies than younger mothers.