H.E.K. de Walle

Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase ( MTHFR ): findings from over 7000 newborns from 16 areas world wide

Since its biochemical characterisation in 19911 and its genetic identification in 1995,2 677C>T allele (T allele) of the 5,10 methylenetetrahydrofolate reductase ( MTHFR ) gene has been a focus of increasing interest from researchers world wide. The expanding spectrum of common conditions linked with the 677C>T allele now includes certain adverse birth outcomes (including birth defects), pregnancy complications, cancers, adult cardiovascular diseases, and psychiatric disorders.3–8 Although several of these associations remain unconfirmed or controversial,4 their scope is such that it becomes of interest to explore the geographical and ethnic distribution of the allele and associated genotypes.9 Accurate information on such distribution can contribute to studies of gene-disease associations (by providing reference population data) and population genetics (by highlighting geographical and ethnic variations suggestive of evolutionary pressures),10 as well as help to evaluate health impact (by allowing estimates of population attributable fraction). Current population data, however, show gaps and even for some ethnic groups or large geographical areas (for example, China) few data are available.3 Our aim was to supplement the available data by collecting a large and diverse sample of newborns from different geographical areas and ethnic groups, and to examine international variations in the distribution of the 677C>T allele. We present findings relating to more than 7000 newborns from 16 areas around the world. The study was conducted under the auspices of the International Clearinghouse for Birth Defect Monitoring Systems (ICBDMS) and was coordinated through its head office, the International Center on Birth Defects (ICBD). ### Sample selection Participating programmes, in consultation with the coordinating group, identified a population sampling approach that would be simple yet minimise sampling bias with respect to the MTHFR genotype. We made an explicit attempt to sample systematically the newborn population. Details of each programme’s approach are listed below, and further …

A demographic approach to the assessment of Down syndrome screening performance

The aim of this article is to examine the performance of screening for fetal Down syndrome (DS) in the context of demographic variation in time and place, using population and fertility data for several European countries. Two screening approaches are distinguished: one on the basis of maternal serum screening with human chorionic gonadotropin (hCG) and alpha‐fetoprotein (AFP) in combination with maternal age, and one on the basis of maternal age only. Screening performance, as measured by detection and false‐positive ratios, is shown to be the result of the screening approach chosen and of the demographic characteristics of the population under consideration. A proper distinction between these two determinants of DS screening performance should be made, in order to distinguish between an improvement in screening performance that is brought about by a new screening approach and an improvement that is brought about by demographic change. We recommend that measures of DS screening performance be standardized for demographic variation. The methodology and demographic data presented in this article can be used for this purpose.

Impact of introduction of 20‐week ultrasound scan on prevalence and fetal and neonatal outcomes in cases of selected severe congenital heart defects in The Netherlands

To evaluate in a population‐based cohort the effect of the introduction of the 20‐week ultrasound scan in 2007 on the time of diagnosis, pregnancy outcome and total prevalence and liveborn prevalence of cases with selected congenital heart defects (CHDs) in The Netherlands.

Birth Defect and Risk Factor Surveillance in the Northern and Southwestern Netherlands

Objective: To survey the associations between several risk factors and birth defects, in order to detect potential new teratogens. Methods: Data of the two Dutch European Registration of Congenital Anomalies (EUROCAT) registries collected before January 1, 1998 were used to perform χ2 tests for a large number of risk factors and birth defects. Defects caused by chromosomal or monogenic disorders were analyzed separately. Results: Cross-tabulations of 80 groups of birth defects with 303 risk factors were studied. Of these, 126 combinations had a p value under 0.05, and 34 had a p value under 0.001. Of these 34 associations, some are known in the literature, some were found before in the same databases and some were new associations. Conclusions: This is a good method for generating new hypotheses for associations between risk factors and birth defects. It can be a start for new, more in-depth studies of potential teratogens.

Letter to the Editor: Folic acid prevents more than neural tube defects: A registry-based study in the northern Netherlands

It has been shown that periconceptional intake of folic acid (FA) reduces the recurrence and occurrence of neural tube defects (NTDs) with 50-70% [1, 2]. The randomised clinical trial of Czeizel [1] suggested a protective effect on other defects as well. Some later studies confirmed his findings, while others did not. Using data from the EUROCAT northern Netherlands registry, we have investigated the possible preventive effect of FA in five selected groups of malformations. These malformations are NTDs, heart defects, oral clefts, urinary tract defects, and limb reduction defects.

The association of air pollution with congenital anomalies : An exploratory study in the northern Netherlands

BACKGROUND There are a growing number of reports on the association between air pollution and the risk of congenital anomalies. However, the results are inconsistent and most studies have only focused on the association of air pollution with congenital heart defects and orofacial clefts. OBJECTIVES Using an exploratory study design, we aimed to identify congenital anomalies that may be sensitive to maternal exposure to specific air pollutants during the periconceptional period. METHODS We conducted a case-control study of 7426 subjects born in the 15 years between 1999 and 2014 and registered in the European Registration of Congenital Anomalies and Twins Northern Netherlands (EUROCAT NNL). Concentrations of various air pollutants (PM10, PM2.5, PM10-2.5, NO2, NOX, absorbance) were obtained using land use regression models from the European Study of Cohorts for Air Pollution Effects (ESCAPE). We linked these data to every subject in the EUROCAT NNL registry via their full postal code. Cases were classified as children or fetuses born in the 15-year period with a major congenital anomaly that was not associated with a known monogenic or chromosomal anomaly. Cases were divided into anomaly subgroups and compared with two different control groups: control group 1 comprised children or fetuses with a known monogenic or chromosomal anomaly, while control group 2 comprised all other non-monogenic and non-chromosomal registrations. RESULTS Using control group 1 (n = 1618) for analysis, we did not find any significant associations, but when we used control group 2 (ranges between n = 4299 and n = 5771) there were consistent positive associations between several air pollutants (NO2, PM2.5, PM10-2.5, absorbance) and the genital anomalies subgroup. CONCLUSION We examined various congenital anomalies and their possible associations with a number of air pollutants in order to generate hypotheses for future research. We found that air pollution exposure was positively associated with genital anomalies, mainly driven by hypospadias. These results broaden the evidence of associations between air pollution exposure during gestation and congenital anomalies in the child. They warrant further research, which should also focus on possible underlying mechanisms.

OP12.08: Prenatal diagnosis of urinary tract anomalies: a cohort study in the northern Netherlands

of amniotic fluid and abnormal protruding mass on the lower abdominal wall was additionally detected by 3D. In the case of hymen polyp with hymenal atresia, the polyp pedunculated to hymen was clearly detected by 3D. In the case of perineal lipoma with aproctia, the lack of ‘‘target sign’’ detected by 2D was one of the clues for the diagnosis. Conclusions: In the cases with ambiguous fetal sex and/or abnormal appearance of the external genitalia, 3D ultrasonography, enabling to depict a superficial stereoscopic abnormal appearance including external genitalia, is helpful to diagnosis DSD in utero.

OP18.07: Pre‐ and postnatal diagnosis of fetal trisomy in the north‐east of the Netherlands

Objectives: To describe the diagnostic pathway for 175 consecutive cases of trisomy 21, 18 or 13. Methods: Prenatal and postnatal data were examined from 118 consecutive cases of trisomy 21 and 57 cases of trisomy 18 or trisomy 13 with an estimated date of delivery was between 1-6-2008 and 1-6-2010. Results: In 73 (42%) of 175 trisomic pregnancies a first trimester (FTS) scan was performed and in 62 (85%) of these cases an anomaly was diagnosed or the risk of the combined test was increased. In 61 (35%) trisomic pregnancies FTS was declined but a second trimester scan (STS) was performed which revealed anomalies in 38% of cases with trisomy 21 and a 83% with trisomy 18 or 13. In 18 (10%) of the affected pregnancies neither invasive testing nor FTS or STS were performed. Conclusions: The first trimester scan (FTS) and the combined test (CT) are effective in detecting fetal trisomy. If screening is postponed to the second trimester the detection of trisomy 21 is less than 50%; fetuses with trisomy 18 or 13 are almost always identified but not always before the legal limit for abortion.

Report on the Second National Conference on Genetics and Public Health

Abstracts Community Genet 1999;2:119–136 121 Plenary Sessions Community Genet 1999;2:119–136 121 Plenary Session