Maternal occupational exposure to endocrine-disrupting chemicals and urogenital anomalies in the offspring.

STUDY QUESTION: Is there an association between maternal occupational exposure to endocrine-disrupting chemicals (EDCs) early in pregnancy and subgroups of congenital anomalies of kidney and urinary tract (CAKUT), and hypospadias? SUMMARY ANSWER: Exposure to specific EDCs can increase the risk of CAKUT and no association with hypospadias was observed. WHAT IS KNOWN ALREADY: Previous studies showed an association between maternal occupational exposure to EDCs and hypospadias. However, little is known about the effect of these chemicals on the development of CAKUT, especially subgroups of urinary tract anomalies. STUDY DESIGN, SIZE, DURATION: For this case-control study, cases with urogenital anomalies from the European Concerted Action on Congenital Anomalies and Twins Northern Netherlands (Eurocat NNL) registry and non-malformed controls from the Lifelines children cohort (living in the same catchment region as Eurocat NNL) born between 1997 and 2013 were selected. This study included 530 cases with CAKUT, 364 cases with hypospadias, 7 cases with both a urinary tract anomaly and hypospadias and 5602 non-malformed controls. Cases with a genetic or chromosomal anomaly were excluded, and to avoid genetic correlation, we also excluded cases in which a sibling with the same defect was included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Information on maternal occupation held early in pregnancy was collected via self-administered questionnaires. Job titles were translated into occupational exposure to EDCs using a job-exposure matrix (JEM). Adjusted odds ratios (aORs) and 95% CIs were estimated to assess the association between maternal occupational exposure to EDCs (and to specific types of EDCs) and CAKUT and hypospadias. MAIN RESULTS AND THE ROLE OF CHANCE: For CAKUT and hypospadias, 23.1% and 22.9% of the cases were exposed to EDCs, respectively, whereas 19.8% of the controls were exposed. We found an association between maternal occupational exposure to organic solvents/alkylphenolic compounds and CAKUT (aOR 1.41, 95% CI 1.01-1.97) that became stronger when combinations of urinary tract anomalies co-occurred with other defects (aOR 7.51, 95% CI 2.41-23.43). An association was also observed for exposure to phthalates/benzophenones/parabens/siloxanes and CAKUT (aOR 1.56, 95% CI 1.06-2.29), specifically urinary collecting system anomalies (aOR 1.62, 95% CI 1.03-2.54) and combinations of urinary tract anomalies (aOR 2.90, 95% CI 1.09-7.71). We observed no association between EDC exposure and hypospadias. LIMITATIONS, REASONS FOR CAUTION: The different study designs of Eurocat NNL and Lifelines could have introduced differential information bias. Also, exposure misclassification could be an issue: it is possible that the actual exposure differed from the exposure estimated by the JEM. In addition, women could also have been exposed to other exposures not included in the analysis, which could have resulted in residual confounding by co-exposures. WIDER IMPLICATIONS OF THE FINDINGS: Women, their healthcare providers, and their employers need to be aware that occupational exposure to specific EDCs early in pregnancy may be associated with CAKUT in their offspring. An occupational hygienist should be consulted in order to take exposure to those specific EDCs into consideration when risk assessments are carried out at the workplace. STUDY FUNDING/COMPETING INTEREST(S): N.S. was paid by the Graduate School of Medical Sciences (MD/PhD programme), University Medical Center Groningen (UMCG), Groningen, the Netherlands. Eurocat Northern Netherlands is funded by the Dutch Ministry of Health, Welfare and Sports. The Lifelines Biobank initiative has been made possible by subsidy from the Dutch Ministry of Health, Welfare and Sport, the Dutch Ministry of Economic Affairs, the University Medical Center Groningen (UMCG the Netherlands), University Groningen and the Northern Provinces of the Netherlands. The authors report no conflict of interest. TRIAL REGISTRATION NO: N/A.

Congenital anomalies in the offspring of occupationally exposed mothers: a systematic review and meta-analysis of studies using expert assessment for occupational exposures.

STUDY QUESTION: Is there an association between maternal occupational exposure to solvents, pesticides and metals as assessed by expert-based assessment and congenital anomalies in the offspring? SUMMARY ANSWER: There is an association between maternal occupational exposure to solvents and congenital anomalies in the offspring, including neural tube defects, congenital heart defects and orofacial clefts. WHAT IS KNOWN ALREADY: One important environmental risk factor for development of congenital anomalies is maternal occupational exposure to chemicals in the workplace prior to and during pregnancy. A number of studies have assessed the association with often conflicting results, possibly due to different occupational exposure assessing methods. STUDY DESIGN, SIZE, DURATION: For this systematic review with meta-analysis, the search terms included maternal occupation, exposure, congenital anomalies and offspring. Electronic databases MEDLINE and EMBASE were searched for English studies up to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two reviewers independently screened all citations identified by the search. Case-control studies and cohort studies were included if (I) they reported on the association between maternal occupational exposure to solvents, pesticides or metals and congenital anomalies, and (II) assessment of occupational exposure was performed by experts. Data on study characteristics, confounders and odds ratios (ORs) were extracted from the included studies for four subgroups of congenital anomalies. Methodological quality was assessed using the Newcastle-Ottawa Scale. In the meta-analysis, random effects models were used to pool estimates. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 2806 titles and abstracts and 176 full text papers were screened. Finally, 28 studies met the selection criteria, and 27 studies could be included in the meta-analysis. Our meta-analysis showed that maternal occupational exposure to solvents was associated with neural tube defects (OR: 1.51, 95%CI: 1.09-2.09) and congenital heart defects (OR: 1.31, 95%CI:1.06-1.63) in the offspring. Also maternal occupational exposure to glycol ethers, a subgroup of solvents, was associated with neural tube defects (OR: 1.93, 95%CI: 1.17-3.18) and orofacial clefts (OR: 1.95, 95%CI: 1.38-2.75) in the offspring. Only one study investigated the association between maternal occupational exposure to solvents and hypospadias and found an association (OR: 3.63, 95%CI: 1.94-7.17). Results of the included studies were consistent. In our meta-analysis, we found no associations between occupational exposure to pesticides or metals and congenital anomalies in the offspring. LIMITATIONS, REASONS FOR CAUTION: A limited number of studies was included, which made it impossible to calculate pooled estimates for all congenital anomalies, analyse individual chemicals or calculate exposure-response relations. Bias could have been introduced because not all included studies corrected for potentially confounding factors. WIDER IMPLICATIONS OF THE FINDINGS: Employers and female employees should be aware of the possible teratogenic effects of solvent exposure at the workplace. Therefore, is it important that clinicians and occupational health specialist provide women with preconception advice on occupational solvent exposure, to reduce the congenital anomaly risk. STUDY FUNDING/COMPETING INTEREST(S): NSp was paid by the Graduate School of Medical Sciences (MD/PhD program), UMCG, Groningen, the Netherlands. EUROCAT Northern Netherlands is funded by the Dutch Ministry of Health, Welfare and Sports. There are no competing interests. REGISTRATION NUMBER: CRD42017053943.

Deviant early pregnancy maternal triglyceride levels and increased risk of congenital anomalies: a prospective community-based cohort study.

OBJECTIVE: The maternal lipid profile could be of importance in congenital anomaly development. This study therefore investigates whether the maternal lipid profile during early pregnancy is associated with major nonsyndromic congenital anomalies (MNCA). DESIGN: Prospective community-based cohort study. SETTING: Amsterdam Born Children and their Development (ABCD) study. POPULATION: A cohort of 3074 pregnant women recruited in 2003-2004 and their offspring. METHODS: Non-fasting blood samples from pregnant women participating in the ABCD-study (median 12.9 weeks of gestation) were analysed for triglycerides (TG), cholesterol (TC), free fatty acids (FFA), apolipoprotein B (ApoB), and apolipoprotein A1 (ApoA) (n = 3074). The perinatal outcome (MNCA) was obtained from the Youth Health Care Registration and two questionnaires. Adjustment was made for ethnicity. MAIN OUTCOME MEASURE: MNCA prevalence. RESULTS: The prevalence of MNCA was 2.2% (n = 68: 20 cardiovascular, 25 bone and muscle, and 23 other single anomalies). A nonlinear association was found between maternal TG levels and MNCA prevalence. With a lower or higher level of maternal TG, the estimated probability increased: a TG level of 0.73 mmol/l (5th percentile), of 1.28 mmol/l (50th percentile), and of 2.35 mmol/l (95th percentile) corresponded with an estimated probability of 3.6, 2.1, and 2.9%, respectively. Unadjusted subgroup analyses showed that the U-shaped association was most prominent for cardiovascular congenital anomalies. Other lipids were not associated with MNCA. CONCLUSIONS: Both low and high maternal TG levels during early pregnancy were associated with an increased risk of MNCA in offspring. This suggests that an attempt should be made to normalise TG levels before or during early pregnancy; however, replication of our results is necessary before clinical practice recommendations can be made.

Impact of introduction of mid-trimester scan on pregnancy outcome of open spina bifida in The Netherlands.

OBJECTIVE: To examine the impact of introduction of the mid-trimester scan on pregnancy outcome in cases of open spina bifida in two regions of The Netherlands. METHODS: This was a retrospective cohort study of 190 cases of open spina bifida diagnosed pre- or postnatally, with an estimated date of delivery between 2003 and 2011. RESULTS: With implementation of the mid-trimester scan the percentage of cases of open spina bifida detected before the 24(th) week of pregnancy increased from 43% to 88%. The rise in prenatal detection rate was associated with a significant increase in the number of terminated pregnancies and a decrease in the rate of perinatal loss; the percentage of children born alive did not change significantly. In the subgroup that underwent a scan between 18 and 24 weeks of pregnancy, cranial signs were present in 94.4% of cases. CONCLUSION: Introduction of the mid-trimester scan has led to an increase in early identification of pregnancies complicated by open spina bifida. Pregnancies previously destined to end in perinatal loss are now terminated whilst pregnancies with a relatively good prognosis are frequently continued; the number of children with open spina bifida who are born alive has not changed significantly. Our study confirms that prenatal diagnosis is usually triggered by visualization of a lemon-shaped skull or a banana-shaped cerebellum.

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.

OBJECTIVES: 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. METHODS: We included children and fetuses diagnosed with selected severe CHD, born in the 11-year period from 2001 to 2011. Two groups of CHD were defined: those associated with an abnormal four-chamber view at ultrasound (Group 1), and those associated with a normal four-chamber view at ultrasound (Group 2). The time of diagnosis, pregnancy outcome and total liveborn prevalence were compared for both groups over two 5-year periods, before and after the introduction of the 20-week ultrasound scan. Trends in total and liveborn prevalence were examined over 2001 to 2011. RESULTS: Information was collected on 269 children and fetuses. After the introduction of the 20-week ultrasound scan, the prenatal detection rate of CHDs increased in both groups (Group 1, 34.6% in 2001-2005 vs 84.8% in 2007-2011 (P < 0.001); Group 2, 14.3% in 2001-2005 vs 29.6% in 2007-2011 (P = 0.037)). The rate of termination of pregnancy (TOP) increased significantly only for Group 1 (15.4% vs 51.5% (P < 0.001)). The total prevalence of CHD in Group 1 increased over time from 2.9 per 10 000 births in 2001 to 6.4 per 10 000 births in 2011 (P = 0.016). The liveborn prevalence did not show a trend over time. For Group 2, no trends in total or liveborn prevalence could be detected over time. CONCLUSIONS: Since the implementation of the routine 20-week ultrasound scan in The Netherlands, prenatal detection rate of selected severe CHDs increased significantly. Improved prenatal detection was accompanied by a more than three-fold increase in TOP, although only in those CHDs with an abnormal four-chamber view at prenatal ultrasound.

Anorectal malformations and pregnancy-related disorders: a registry-based case-control study in 17 European regions.

OBJECTIVE: To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations (ARMs). DESIGN: A population-based case-control study. SETTING: Seventeen EUROCAT (European Surveillance of Congenital Anomalies) registries, 1980-2008. POPULATION: The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM-VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. METHODS: Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. MAIN OUTCOME MEASURES: Adjusted ORs for pregnancy-related risk factors for ARM. RESULTS: The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). CONCLUSIONS: This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.

Desmin-related myopathy.

Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We provide (i) a literature review on DRM, including clinical manifestations, inheritance, molecular genetics, myopathology and management and (ii) a meta-analysis of reported DES mutation carriers, focusing on their clinical characteristics and potential genotype-phenotype correlations. Meta-analysis: DES mutation carriers (n = 159) with 40 different mutations were included. Neurological signs were present in 74% and cardiological signs in 74% of carriers (both neurological and cardiological signs in 49%, isolated neurological signs in 22%, and isolated cardiological signs in 22%). More than 70% of carriers exhibited myopathy or muscular weakness, with normal creatine kinase levels present in one third of them. Up to 50% of carriers had cardiomyopathy and around 60% had cardiac conduction disease or arrhythmias, with atrioventricular block as an important hallmark. Symptoms generally started during the 30s; a quarter of carriers died at a mean age of 49 years. Sudden cardiac death occurred in two patients with a pacemaker, suggesting a ventricular tachyarrhythmia as cause of death. The majority of DES mutations were missense mutations, mostly located in the 2B domain. Mutations in the 2B domain were predominant in patients with an isolated neurological phenotype, whereas head and tail domain mutations were predominant in patients with an isolated cardiological phenotype.

Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records: A EUROlinkCAT study.

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed.

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.

Prevalence of valproate syndrome in Europe from 2005 to 2014: A registry based multi-centre study.

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

Growing gap in folic acid intake with respect to level of education in the Netherlands.

OBJECTIVE: To evaluate the prevalence of the awareness of and the behaviour towards folic acid in 2003 and the trend of folic acid use among pregnant Dutch women between 1995 and 2003 with regard to socio-economic status (SES). METHOD: We conducted 2-yearly cross-sectional studies among pregnant women who filled in a questionnaire during the first or second antenatal visit. The highest achieved level of education was taken as a proxy for SES. RESULTS: In 2003 the general level of folic acid awareness was high but with significant differences relating to SES; a quarter of the lower educated women did not know about folic acid before pregnancy. Of the subjects with a lower SES 20% knew the correct period of use compared with nearly 50% in the higher SES group. The reported correct use of folic acid among the lower educated women has decreased over the past 3 years (22% in 2003), while it has increased for the higher SES groups (59% in 2003), implying larger differences in health. CONCLUSION: In 2003, 8 years after a mass media campaign, awareness and use of folic acid were increased considerably in comparison with the start of the campaign. However, differences in knowledge and use of folic acid with respect to the level of education had never been so impressive in the Netherlands as in 2003. A once-only campaign has a short-term effect especially for lower educated women. Implementing strategies to promote folic acid use in daily structural health care systems are needed.

Folic acid supplementation influences the distribution of neural tube defect subtypes: A registry-based study.

Periconceptional folic acid (FA) reduces neural tube defect (NTD) risk, but seems to have a varying effect per NTD subtype. We aimed to study the effect of FA supplementation on NTD subtype distribution using data from EUROCAT Northern Netherlands. We included all birth types with non-syndromal NTDs born in 1997-2012. By Fisher's exact test we analyzed possible differences in NTD subtype distribution between a correct FA supplementation group and incorrect FA supplementation group. We found proportionally fewer cervical/thoracic spina bifida cases and more lumbar/sacral spina bifida cases in the correct FA supplementation group, irrespective of the presence of the main NTD risk factors. The effect on NTD subtype distribution was only seen when FA supplementation was started before conception. We conclude that FA not only prevents the occurrence of a significant proportion of NTDs, but might also decrease the severity of NTDs, as long as supplementation is started before conception.

[Differences in folic-acid policy and the prevalence of neural-tube defects in Europe; recommendations for food fortification in a EUROCAT report]. / Verschillen in foliumzuurbeleid en prevalentie van neuralebuisdefecten in europa; aanbevelingen voor voedselverrijking in een EUROCAT-rapport.

The European Registration Of Congenital Anomalies and Twins (EUROCAT), a network of 40 European registries of congenital anomalies, has published a special report on the prevention of neural-tube defects by, periconceptional folic-acid supplementation in Europe. This report reviews the progress made in 17 European countries since i99I in terms of developing and implementing public health policies to raise periconceptional folate status. Data on the prevalence of neural-tube defects in 1980-2000 were also analysed. - At the beginning of 2002, 10 of the 17 countries had an official government recommendation that women planning a pregnancy should take folic-acid supplementation daily. Only 7 countries implemented official health-education initiatives. - Despite the various measures taken to date, the majority of women in all countries surveyed are not taking periconceptional folic-acid supplements. Even in the Netherlands, where the percentage of planned pregnancies is estimated at 85%, only 36% of women take folic-acid supplements during the advised period. - Overall, the number of neural-tube defects has not decreased in Europe. A slight decrease was seen in those countries with an official policy regarding periconceptional folic-acid supplementation. - It is clear from the report that more effective prevention of neuraltube defects could be achieved with folic-acid fortification of staple foods; this approach has led to a reduction in the prevalence of neuraltube defects in the US and Canada. This approach can also prevent the majority of neural-tube defects in unplanned pregnancies and reduce the socioeconomic differences in prevalence.

Accuracy of family history of cancer: clinical genetic implications.

Family medical history is the cornerstone of clinical genetic diagnosis and management in cases of familial cancer. The soundness of medical decisions can be compromised if reports by the family on affected relatives are inaccurate. Although very time consuming, family medical histories are therefore routinely verified. To investigate whether such verification is clinically justified, we retrospectively analysed the accuracy of a consecutive series of 383 tumour reports from counsellees on 120 families in our clinic. We evaluated these families for the impact of verification on clinical genetic diagnosis and management. Accuracy according to cancer type showed marked variation, ranging from 93% and 89% for breast cancer and colorectal cancer, respectively, to 42% and 37% for extra-colorectal alimentary tract cancer and uterine cancer. Accuracy was related to the degree of kinship of the affected relative, but not to age and gender of the counsellee, nor to the reason for referral or personal history of cancer. Age at diagnosis and multiple primary tumours were reported accurately in 97% and 94% of cases, respectively. In six out of 120 families verification data changed clinical genetic management, in five of these the genetic risk was reduced. Although verification of all reported cancer cases in a family remains the 'gold standard' for clinical as well as research purposes, verification of reports on breast cancer can be limited without seriously compromising medical decision making. In cases where verification is impossible because medical records are unavailable, findings from studies such as ours may help in interpreting family histories.

Therapeutic drug use during pregnancy: a comparison in four European countries. OECM Working Group. Occupational Exposures and Congenital Anomalies.

A drug utilization study was performed using data of the OECM study on Occupational Exposures and Congenital Malformations, which was conducted in six European Registries of Congenital Anomalies (two in France, two in Italy, one in Great Britain, and one in The Netherlands): the mothers were interviewed after delivery for exposures during pregnancy, including use of therapeutic drugs. The analysis of drug use considered only the 1134 control mothers of healthy newborns, and focused on the first trimester of pregnancy: 36.2% of the interviewed mothers used at least one drug (excluding vitamins and minerals) during the first trimester. This rate varied from 22.5% in Glasgow to 50.3% and 44.2% in the French centers. Anti-infectives were the most frequent drugs (12.3% of mothers), then antinauseants (10.6%), and treatments for threatened abortion (5.5%). Important variations between countries were observed, reflecting different medical attitudes towards drug use during pregnancy.

Artefactual increasing frequency of omphaloceles in the Northern Netherlands: lessons for systematic analysis of apparent epidemics.

BACKGROUND: While monitoring birth defects in a registry, statistically significant increases in prevalence occasionally occur. In the European Registration Of Congenital Anomalies (EUROCAT) in the Northern Netherlands 20000 births are monitored every year. For omphaloceles, a steady increase in the prevalence from 0.86 per 10000 live- and stillbirths in 1981-1983 to 3.11 per 10000 live- and stillbirths in 1994 was seen in the three northern provinces of The Netherlands. METHODS: A stepwise enquiry into this increase, which included checking for misclassification and change in coding and ascertainment when necessary, was done. All cases of omphalocele and associated or similar birth defects registered at the EUROCAT registry were retrieved and if necessary recoded. RESULTS: This study showed that the increase reported previously was not a true time trend. A few cases of e.g. diastasis recti and trisomy 18 were misclassified. The prevalence in more recent years is comparable with that in the rest of Europe, whereas it used to be lower. There was an increase in isolated omphalocele, but the numbers are small. CONCLUSIONS: The stepwise enquiry described should be a standard procedure after noticing an increasing prevalence in a registry. A better subdivision, e.g. in isolated cases versus children with multiple congenital anomalies, before monitoring can contribute to a lower number of false positive signals.

Evaluation of the prenatal diagnosis of neural tube defects by fetal ultrasonographic examination in different centres across Europe.

OBJECTIVE: Evaluation of prenatal diagnosis of neural tube defects by ultrasound examination in unselected populations across Europe. SETTING: Prenatal ultrasound units in areas that report to contributing congenital malformation registers. METHODS: All cases with a suspected or confirmed neural tube defect and delivered within the 30 month study period were identified from 18 Congenital Malformation Registers from 11 European countries. Data on the pregnancy, prenatal scans, outcome of pregnancy, and information on different screening policies for each country were analysed. RESULTS: 670766 deliveries occurred in the area covered by the registers during the study period. A neural tube defect was diagnosed at delivery in 542 cases. In 84% of these, the lesion was isolated (166 anencephaly, 252 spina bifida, 35 encephalocele). Of the 166 isolated cases with anencephaly, 96% were correctly identified prenatally; one was missed on scan, two were wrongly diagnosed, and four were not scanned (sensitivity 98%). 84% of the prenatal diagnoses were made before 24 weeks' gestation; 86% of isolated anencephalic pregnancies were terminated. Of the 252 cases of isolated spina bifida, 171 (68%) were correctly identified prenatally; 66% of these before 24 weeks' gestation. The diagnosis was missed on scan in 60 cases and 21 were not scanned (sensitivity 75%). The mean reduction in birth prevalence because of termination of pregnancy for spina bifida was 49% (range 6-100%). There was a wide variation between centres in prenatal detection rate (33-100%), termination of pregnancy of prenatally diagnosed cases (17-100%), and gestation both at diagnosis and termination of pregnancy. CONCLUSION: A high prenatal detection rate for anencephaly was reported by all registers. There is a large variation in prenatal detection and termination rates for spina bifida between centres, reflecting differences both in policy and culture.

Maternal occupational risk factors for oral clefts. Occupational Exposure and Congenital Malformation Working Group.

OBJECTIVES: This study investigated the role of maternal exposures at work during pregnancy in the occurrence of oral clefts. METHODS: The occupational exposures of 851 women (100 mothers of babies with oral clefts and 751 mothers of healthy referents) who worked during the first trimester of pregnancy were studied. All the women were part of a multicenter European case-referent study conducted using 6 congenital malformation registers between 1989 and 1992. In each center, the mother's occupational history, obtained from an interview, was reviewed by industrial hygienists who were blinded to the subject's status and who assessed the presence of chemicals and the probability of exposure. Odds ratios (OR) were estimated by a multivariate analysis including maternal occupation or occupational exposures during the first trimester of pregnancy and possible confounding factors such as center of recruitment, maternal age, urbanization, socioeconomic status, and country of origin. RESULTS: After adjustment for confounding factors, cleft palate only was significantly associated with maternal occupation in services such as hairdressing [OR 5.1, 95% confidence interval (95% CI) 1.0-26.0] and housekeeping (OR 2.8, 95% CI 1.1-7.2). The analysis suggests that the following occupational exposures are associated with orofacial clefts: aliphatic aldehydes (OR 2.1, 95% CI 0.8-5.9) and glycol ethers (OR 1.7, 95% CI 0.9-3.3) for cleft lip with or without cleft palate and lead compounds (OR 4.0, 95% CI 1.3-12.2), biocides (OR 2.5, 95% CI 1.0-6.0), antineoplastic drugs (OR 5.0, 95% CI 0.8-34.0), trichloroethylene (OR 6.7, 95% CI 0.9-49.7), and aliphatic acids (OR 6.0, 95% CI 1.5-22.8) for cleft palate only. CONCLUSIONS: Due to the limited number of subjects, these results must be interpreted with caution. However, they point out some chemicals already known or suspected as reproductive toxins.

[Awareness and periconceptional use of folic acid among non-western and western women in the Netherlands following the 1995 publicity campaign]. / Kennis over en gebruik van periconceptioneel foliumzuur onder allochtone en westerse vrouwen, na de publiekscampagne in 1995.

OBJECTIVE: To investigate the influence of ethnicity on the awareness and use of folic acid by pregnant women. DESIGN: Secondary data analysis. METHOD: Using the data on 1555 women, collected during a cross-sectional study conducted among pregnant women with good knowledge of the Dutch language in 1996, the authors determined what was known about the recommendation to use folic acid around the time of conception and what the actual use was. Women were defined as either 'western' or 'non-western' on the basis of the place of birth of the woman and her parents. RESULTS: Of the 1555 pregnant women, 74 (5%) were non-western or of non-western descent. Non-western women more often had a lower educational level than western women (51% versus 34%; p = 0.002) and more often had an unintended pregnancy (24% versus 8%; p < 0.0001). 41% of the non-western women had heard of the recommendation to use folic acid before pregnancy, compared to 79% of the western women (p < 0.0001). However, the use of folic acid was not significantly different between non-western and western women (56% versus 69%) if they had been aware of the recommendation to use folic acid before pregnancy. Awareness of the recommendation to use folic acid was higher in older women (OR: 1.46; 95% CI: 1.13-1.89), women of western descent (0.27; 0.16-0.47), women with a higher level of education (0.35; 0.27-0.45) and in case of planned pregnancy (0.45; 0.31-0.67). The use of folic acid, restricted to women who were aware of the recommendation to use folic acid before their pregnancy, was higher in older women (1.37; 1.05-1.80) and lower in those with more previous pregnancies (0.57; 0.43-0.75) and in case of an unplanned pregnancy (0.55; 0.34-0.88). CONCLUSION: Although non-western women had less knowledge of the recommendation to use folic acid than western women, the use of folic acid was not significantly different from that by western women if they had been aware of the recommendation to use folic acid before pregnancy. Continued education on folic acid targeting non-western and western women is important.

[Epidemiology of prenatal diagnosis and selective pregnancy termination because of fetal neural tube defects in The Netherlands in comparison to other European countries]. / Epidemiologie van prenatale diagnostiek en selective zwangerschapsafbreking vanwege foetale neuralebuisdefecten in Nederland in vergelijking met andere Europese landen.

OBJECTIVE: To describe the epidemiological impact of prenatal diagnosis and selective abortion on the frequency of neural tube defects (NTD) in the period 1980-1992 in the Northern Netherlands in comparison with data from other European regions. DESIGN: Descriptive. SETTING: 17 'European registration of congenital anomalies' (EUROCAT) registrations, localized in 10 European countries. METHOD: Data were collected actively and retrospectively from multiple sources fed by voluntary registration of congenital anomalies in live births, stillbirths and pregnancies terminated because of congenital anomalies. RESULTS: In Europe the total birth prevalence of NTD in the period 1980-1992 ranged from 5.3 per 10,000 in Switzerland to 29.0 per 10,000 in Glasgow, a difference of a factor 5.5. In live births the difference was ninefold: ranging from 2.0 per 10,000 in Paris to 18.8 per 10,000 in Dublin. The Netherlands had a conspicuously high prevalence among live births, higher than in other regions in continental Europe. For spina bifida the live birth prevalence both in other continental regions and in Glasgow was also lower than in the Netherlands. In Glasgow serum alpha-foetoprotein screening apparently led to frequent early prenatal diagnosis of NTD and to frequent termination of pregnancy. In Paris the use of ultrasound screening appears to lead to frequent later prenatal diagnosis, as well as frequent termination of pregnancy. CONCLUSION: In the Netherlands the impact of prenatal diagnosis and selective abortion is limited, so that primary prevention (periconceptional use of folic acid) is more important than in some other European countries.