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.

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.

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.

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.

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.

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.

Primitive pulmonary "malignant epithelioid hemangioendothelioma" versus epithelioid angiosarcoma. A case report and review of the literature.

We describe the case of a 56-year-old man presenting a primary pulmonary epithelioid angiosarcoma versus malignant epithelioid hemangioendothelioma still alive, without recurrence at nearly two years after the beginning of the symptoms. The primary pulmonary angiosarcoma is extremely rare, being reported only in a handful of cases. Metastatic involvement of the lung (90%) is far more common than primary pulmonary involvement (10%). Various predisposing condition for the development of angiosarcoma have been described. Early diagnosis is not common, because of the rarity of angiosarcoma in the lung and consequent low index of suspicion. Due to the paucity of cases, there are no defined treatment regimens for this entity. However, there is a tendency for surgical intervention in all reported cases.

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.

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.

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.

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.

Drug prescription patterns before, during and after pregnancy for chronic, occasional and pregnancy-related drugs in the Netherlands.

OBJECTIVE: To compare the prescription of drugs in women over a period from 2 years before until 3 months after pregnancy, regarding the type of drugs used and the fetal risk. DESIGN: A cohort study based on pharmacy records of women giving birth to a child between 1994 and 2003. SETTING: The study was performed with data from the InterAction database, containing prescription-drug-dispensing data from community pharmacies. POPULATION: The study population included 5412 women for whom complete pharmacy records were available. METHODS: Drugs were classified into three categories: (1) drugs for chronic conditions, (2) drugs for occasional use and (3) drugs for pregnancy-related symptoms and also classified according to the Australian classification system. MAIN OUTCOME MEASURES: The prescription rate was calculated as the number of women per 100 women who received one or more prescriptions for a given drug within a specified time period. RESULTS: About 79.1% of the women received at least one prescription during pregnancy. The prescription rate for most drugs for chronic diseases and for occasional use decreased during pregnancy, whereas, as expected, the prescription rate for pregnancy-related drugs increased. During the first trimester of pregnancy, 1.7% of all drugs prescribed for chronic conditions and 2.3% of the occasional drugs were classified as harmful. CONCLUSIONS: The increase in prescription rate during pregnancy is caused by an increase in prescription rate of drugs for pregnancy-related symptoms. The prescription of harmful drugs is more commonly associated with drugs for occasional use rather than with drugs for chronic conditions. Therefore, a more cautious prescribing of drugs to healthy women in the fertile age is necessary.

Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer.

BACKGROUND: Patients with early-onset colorectal cancer (CRC) or those with multiple tumours associated with hereditary non-polyposis colorectal cancer (HNPCC) raise suspicion of the presence of germline DNA mismatch repair (MMR) gene mutations. AIM: To analyse the value of family history, microsatellite instability (MSI) analysis and MMR protein staining in the tumour to predict the presence of an MMR gene mutation in such patients. METHODS: In 281 patients diagnosed with CRC before the age of 50 years or with CRC and at least one additional HNPCC-associated cancer, germline mutation analysis in MLH1, MSH2 and MSH6 was carried out with denaturing gradient gel electrophoresis and multiplex ligation-dependent probe amplification. MSI analysis with five consensus markers and MMR protein staining for MLH1, MSH2 and MSH6 were carried out in the tumours. RESULTS: 25 pathogenic mutations (8 in MLH1, 9 in MSH2 and 8 in MSH6) were found. MSI analysis missed three and immunohistochemistry (IHC) missed two mutation carriers. Sensitivities of family history, MSI analysis and IHC for the presence of a mutation were 76%, 82% and 88%, specificities were 64%, 70% and 84%, and positive predictive values were 19%, 23% and 38%, respectively. Multivariate analysis showed the highest odds ratio for IHC (38.3, 95% confidence interval 9.0 to 184). Prevalence of pathogenic germline MMR gene mutations in patients with CRC before the age of 50 years was 6% and in those with > or =2 HNPCC-associated tumours was 22%. In the second group, no mutation carriers were found among the 29 patients who were diagnosed with their first tumour after the age of 60 years. CONCLUSION: Family history, MSI analysis and IHC are indicative parameters to select patients with CRC for MMR gene mutation analysis. The data show that IHC is the best single selection criterion.

[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.

Trends and geographic inequalities in the prevalence of Down syndrome in Europe, 1980-1999.

BACKGROUND: EUROCAT is a network of population-based registries for the epidemiologic surveillance of congenital anomalies covering approximately one quarter of births in the European Union. Down syndrome constitutes approximately 8% of cases of registered congenital anomaly in Europe, with over 7000 affected pregnancies in the 15 current member states of the European Union each year. In this paper, we aim to examine trends in the live birth prevalence of Down syndrome in Europe in the light of trends in maternal age and in prenatal diagnosis. METHODS: Descriptive analysis of data from 24 EUROCAT registries, covering 8.3 million births 1980-99. Cases include live births, stillbirths and terminations of pregnancy following prenatal diagnosis. RESULTS: Since 1980, the proportion of births to mothers of 35 years of age and over has risen quite dramatically from 8 to 14% for the European Union as a whole, with steeper rises in some regions. By 1995-1999, the proportion of "older" mothers varied between regions from 10% to 25%, and the total prevalence (including terminations of pregnancy) of Down syndrome varied from 1 to 3 per 1000 births. Some European regions have shown a more than twofold increase in total prevalence of Down syndrome since 1980. The proportion of cases of Down syndrome which were prenatally diagnosed followed by termination of pregnancy in 1995-1999 varied from 0% in the three regions of Ireland and Malta where termination of pregnancy is illegal, to less than 50% in 14 further regions, to 77% in Paris. The extent to which terminations of pregnancy were concen trated among older mothers varied between regions. The live birth prevalence has since 1980 increasingly diverged from the rising total prevalence, in some areas remaining approximately stable, in others decreasing over time. CONCLUSION: The rise in average maternal age in Europe has brought with it an increase in the number of pregnancies affected by Down syndrome. The widespread practice of prenatal screening and termination of pregnancy has in most of the regions covered by EUROCAT counteracted the effect of maternal age in its effect on live birth prevalence. Under the joint influences of maternal age and prenatal screening the pattern of geographic inequalities in Down syndrome live birth prevalence in Europe has also been changed.

Age at postnatal diagnosis of down syndrome in the northern Netherlands for the period 1981-2000.

BACKGROUND: In live-born children with Down syndrome it may be very difficult for the clinician or midwife assisting at the delivery to recognise Down syndrome in newborn babies due to varying physical appearances. Meanwhile more and more therapeutical interventions become available that should start early in life. We were interested in the age at the postnatal diagnosis of Down syndrome, and found no literature on the subject. METHODS: We studied the age at the diagnosis of Down syndrome for live-born babies born in the period of 1981-2000 and registered by the European Registration of Congenital Anomalies in the northern part of The Netherlands. RESULTS: For 289 children, data on the age at the postnatal diagnosis were available, in 70.8% of whom there was suspicion of DS on the day of birth. In 1.7% of the cases, the diagnosis was made after 1 year. Place of birth and the specialty of the health worker assisting at the delivery were associated with age at diagnosis. When the child was delivered at hospital, 96.4% of the Down syndrome cases had been diagnosed within 1 month compared to 81.3% following home delivery. CONCLUSION: In some cases of Down syndrome in live-born babies, the diagnosis is made only after months or a year. The diagnosis was made faster in babies born in hospital compared to those born at home.

Giant cell tumours of the tendon sheath: lack of correlation between nm23-H1 expression and recurrence.

Some authors attribute recurrences of giant cell tumours to biological factors which are only expressed in some tumours. Grover et al. (1998) suggested that the risk for recurrence is associated with the down-regulation of the nm23-H1 gene. We reviewed the charts of the 154 patients operated on for giant cell tumours of the tendon sheath and selected a group of patients with recurrence (ten cases) and a group of patients who did not have a recurrence after a minimum follow-up of 3 years (13 cases). Immunohistochemical detection of nm23-H1 was performed blindly of the clinical outcome on the paraffin-embedded specimens of these patients and no correlation was found between nm23-H1 expression and the risk for recurrence.