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.

Effectiveness of 12-13-week scan for early diagnosis of fetal congenital anomalies in the cell-free DNA era.

OBJECTIVES: The main aim of this study was to assess the proportion and type of congenital anomalies, both structural and chromosomal, that can be detected at an early scan performed at 12-13 weeks' gestation, compared with at the 20-week structural anomaly scan offered under the present screening policy. Secondary aims were to evaluate the incidence of false-positive findings and ultrasound markers at both scans, and parental choice regarding termination of pregnancy (TOP). METHODS: Sonographers accredited for nuchal translucency (NT) measurement were asked to participate in the study after undergoing additional training to improve their skills in late first-trimester fetal anatomy examination. The early scans were performed according to a structured protocol, in six ultrasound practices and two referral centers in the north-east of The Netherlands. All women opting for the combined test (CT) or with an increased a-priori risk of fetal anomalies were offered a scan at 12-13 weeks' gestation (study group). All women with a continuing pregnancy were offered, as part of the 'usual care', a 20-week anomaly scan. RESULTS: The study group consisted of 5237 women opting for the CT and 297 women with an increased a-priori risk of anomalies (total, 5534). In total, 51 structural and 34 chromosomal anomalies were detected prenatally in the study population, and 18 additional structural anomalies were detected after birth. Overall, 54/85 (63.5%) anomalies were detected at the early scan (23/51 (45.1%) structural and all chromosomal anomalies presenting with either an increased risk at first-trimester screening or structural anomalies (31/34)). All particularly severe anomalies were detected at the early scan (all cases of neural tube defect, omphalocele, megacystis, and multiple severe congenital and severe skeletal anomalies). NT was increased in 12/23 (52.2%) cases of structural anomaly detected at the early scan. Of the 12 cases of heart defects, four (33.3%) were detected at the early scan, five (41.7%) at the 20-week scan and three (25.0%) after birth. False-positive diagnoses at the early scan and at the 20-week scan occurred in 0.1% and 0.6% of cases, respectively, whereas ultrasound markers were detected in 1.4% and 3.0% of cases, respectively. After first- or second-trimester diagnosis of an anomaly, parents elected TOP in 83.3% and 25.8% of cases, respectively. CONCLUSIONS: An early scan performed at 12-13 weeks' gestation by a competent sonographer can detect about half of the prenatally detectable structural anomalies and 100% of those expected to be detected at this stage. Particularly severe anomalies, often causing parents to choose TOP, are amenable to early diagnosis. The early scan is an essential part of modern pregnancy care. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Prevalence, diagnosis and outcome of cleft lip with or without cleft palate in The Netherlands.

OBJECTIVE: To examine the accuracy and timing of diagnosis of fetal cleft lip with or without cleft palate (CL ± P) in the years following the introduction of a national screening program, and to assess the completeness and accuracy of information in The Netherlands Perinatal Registry. METHODS: A list was obtained of cases with a prenatal or postnatal diagnosis of CL ± P from two fetal medicine units between 2008 and 2012. All cases of CL ± P were included irrespective of the presence or absence of additional anomalies. Cases were included if the estimated date of delivery was between 1 January 2008 and 31 December 2012. RESULTS: During the study period, 330 cases of CL ± P were identified, with a prevalence of 15 per 10 000 pregnancies. The number of cases that were detected before 24 weeks' gestation increased during the study period, while the rate of termination of pregnancy did not change significantly (P = 0.511). CL ± P was isolated in 217 (66%) cases and karyotype was abnormal in 69 (21%) cases. In 5% of the cases in which CL ± P seemed to be isolated during the 18-23-week anomaly scan, postnatal array comparative genomic hybridization (array-CGH) revealed an abnormal karyotype and 50% of these cases had major additional anomalies. Examination of data from The Netherlands Perinatal Registry demonstrated that in 37% of cases CL±P was not recorded in the pregnancy records. CONCLUSION: CL ± P is increasingly being diagnosed prenatally, without a significant effect on the rate of pregnancy termination. Further improvement in the diagnostic accuracy may be achieved by advocating prenatal array-CGH to reduce the frequency of unexpected anomalies being diagnosed after birth. It is important that healthcare providers register accurately the presence or absence of anomalies in the birth records to ensure that, in the future, data from The Netherlands Perinatal Registry can be relied upon to monitor prevalence. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

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.

Trends in the prevalence, risk and pregnancy outcome of multiple births with congenital anomaly: a registry-based study in 14 European countries 1984-2007.

OBJECTIVE: To assess the public health consequences of the rise in multiple births with respect to congenital anomalies. DESIGN: Descriptive epidemiological analysis of data from population-based congenital anomaly registries. SETTING: Fourteen European countries. POPULATION: A total of 5.4 million births 1984-2007, of which 3% were multiple births. METHODS: Cases of congenital anomaly included live births, fetal deaths from 20 weeks of gestation and terminations of pregnancy for fetal anomaly. MAIN OUTCOME MEASURES: Prevalence rates per 10,000 births and relative risk of congenital anomaly in multiple versus singleton births (1984-2007); proportion prenatally diagnosed, proportion by pregnancy outcome (2000-07). Proportion of pairs where both co-twins were cases. RESULTS: Prevalence of congenital anomalies from multiple births increased from 5.9 (1984-87) to 10.7 per 10,000 births (2004-07). Relative risk of nonchromosomal anomaly in multiple births was 1.35 (95% CI 1.31-1.39), increasing over time, and of chromosomal anomalies was 0.72 (95% CI 0.65-0.80), decreasing over time. In 11.4% of affected twin pairs both babies had congenital anomalies (2000-07). The prenatal diagnosis rate was similar for multiple and singleton pregnancies. Cases from multiple pregnancies were less likely to be terminations of pregnancy for fetal anomaly, odds ratio 0.41 (95% CI 0.35-0.48) and more likely to be stillbirths and neonatal deaths. CONCLUSIONS: The increase in babies who are both from a multiple pregnancy and affected by a congenital anomaly has implications for prenatal and postnatal service provision. The contribution of assisted reproductive technologies to the increase in risk needs further research. The deficit of chromosomal anomalies among multiple births has relevance for prenatal risk counselling.

Clomiphene citrate utilization in the Netherlands 1998-2007.

BACKGROUND: Infertility is a growing problem in western societies. Few studies have examined the drug utilization of common treatments for infertility. Clomiphene citrate (CC) is the first-line treatment for normogonadotropic women with absent or irregular ovulation. We examined CC use among women at reproductive age in the northern Netherlands. METHODS: Drug dispensing data of CC between 1998 and 2007 were retrieved from the IADB.nl database. Two-year prevalences of CC use per 1000 women covered by the database were calculated and stratified by 5-year age group. The duration of CC use was analyzed using Kaplan-Meier survival analysis. RESULTS: From the IADB.nl database, a total of 1854 women aged 20-44 years initiated ovulation induction treatment with CC only in the northern Netherlands during 1998 and 2007. The 2-year prevalence of CC use increased from 6.66 per 1000 women during 1998-1999 to 7.24 per 1000 during 2002-2003, followed by a decrease to 4.82 per 1000 in 2006-2007 (P < 0.05). Median duration of CC use was four cycles for women <30 years of age, three cycles for women aged 30-39 and two cycles for women aged above 40. CONCLUSIONS: There is no increase of CC use during 1998-2007, and indeed a decrease of CC use during recent years, among women at reproductive age in northern Netherlands.

Death in CHARGE syndrome after the neonatal period.

CHARGE syndrome is a multiple congenital anomaly syndrome that can be life-threatening in the neonatal period. Complex heart defects, bilateral choanal atresia, esophageal atresia, severe T-cell deficiency, and brain anomalies can cause neonatal death. As little is known about the causes of death in childhood and adolescence, we studied post-neonatal death in patients with CHARGE syndrome. We collected medical data on three deceased children from a follow-up cohort of 48 CHARGE patients and retrospectively on an additional four deceased patients (age at death 11 months to 22 years). We analyzed the factors that had contributed to their death. In five patients respiratory aspiration had most likely contributed to premature death, one died of post-operative complications, and another choked during eating. From our findings and a literature review, we suggest that swallowing problems, gastro-esophageal reflux disease, respiratory aspiration and post-operative airway events are important contributors to post-neonatal death in CHARGE syndrome. Cranial nerve dysfunction is proposed as the underlying pathogenic mechanism. We recommend every CHARGE patient with feeding difficulties to be assessed by a multidisciplinary team to evaluate cranial nerve function and swallowing. Timely treatment of swallowing problems and gastro-esophageal reflux disease is important. Surgical procedures on these patients should be combined whenever possible because of their increased risk of post-operative complications and intubation problems. Finally, we recommend performing autopsy in deceased CHARGE patients in order to gain more insight into causes of death.

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.

[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.