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Introduction: There is no non-invasive treatment to prevent aneurysmal subarachnoid hemorrhage (ASAH) caused by intracranial aneurysm (IA) rupture. We aimed to identify drug classes that may affect liability to IA using a genetic approach., Patients and Methods: Using genome-wide association summary statistics we calculated genetic correlation between unruptured IA ( N  = 2140 cases), ASAH ( N  = 5140) or the combined group, and liability to drug usage from 23 drug classes ( N up to 320,000) independent of the risk factor high blood pressure. Next, we evaluated the causality and therapeutic potential of correlated drug classes using three different Mendelian randomization frameworks., Results: Correlations with IA were found for antidepressants, paracetamol, acetylsalicylic acid, opioids, beta-blockers, and peptic ulcer and gastro-esophageal reflux disease drugs. MR showed no evidence that genetically predicted usage of these drug classes caused IA. Genetically predicted high responders to antidepressant drugs were at higher risk of IA (odds ratio [OR] = 1.61, 95% confidence interval (CI) = 1.09-2.39, p  = 0.018) and ASAH (OR = 1.68, 95% CI = 1.07-2.65, p  = 0.024) if they used antidepressant drugs. This effect was absent in non-users. For beta-blockers, additional analyses showed that this effect was not independent of blood pressure after all. A complex and likely pleiotropic relationship was found between genetic liability to chronic multisite pain, pain medication usage (paracetamol, acetylsalicylic acid, and opioids), and IA., Conclusions: We did not find drugs decreasing liability to IA and ASAH but found that antidepressant drugs may increase liability. We observed pleiotropic relationships between IA and other drug classes and indications. Our results improve understanding of pathogenic mechanisms underlying IA., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors., Aims: The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA., Methods: We conducted a sex-specific two-sample Mendelian randomization study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e. aSAH and unruptured IA combined) as outcomes., Results: We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men ( p -value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women ( p -value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women ( p -value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men., Conclusions: Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics., Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients., Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10 -3 per year [95% CI, -6.49×10 -3 to -3.14×10 -3 ]; P =1.82×10 -8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P =0.0041)., Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Introduction: First-trimester anatomical screening (FTAS) by ultrasound has been introduced in many countries as screening for aneuploidies, but also as early screening for fetal structural abnormalities. While a lot of emphasis has been put on the detection rates of FTAS, little is known about the performance of quality control programs and the sonographers' learning curve for FTAS. The aims of the study were to evaluate the performance of a score-based quality control system for the FTAS and to assess the learning curves of sonographers by evaluating the images of the anatomical planes that were part of the FTAS protocol., Methods: Between 2012-2015, pregnant women opting for the combined test in the North-Netherlands were also invited to participate in a prospective cohort study extending the ultrasound investigation to include a first-trimester ultrasound performed according to a protocol. All anatomical planes included in the protocol were documented by pictures stored for each examination in logbooks. The logbooks of six sonographers were independently assessed by two fetal medicine experts. For each sonographer, logbooks of examination 25-50-75 and 100 plus four additional randomly selected logbooks were scored for correct visualization of 12 organ-system planes. A plane specific score of at least 70% was considered sufficient. The intra-class correlation coefficient (ICC), was used to measure inter-assessor agreement for the cut-off scores. Organ-specific learning curves were defined by single-cumulative sum (CUSUM) analysis., Results: Sixty-four logbooks were assessed. Mean duration of the scan was 22 ± 6 minutes and mean gestational age was 12+6 weeks. In total 57% of the logbooks graded as sufficient. Most sufficient scores were obtained for the fetal skull (88%) and brain (70%), while the lowest scores were for the face (29%) and spine (38%). Five sonographers showed a learning curve for the skull and the stomach, four for the brain and limbs, three for the bladder and kidneys, two for the diaphragm and abdominal wall and one for the heart and spine and none for the face and neck., Conclusion: Learning curves for FTAS differ per organ system and per sonographer. Although score-based evaluation can validly assess image quality, more dynamic approaches may better reflect clinical performance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bardi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: In a genome-wide association study of intracranial aneurysms (IA), enrichment was found between genes associated with IA and genes encoding targets of effective anti-epileptic drugs. Our aim was to assess if this pleiotropy is driven by shared disease mechanisms that could potentially highlight a treatment strategy for IA., Methods: Using 2-sample inverse-variance weighted Mendelian randomization and genetic colocalization analyses we assessed: (1) if epilepsy liability in general affects IA risk, and (2) whether changes in gene- and protein-expression levels of anti-epileptic drug targets in blood and arterial tissue may causally affect IA risk., Results: We found no overall effect of epilepsy liability on IA. Expression of 21 genes and 13 proteins corresponding to anti-epileptic drug targets supported a causal effect ( P <0.05) on IA risk. Of those genes and proteins, genetic variants affecting CNNM2 levels showed strong evidence for colocalization with IA risk (posterior probability>70%). Higher CNNM2 levels in arterial tissue were associated with increased IA risk (odds ratio, 3.02; [95% CI, 2.32-3.94]; P =3.39×10 - 16 ). CNNM2 expression was best proxied by rs11191580. The magnitude of the effect of this variant was greater than would be expected if systemic blood pressure was the sole IA-causing mechanism in this locus., Conclusions: CNNM2 is a driver of the pleiotropy between IA and anti-epileptic drug targets. Administration of the anti-epileptic drugs phenytoin, valproic acid, or carbamazepine may be expected to decrease CNNM2 levels and therefore subsequently decrease IA risk. CNNM2 is therefore an important target to investigate further for its role in the pathogenesis of IA.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries., (© 2022. The Author(s).)

Background: The risk of aneurysmal subarachnoid hemorrhage (aSAH) is increased in postmenopausal women compared with men of similar age, suggesting a role for sex hormones. We aimed to explore whether sex hormones, and age at menarche/menopause have a causal effect on aSAH risk by conducting a 2-sample MR study (Mendelian randomization)., Methods: We obtained sex-specific genetic instruments for serum estradiol, bioavailable testosterone (BioT), SHBG (sex hormone-binding globulin), and age at menarche/menopause from genome-wide association studies. The associated sex-specific aSAH risk was estimated with inverse-variance weighted MR analyses with various statistical sensitivity analyses. Multivariable and cluster MR analyses were performed for BioT and SHBG to account for a genetic and phenotypic correlation between the 2 exposures. The clusters represented (1) single-nucleotide polymorphisms primarily increasing SHBG, with secondary decreasing effects on BioT, and (2) single-nucleotide polymorphisms affecting BioT without affecting SHBG., Results: Univariable MR analyses showed an 18% increased aSAH risk among women per 1-SD increase in genetically determined SHBG levels (odds ratio, 1.18 [95% CI, 1.05-1.34]; P =0.007). Suggestive evidence was identified for a 27% decreased risk of aSAH among women per 1-SD increase in BioT (odds ratio, 0.73 [95% CI, 0.55-0.95]; P =0.02). The latter association disappeared in cluster analysis when only using SHBG-independent variants. MR analyses with variants from the cluster with primary SHBG effects and secondary (opposite) BioT-effects yielded a statistically significant association (odds ratio, 1.21 [95% CI, 1.05-1.40]; P =0.008). No other causal associations were identified., Conclusions: Genetic predisposition to elevated serum levels of SHBG, with secondary lower serum BioT levels, is associated with an increased aSAH risk among women, suggesting that SHBG and BioT causally elevate aSAH risk. Further studies are required to elucidate the underlying mechanisms and their potential as an interventional target to lower aSAH incidence.

Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making., Competing Interests: The authors declare no conflict of interest.

Rupture of an intracranial aneurysm (IA) leads to aneurysmal subarachnoid haemorrhage (ASAH), a severe type of stroke. Some rare variants that cause IA in families have been identified, but still, the majority of genetic causes, as well as the biological mechanisms of IA development and rupture, remain unknown. We aimed to identify rare, damaging variants for IA in three large Dutch families with multiple affected members with IA (N = 9, 11, and 6). By combining linkage analysis and genome sequencing (GS), we identified six rare and damaging variants for which all cases within one of the families were heterozygous. These variants were p.Tyr87Cys in SYCP1, p.Phe1077Leu in FMNL2, p.Thr754Lys in TBC1D2, p.Arg321His in ZNF782, p.Arg979Trp in CCDC180, and p.Val125Met in NCBP1. None of the variants showed association with IA status in a large cohort of 937 patients from the general IA patient population and 1046 controls. Gene expression in IA and cerebral artery tissue further prioritized FMNL2 and TBC1D2 as potential important players in IA pathophysiology. Further studies are needed to characterize the functional consequences of the identified variants and their role in the biological mechanisms of IA., (© 2022. The Author(s).)

Background The aim of this study was to assess the associations of modifiable lifestyle factors (smoking, coffee consumption, sleep, and physical activity) and cardiometabolic factors (body mass index, glycemic traits, type 2 diabetes, systolic and diastolic blood pressure, lipids, and inflammation and kidney function markers) with risks of any (ruptured or unruptured) intracranial aneurysm and aneurysmal subarachnoid hemorrhage using Mendelian randomization. Methods and Results Summary statistical data for the genetic associations with the modifiable risk factors and the outcomes were obtained from meta-analyses of genome-wide association studies. The inverse-variance weighted method was used as the main Mendelian randomization analysis, with additional sensitivity analyses conducted using methods more robust to horizontal pleiotropy. Genetic predisposition to smoking, insomnia, and higher blood pressure was associated with an increased risk of both intracranial aneurysm and aneurysmal subarachnoid hemorrhage. For intracranial aneurysm, the odds ratios were 3.20 (95% CI, 1.93-5.29) per SD increase in smoking index, 1.24 (95% CI, 1.10-1.40) per unit increase in log-odds of insomnia, and 2.92 (95% CI, 2.49-3.43) per 10 mm Hg increase in diastolic blood pressure. In addition, there was weak evidence for associations of genetically predicted decreased physical activity, higher triglyceride levels, higher body mass index, and lower low-density lipoprotein cholesterol levels with higher risk of intracranial aneurysm and aneurysmal subarachnoid hemorrhage, with 95% CI overlapping the null for at least 1 of the outcomes. All results were consistent in sensitivity analyses. Conclusions This Mendelian randomization study suggests that smoking, insomnia, and high blood pressure are major risk factors for intracranial aneurysm and aneurysmal subarachnoid hemorrhage.

Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women. We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We find an estimate of SNP-based heritability compatible with FMD having a polygenic basis, and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identifies one additional locus (SLC24A3). We characterize open chromatin in arterial primary cells and find that FMD associated variants are located in arterial-specific regulatory elements. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We find significant genetic overlap between FMD and more common cardiovascular diseases and traits including blood pressure, migraine, intracranial aneurysm, and coronary artery disease., (© 2021. The Author(s).)

Rupture of an intracranial aneurysm leads to aneurysmal subarachnoid hemorrhage, a severe type of stroke which is, in part, driven by genetic variation. In the past 10 years, genetic studies of IA have boosted the number of known genetic risk factors and improved our understanding of the disease. In this review, we provide an overview of the current status of the field and highlight the latest findings of family based, sequencing, and genome-wide association studies. We further describe opportunities of genetic analyses for understanding, prevention, and treatment of the disease.

Introduction: The primary aim of this study is to investigate the impact of a 13-week anomaly scan on the experienced levels of maternal anxiety and well-being. Secondly, to explore women's knowledge on the possibilities and limitations of the scan and the preferred timing of screening for structural abnormalities., Material and Methods: In a prospective-cohort study conducted between 2013-2015, pregnant women in the North-Netherlands underwent a 13-week anomaly scan. Four online-questionnaires (Q1, Q2, Q3 and Q4) were completed before and after the 13- and the 20-week anomaly scans. In total, 1512 women consented to participate in the study and 1118 (74%) completed the questionnaires at Q1, 941 (64%) at Q2, 807 (55%) at Q3 and 535 (37%) at Q4. Psychological outcomes were measured by the state-trait inventory-scale (STAI), the patient's positive-negative affect (PANAS) and ad-hoc designed questionnaires., Results: Nine-nine percent of women wished to be informed as early as possible in pregnancy about the absence/presence of structural abnormalities. In 87% of women levels of knowledge on the goals and limitations of the 13-week anomaly scan were moderate-to-high. In women with a normal 13-week scan result, anxiety levels decreased (P < .001) and well-being increased over time (P < .001). In women with false-positive results (n = 26), anxiety levels initially increased (STAI-Q1: 39.8 vs. STAI-Q2: 48.6, P = 0.025), but later decreased around the 20-week anomaly scan (STAI-Q3: 36.4 vs. STAI-Q4: 34.2, P = 0.36)., Conclusions: The 13-week scan did not negatively impact the psychological well-being of pregnant women. The small number of women with screen-positive results temporarily experienced higher anxiety after the scan but, in false-positive cases, anxiety levels normalized again when the abnormality was not confirmed at follow-up scans. Finally, most pregnant women have moderate-to-high levels of knowledge and strongly prefer early screening for fetal structural abnormalities., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Maternal nutrition during pregnancy is linked with birth outcomes including fetal growth, birth weight, congenital anomalies and long-term health through intra-uterine programming. However, a woman's nutritional status before pregnancy is a strong determinant in early embryo-placental development, and subsequently outcomes for both mother and child. Therefore, the aim of this study was to investigate the association between dietary macronutrient intake in the preconception period with birth weight., Methods: We studied a group of 1698 women from the Dutch Perined-Lifelines linked birth cohort with reliable detailed information on preconception dietary macronutrient intake (using a semi quantitative food frequency questionnaire) and data available on birth weight of the offspring. Birth weight was converted into gestational age adjusted z-scores, and macronutrient intake was adjusted for total energy intake using the nutrient residual method. Preconception BMI was converted into cohort-based quintiles. Multivariable linear regression was performed, adjusted for other macronutrients and covariates., Results: Mean maternal age was 29.5 years (SD 3.9), preconception BMI: 24.7 kg/m2 (SD 4.2) and median daily energy intake was 1812 kcal (IQR 1544-2140). Mean birth weight was 3578 grams (SD 472). When adjusted for covariates, a significant association (adjusted z score [95% CI], P) between polysaccharides and birth weight was shown (0.08 [0.01-0.15], 0.03). When linear regression analyses were performed within cohort-based quintiles of maternal BMI, positive significant associations between total protein, animal protein, fat, total carbohydrates, mono-disaccharides and polysaccharides with birth weight were shown in the lowest quintile of BMI independent of energy intake, intake of other macronutrients and covariates., Conclusion: Out of all macronutrients studied, polysaccharides showed the strongest association with birth weight, independent of energy intake and other covariates. Our study might suggest that specifically in women with low preconception BMI a larger amount of macronutrient intake was associated with increased birth weight. We recommend that any dietary assessment and advise during preconception should be customized to preconception weight status of the women., Competing Interests: Authors EB and FL are (part-time) employees of Danone Nutricia Research, Utrecht, The Netherlands. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The preconception period has been recognized as one of the earliest sensitive windows for human development. Maternal dietary intake during this period may influence the oocyte quality, as well as placenta and early embryonic development during the first trimester of pregnancy. Previous studies have found associations between macronutrient intake during preconception and pregnancy outcomes. However, as food products consist of multiple macro- and micronutrients, it is difficult to relate this to dietary intake behavior. Therefore, the aim of this study was to investigate the association between intake of specific food groups during the preconception period with birth weight, using data from the Perined-Lifelines linked birth cohort. The Perined-Lifelines birth cohort consists of women who delivered a live-born infant at term after being enrolled in a large population-based cohort study (The Lifelines Cohort). Information on birth outcome was obtained by linkage to the Dutch perinatal registry (Perined). In total, we included 1698 women with data available on birth weight of the offspring and reliable detailed information on dietary intake using a semi-quantitative food frequency questionnaire obtained before pregnancy. Based on the 2015 Dutch Dietary Guidelines and recent literature 22 food groups were formulated. Birth weight was converted into gestational age-adjusted z-scores. Multivariable linear regression was performed, adjusted for intake of other food groups and covariates (maternal BMI, maternal age, smoking, alcohol, education level, urbanization level, parity, sex of newborn, ethnicity). Linear regression analysis, adjusted for covariates and intake of energy (in kcal) (adjusted z score [95% CI], P) showed that intake of food groups "artificially sweetened products" and "vegetables" was associated with increased birth weight (resp. ( β = 0.001 [95% CI 0.000 to 0.001, p = 0.002]), ( β = 0.002 [95% CI 0.000 to 0.003, p = 0.03])). Intake of food group "eggs" was associated with decreased birth weight ( β = -0.093 [95% CI -0.174 to -0.013, p = 0.02]). Intake in food groups was expressed in 10 g per 1000 kcal to be able to draw conclusions on clinical relevance given the bigger portion size of the food groups. In particular, preconception intake of "artificially sweetened products" was shown to be associated with increased birth weight. Artificial sweeteners were introduced into our diets with the intention to reduce caloric intake and normalize blood glucose levels, without compromising on the preference for sweet food products. Our findings highlight the need to better understand how artificial sweeteners may affect the metabolism of the mother and her offspring already from preconception onwards.

Background: Maternal nutrition status (e.g. dietary/nutrient intake) during pregnancy has been associated with pregnancy outcomes including birth weight, infant survival and metabolic health of the offspring during later life. During the past few years, maternal dietary intake, at least three months before conception, has been shown to affect pregnancy outcomes also. However, literature investigating this link is still scarce. The studies that have looked at preconception dietary intake in relation to pregnancy outcome were either animal studies, had small sample sizes or focused on only selected macronutrient intake rather than complete (macro)nutrient composition or dietary intakes (e.g. food groups). Therefore, we aim to investigate the association between preconception diet and pregnancy outcomes in a linked birth cohort. The main objective of this manuscript is to describe the methodology of establishing this birth cohort and to describe both the characteristics of the study population included as well as the representativeness in terms of dietary intake., Methods: We created the birth cohort by linking two existing databases; a large population-based cohort study in the Netherlands (The Lifelines Cohort study) and the Dutch national birth registry (Perined), through a 'trusted third party'. The birth cohort contains information on maternal dietary intake during preconception as well as pregnancy outcomes., Results and Discussion: In the Lifelines Cohort study, 3,418 pregnancies were available for linking with Perined. In total, 2,368 pregnancies (86.9%) were linked with Perined, resulting in the birth cohort. With this linked cohort we are able to provide insights on the associations between dietary intake before conception and pregnancy outcomes. Such data could potentially improve nutritional care for women of childbearing age. Lifestyle changes in the period preceding pregnancy may be most effective in improving pregnancy outcomes. A focus on this window of opportunity may provide both sufficient time, as well as a period when women are potentially motivated to adopt health optimizing behaviours., Competing Interests: Author EB is part-time employee of Danone Nutricia Research, Utrecht, The Netherlands. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background and Purpose- Finding adequate control tissue for intracranial aneurysm (IA) pathophysiological studies, including gene expression studies, can be challenging. We compared gene expression profiles of superficial temporal, cortical, and circle of Willis (CoW) arteries and IA in search of the most optimal control tissue for future experiments. Methods- We compared RNA-sequencing data of IA samples and of superficial temporal, cortical, and CoW artery samples using Pearson correlation, Euclidean distance, and principal component analysis. We used the Mann-Whitney U test for comparison of Pearson correlation coefficients and Euclidean distances, to assess which control tissue is most similar to IA in terms of gene expression. Other unrelated tissues were used as negative controls. Results- The cortical and the CoW arteries were more similar to IA in terms of gene expression than the superficial temporal artery. This was based on Pearson correlation (+0.023 [90% CI, 0.017/0.029; P =1.9E-09] for the cortical artery and +0.034 [90% CI, 0.028/0.040; P =6.0E-15] for the CoW artery compared with the superficial temporal artery), Euclidean distance (-25.71 [90% CI, -31.54/-20.02; P =1.9E-11] for the cortical artery and -38.09 [90% CI, -44.08/-32.19; P <2.2E-16] for the CoW artery compared with the superficial temporal artery) and principal component analysis. In all analyses, the unrelated tissues formed separate groups compared with IA and the 3 control arteries. Conclusions- The cortical arteries and the CoW arteries are better controls for gene expression studies on IA than the superficial temporal artery. This probably relates to differences in anatomy of these tissues, such as the presence of an external elastic lamina in the extracranial vasculature and absence in the intracranial vasculature, because IAs, cortical arteries, and CoW arteries are all intracranial while the superficial temporal artery is extracranial. Since CoW arteries can only be obtained postmortem, cortical arteries are preferred over CoW arteries.

Objectives: To assess international trends and patterns of prenatal diagnosis of critical congenital heart defects (CCHDs) and their relation to total and live birth CCHD prevalence and mortality., Setting: Fifteen birth defect surveillance programmes that participate in the International Clearinghouse for Birth Defects Surveillance and Research from 12 countries in Europe, North and South America and Asia., Participants: Live births, stillbirths and elective terminations of pregnancy for fetal anomaly diagnosed with 1 of 12 selected CCHD, ascertained by the 15 programmes for delivery years 2000 to 2014., Results: 18 243 CCHD cases were reported among 8 847 081 births. The median total prevalence was 19.1 per 10 000 births but varied threefold between programmes from 10.1 to 31.0 per 10 000. CCHD were prenatally detected for at least 50% of the cases in one-third of the programmes. However, prenatal detection varied from 13% in Slovak Republic to 87% in some areas in France. Prenatal detection was consistently high for hypoplastic left heart syndrome (64% overall) and was lowest for total anomalous pulmonary venous return (28% overall). Surveillance programmes in countries that do not legally permit terminations of pregnancy tended to have higher live birth prevalence of CCHD. Most programmes showed an increasing trend in prenatally diagnosed CCHD cases., Discussion and Conclusions: Prenatal detection already accounts for 50% or more of CCHD detected in many programmes and is increasing. Local policies and access likely account for the wide variability of reported occurrence and prenatal diagnosis. Detection rates are high especially for CCHD that are more easily diagnosed on a standard obstetric four-chamber ultrasound or for fetuses that have extracardiac anomalies. These ongoing trends in prenatal diagnosis, potentially in combination with newborn pulse oximetry, are likely to modify the epidemiology and clinical outcomes of CCHD in the near future., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

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., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: To evaluate the risk of major congenital anomaly associated with first-trimester exposure to insulin analogues compared with human insulin in offspring of women with pregestational diabetes., Design and Setting: A population-based cohort of women with pregestational diabetes (n=1661) who delivered between 1996 and 2012 was established retrospectively from seven European regions covered bythe European Surveillance of Congenital Anomalies (EUROCAT) congenital anomaly registries., Primary Outcome Measures: The risk of non-chromosomal major congenital anomaly in live births, fetal deaths and terminations for a fetal anomaly exposed to insulin analogues in the first trimester of pregnancy was compared with the risk in those exposed to human insulin only., Results: During the first trimester, 870 fetuses (52.4%) were exposed to human insulin only, 397 fetuses (23.9%) to insulin analogues only and 394 fetuses (23.7%) to both human insulin and insulin analogues. The risk of major congenital anomaly in fetuses exposed to insulin analogues only was lower than those exposed to human insulin only; the relative risk adjusted for glycaemic control and region was 0.56 (95% CI 0.29 to 1.06). The significantly lower risk related to exposure of insulin analogues only was observed in congenital heart defects: adjusted relative risk 0.14 (95% CI 0.03 to 0.62)., Conclusions: In this retrospective population-based cohort study across Europe, first-trimester exposure to insulin analogues did not increase the risk of major congenital anomaly compared with exposure to human insulin. A possible lower risk of congenital heart defects among fetuses exposed to insulin analogues only deserves further investigation., Competing Interests: Competing interests: EW-O is a member of Polish Novo Nordisk advisory board, she gives lectures and leads workshops organised by Eli Lilly and Novo Nordisk in Poland., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: To evaluate the impact of the introduction of prenatal screening on time of detection and pregnancy outcome for trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13)., Methods: We performed a retrospective, population-based cohort study in the Northern Netherlands including 503 trisomy cases born between 2005 and 2012. Screening tests and invasive procedures, timing of diagnosis and pregnancy outcome were compared between the period before (2005-2006) and after introduction (2007-2012) using X 2 tests., Results: There was an increase in proportion of women who had a prenatal screening and/or invasive test, from 62% in 2005-2006 to 84% in 2010-2012 (p < 0.01), while the proportion of prenatally diagnosed cases did not change (60% overall). In women < =35 years 47% of the cases were diagnosed prenatally vs 73% in women >35 years (p < 0.01). More T13/T18 cases were diagnosed <24 weeks after introduction (62% vs 84%; p < 0.01). In T13/T18 intra-uterine death decreased (26% vs 15%), while terminations increased: 55% vs 72%., Conclusion: The introduction of prenatal screening had limited impact on the time of detection and outcome of the most common trisomies. The introduction of the 20-week anomaly scan has resulted in more trisomy cases diagnosed <24 weeks and a shift from fetal death to terminations.

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., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.)

Cardiovascular manifestations in patients with Marfan syndrome (MFS) are related to aortic and valvular abnormalities. However, dilatation of the left ventricle (LV) can occur, even in the absence of aortic surgery or valvular abnormalities. We evaluated genetic characteristics of patients with MFS with LV dilatation. One hundred eighty-two patients fulfilling the MFS criteria, without valvular abnormalities or previous aortic surgery, with a complete FBN1 analysis, were studied. FBN1 mutations were identified in over 81% of patients. Twenty-nine patients (16%) demonstrated LV dilatation (LV end diastolic diameter corrected for age and body surface area >112%). FBN1-positive patients carrying a non-missense mutation more often had LV dilatation than missense mutation carriers (14/74 versus 5/75; p<0.05). Finally, FBN1-negative MFS patients significantly more often demonstrated LV dilatation than FBN1-positive patients (10/33 versus 19/149; p<0.05). It is concluded that LV dilatation in MFS patients is more often seen in patients with a non-missense mutation and in those patients without an FBN1 mutation. Therefore physicians should be aware of the possibility of LV dilatation in these patients even in the absence of valvular pathology., (© 2013 Elsevier B.V. All rights reserved.)

The importance of maternal cholesterol as an exogenous cholesterol source for the growing embryo was first reported in studies of Smith-Lemli-Opitz syndrome. Although most of the fetus's cholesterol is synthesized by the fetus itself, there is now growing evidence that during the first weeks of life, when most organs develop, the fetus largely depends on maternal cholesterol as its cholesterol source. The maternal-fetal cholesterol transport mechanism, by transporters in both the yolk sac and placenta, is becoming better understood. This minireview summarizes current insights on maternal-fetal cholesterol transport based on in vitro and in vivo studies. As the prevalence of maternal diseases, such as diabetes, obesity, and the metabolic syndrome that adversely affect maternal cholesterol levels, is now rapidly reaching epidemic proportions, we urgently need to determine the impact of these maternal conditions on the developing human fetus.

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.

Aims: To investigate the potentially protective of periconceptional folic acid use on the risk of congenital heart defects (CHDs) relative to other non-folate related malformations., Methods and Results: We analysed data from a large regional register of birth defects (EUROCAT-Northern Netherlands), over a 10 year period (1996-2005) for a case-control study. The cases were mothers who had delivered infants with isolated or complex heart defects, without any related syndrome or genetic abnormality (n = 611). We used two control groups; one from the EUROCAT database and another from the general population. The registry controls consisted of mothers of children with a known chromosomal or genetic defect, and with infants with other non-folate related congenital malformations (n = 2401). Additional folic acid was taken as a single supplement or as a multivitamin containing folic acid in a dose of >or=400 microg daily. Mothers who had used folate antagonists or who had diabetes, and mothers of children with oral clefts, hypospadias, limb reduction- or neural tube defects, were excluded from both groups. Potentially confounding factors of periconceptional folic acid use in relation to CHD were explored, including baby's birth year, maternal body mass index, education, maternal age at delivery of index baby, smoking behaviour, and alcohol use during pregnancy. Periconceptional folic acid use revealed an odds ratio (OR) of 0.82 (95% CI 0.68-0.98) for all types of CHD relative to other malformations. The estimated relative risk for CHDs of additional folic acid use compared with the general population was comparable [OR 0.74 (95%CI 0.62-0.88)]. Subgroup analysis showed an OR of 0.62 (95% CI 0.47-0.82) for isolated septal defects. The proportions of the potential confounders between mothers of case and control infants did not differ significantly., Conclusion: Our results support the hypothesis that additional periconceptional folic acid use reduces CHD risk in infants. Use of periconceptional folic acid supplements was related to approximately 20% reduction in the prevalence of any CHD. Given the relatively high prevalence of CHD worldwide, our findings are important for public health.

What Is Already Known About This Subject: * Recently, the use of selective serotonin reuptake inhibitors (SSRIs), particularly paroxetine, in pregnancy has been associated with an increased risk on specific birth defects or other adverse pregnancy outcomes. * However, the extent of SSRI use in pregnancy is largely unknown., What This Study Adds: * In the last decade the use of SSRIs in the year preceding delivery has increased twofold. * This increase runs parallel with the increase in use of SSRIs among women of fertile age. * Paroxetine is one of the most commonly used SSRIs. * Only recently have sufficient data become available on the use of paroxetine to detect moderate increased risks for specific malformations. * The safety of SSRIs which are less frequently used is not yet established. * Case-control birth defect-monitoring systems may be helpful in providing safety and risk estimates that become more precise as data accumulate for these drugs., Aims: Recent case-control studies suggest a relationship between the use of selective serotonin reuptake inhibitors (SSRIs) and the occurrence of birth defects and other adverse pregnancy outcomes. The aim was to determine the extent of the use of SSRIs before and during pregnancy and its trend over the years 1995-2004 in the Netherlands., Methods: The study was performed with data from a population-based prescription database. Within this database, women giving birth to a child between 1995 and 2004 were identified. The exposure rate and 95% confidence interval (CI) were calculated as the number of pregnancies per 1000 that were exposed to an SSRI in a defined period (per trimester or in the year preceding delivery). Exposure rates were calculated for 2-year periods: 1995/1996, 1997/1998, 1999/2000, 2001/2002 and 2003/2004. Trends in exposure rates were analysed using the chi(2) test for trend., Results: Included were 14,902 pregnancies for which complete pharmacy records were available from 3 months before pregnancy until delivery. A total of 310 pregnancies were exposed to an SSRI in the year preceding delivery. The exposure rate increased from 12.2 (95% CI 7.0, 19.8) in 1995/1996 to 28.5 (95% CI 23.0, 34.9) in 2003/2004., Conclusion: There has been a significant increase in the use of SSRIs among pregnant women in the Netherlands over the last 10 years, parallel with the increase in exposure in women of fertile age. In light of the recent warnings about the use of SSRIs in pregnancy, healthcare professionals should be careful in prescribing SSRIs to women planning a pregnancy.

Objective: To describe treatment, survival, and morbidity for liveborn infants with isolated transposition of great arteries (TGA)., Design: Population-based data from 7 European registries of congenital malformations (EUROCAT)., Results: Ninety-seven infants were diagnosed with isolated TGA and livebirth prevalence was 2.0 per 10,000 livebirths. The majority of infants were treated with prostaglandins (83%) and 57% had a catheter atrial septostomia performed. Arterial switch surgery was performed in 78 infants, other or unknown type of surgery was performed in 3 cases, and for 6 infants there was no information on surgery. At 1 year of age 69 infants were alive (71%) and 24 (25%) were dead (4 unknown). There were 10 deaths before surgery and 58% of all deaths took place during the first week. There was no statistically significant regional difference in mortality. Eight infants diagnosed prenatally all survived to 1 year and only 71% of infants diagnosed after birth survived (P = 0.08). Data on morbidity at 1 year of age was available for 57 infants. Fifty-one infants were reported with normal health and development., Conclusions: In this population-based study survival for liveborn infants with TGA is lower than in studies published from tertiary centers. Outcome for survivors at 1 year of age seems favorable.