Offspring Birth Weight Is Associated with Specific Preconception Maternal Food Group Intake: Data from a Linked Population-Based Birth Cohort.

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. (ß = 0.001 [95% CI 0.000 to 0.001, p = 0.002]), (ß = 0.002 [95% CI 0.000 to 0.003, p = 0.03])). Intake of food group "eggs" was associated with decreased birth weight (ß = -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.

Beta-Blocker Use in Pregnancy and Risk of Specific Congenital Anomalies: A European Case-Malformed Control Study.

INTRODUCTION: The prevalence of chronic hypertension is increasing in pregnant women. Beta-blockers are among the most prevalent anti-hypertensive agents used in early pregnancy. OBJECTIVE: The objective of this study was to investigate whether first-trimester use of beta-blockers increases the risk of specific congenital anomalies in offspring. METHODS: A population-based case-malformed control study was conducted in 117,122 registrations of congenital anomalies from 17 European Concerted Action on Congenital Anomalies and Twins (EUROCAT) registries participating in EUROmediCAT with data for all or part of the period between 1995 and 2013. Associations previously reported in the literature (signals) were tested and an exploratory analysis was performed to identify new signals. Odds ratios of exposure to any beta-blocker or to a beta-blocker subgroup were calculated for each signal anomaly compared with two control groups (non-chromosomal, non-signal anomalies and chromosomal anomalies). The exploratory analyses were performed for each non-signal anomaly compared with all the other non-signal anomalies. RESULTS: The signals from the literature (congenital heart defects, oral clefts, neural tube defects and hypospadias) were not confirmed. Our exploratory analysis revealed that multi-cystic renal dysplasia had significantly increased odds of occurring after maternal exposure to combined alpha- and beta-blockers (adjusted odds ratio 3.8; 95% confidence interval 1.3-11.0). CONCLUSION: Beta-blocker use in the first trimester of pregnancy was not found to be associated with a higher risk of specific congenital anomalies in the offspring, but a new signal between alpha- and beta-blockers and multi-cystic renal dysplasia was found. Future large epidemiological studies are needed to confirm or refute our findings.

The impact of national prenatal screening on the time of diagnosis and outcome of pregnancies affected with common trisomies, a cohort study in the Northern Netherlands.

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.

Prenatal diagnosis and epidemiology of multicystic kidney dysplasia in Europe.

OBJECTIVES: The aim of this study is to describe the prenatal diagnosis and epidemiology of multicystic kidney dysplasia (MCKD). METHODS: The study is based on routinely collected data from a European database of major congenital anomalies including 13 registries with cases born in 1997-2006 and covering 1 458 552 births. RESULTS: There were 601 MCKD cases giving an overall prevalence of 4.12 per 10 000 births with regional variation. In live births, 87% of cases had an isolated renal anomaly and 13% had associated major nonrenal anomalies (chromosomal, syndrome or other major anomalies). For the cases with isolated renal anomalies, 51/386 (11%) and 7/386 (2%) choose to terminate the pregnancy or resulted in an intrauterine fetal death, respectively. The prenatal detection rate was 88% in both unilateral and bilateral cases. Birth outcome differed with 92% of unilateral MCKD cases being liveborn compared with 33% of bilateral MCKD cases. For unilateral MCKD cases, 84% had an isolated renal anomaly compared with 51% of bilateral MCKD cases (p < 0.001). CONCLUSIONS: Cases with unilateral MCKD are mainly liveborn, and only 16% have associated major malformations or a syndrome. Cases with bilateral MCKD are often associated with nonrenal major congenital anomalies or part of a syndrome, and only one third of bilateral MCKD cases in this study were liveborn. Prenatal detection rate of MCKD was high for both unilateral and bilateral cases. © 2014 John Wiley & Sons, Ltd.

Pharmacogenetics of drug-induced birth defects: the role of polymorphisms of placental transporter proteins.

One of the ongoing issues in perinatal medicine is the risk of birth defects associated with maternal drug use. The teratogenic effect of a drug depends, apart from other factors, on the exposition of the fetus to the drug. Transporter proteins are known to be involved in the pharmacokinetics of drugs and have an effect on drug level and fetal drug exposure. This condition may subsequently alter the risk of teratogenicity, which occurs in a dose-dependent manner. This review focuses on the clinically important polymorphisms of transporter proteins and their effects on the mRNA and protein expression in placental tissue. We also propose a novel approach on how the different genotypes of the polymorphism can be translated into phenotypes to facilitate genetic association studies. The last section looks into the recent studies exploring the association between P-glycoprotein polymorphisms and the risk of fetal birth defects associated with medication use during pregnancy.

Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome.

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.

Maternal recall of prescription medication use during pregnancy using a paper-based questionnaire: a validation study in the Netherlands.

BACKGROUND: In case-control studies that assess associations between medication use and birth defects, detailed information on type of medication and timing of use is essential to prevent misclassification. However, data on the accuracy of recall of medication use during pregnancy are scarce. OBJECTIVE: The aim of this study was to validate a self-administered questionnaire to assess prescription medication use in the 3 months before and during pregnancy. METHODS: This validation study was embedded in Eurocat Northern Netherlands, a population-based birth defects registry that covers 10% of all births in The Netherlands. The questionnaire was validated among 560 mothers of infants with major birth defects registered from 1 January 2009 through 30 June 2010 by comparing it with a reference standard consisting of pharmacy data which were checked for compliance by maternal interviews. Sensitivity and specificity were calculated to quantify validity for any prescription medication use, groups of medications and individual medications. In addition, we determined whether maternal characteristics influenced disagreement between the questionnaire and the reference standard using logistic regression analyses. RESULTS: The sensitivity for any prescription medication use was 0.57, ranging between 0.07 (dermatological corticosteroids) and 0.83 (antihypertensives) for medication groups, and between 0.00 (naproxen) and 0.73 (salbutamol) for individual medications. Overall, specificity was high (0.93-1.00). Smoking during pregnancy and completing the questionnaire>2 years after delivery were associated with increased disagreement between the questionnaire for prescription medication use and the reference standard. CONCLUSIONS: The validity of the self-administered questionnaire for prescription medication use during pregnancy was moderate to poor for most medications and disagreement differed by some maternal characteristics. As many epidemiological studies use similar questionnaires to assess medication use these studies may need additional data sources such as pharmacy records or prescription databases for medication use next to self-reported methods. Also, previous knowledge on the effect of questionnaire design should be taken into account.

Combined adverse effects of maternal smoking and high body mass index on heart development in offspring: evidence for interaction?

OBJECTIVE: To study the influence of a possible interaction between maternal smoking and high body mass index (BMI) on the occurrence of specific congenital heart anomalies (CHA) in offspring. DESIGN: Case-control study. SETTING: Data from a population-based birth defects registry in the Netherlands. PATIENTS: Cases were 797 children and fetuses born between 1997 and 2008 with isolated non-syndromic CHA. They were classified into five cardiac subgroups: septal defects (n=349), right ventricular outflow tract obstructive anomalies (n=126), left ventricular outflow tract obstructive anomalies (n=139), conotruncal defects (n=115) and other CHA (n=68). Controls were 322 children and fetuses with chromosomal anomalies without cardiac anomalies. MAIN OUTCOME MEASURES: Investigation of whether an interaction between maternal smoking and high BMI influences the occurrence of CHA in offspring by calculation of the synergy factors and 95% CIs. RESULTS: As opposed to smoking or high BMI alone, the risk for CHA in the offspring of women with high BMI (≥25 kg/m(2)) who also smoked was significantly increased. The adjusted OR was 2.65 (95% CI 1.20 to 5.87) for all CHA, 2.60 (95% CI 1.05 to 6.47) for septal defects and 3.58 (95% CI 1.46 to 8.79) for outflow tract anomalies. The interaction between maternal high BMI and smoking contributed significantly to the occurrence of all offspring-CHA combined, and to the occurrence of all cardiac subgroup anomalies except right ventricular outflow tract obstructive anomalies. CONCLUSIONS: Maternal overweight and smoking may have a synergistic adverse effect on the development of the fetal heart. Overweight women who wish to become pregnant should be strongly encouraged to stop smoking and to lose weight.

Fluoxetine and infantile hypertrophic pylorus stenosis: a signal from a birth defects-drug exposure surveillance study.

PURPOSE: We report an association found in a surveillance study which systematically evaluated combinations of specific birth defects and drugs used in the first trimester of pregnancy. METHOD: The database of a population-based birth defects registry (birth years 1997-2007) was systematically screened for combinations of drugs and malformations that were disproportionately present compared to the rest of the database. Combinations with at least three exposed cases and a p < 0.01 (Fisher Exact test) were studied to analyse details of the malformation, timing of exposure, and additional case-control analyses. RESULTS: Among the significant associations found, an association between maternal use of fluoxetine and infantile hypertrophic pyloric stenosis (IHPS) was of particular interest. In total 3/178 (1.7%) of the children with a HPS were exposed to fluoxetine in the first trimester compared to 8/4077 (0.2%) fluoxetine exposures among the children with other malformations (p = 0.009, OR = 8.7, 95%CI = 2.3-33.2). The three exposed cases were all isolated and fluoxetine was used in gestational weeks 4-8, 2-8 and -10-19, respectively. In additional case-control analyses, using controls with a genetic disorder and after adjustment for maternal age and smoking in the first trimester of pregnancy, the adjusted odds ratio was 9.8 (95% confidence interval: 1.5-62.0). CONCLUSIONS: Because we cannot rule out the possibility that the association between IHPS and fluoxetine is caused by chance, we encourage other investigators to study the association between IHPS and fluoxetine in their data.

Protective effect of periconceptional folic acid supplements on the risk of congenital heart defects: a registry-based case-control study in the 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.

First-trimester use of paroxetine and congenital heart defects: a population-based case-control study.

BACKGROUND: There is a need for case-control studies of the effect of paroxetine on the occurrence of specific heart defects. METHODS: We performed a case-control study with data from a population-based birth defects registry in the Netherlands. All the children born between 1997 and 2006 were selected. Cases were defined as fetuses and children with isolated heart defects, and the controls were fetuses and children with a genetic disorder with no heart defect. We excluded children for whom there was no information on maternal medication use and deceased children and fetuses who were not examined postmortem. First-trimester exposure to paroxetine was compared between cases and controls by calculating adjusted odds ratios (AOR). RESULTS: We included 678 cases with isolated heart defects and 615 controls. The first trimester exposure rate was 1.5% for cases and 1.0% for controls. After excluding mothers who used paroxetine outside the first trimester, or who had used another SSRI, we found no significantly increased risk for heart defects overall (10 exposed cases; AOR, 1.5; 95% confidence interval [CI], 0.5-4.0), but we did find a significantly increased risk for atrium septum defects (three exposed cases; AOR, 5.7; 95% CI, 1.4-23.7). CONCLUSIONS: Our results suggest that the use of paroxetine in early pregnancy is associated with an increased risk of atrium septum defects. The results stress the importance of studying possible teratogenic effects of a drug, preferably in regard to well-specified malformations.

[Congenital anomalies in Amsterdam: results of the 'Amsterdam-Born Children and their Development' study]. / Congenitale afwijkingen in Amsterdam: resultaten 'Amsterdam born children and their development'-studie.

OBJECTIVE: To describe the prevalence of congenital anomalies in children born in Amsterdam and to analyse potential differences between groups based on risk factors such as ethnicity and maternal age. DESIGN: Secondary analysis of a prospective cohort study. METHODS: Between 2003 and 2004, mothers filled in questionnaires on their newborn children on behalf of the Amsterdam-Born Children and their Development study (ABCD study). Data from 5,276 liveborn children in this cohort were used to calculate the prevalence rates of congenital anomalies in Amsterdam. These were compared with expected prevalence rates based on Eurocat data for the Northern region of the Netherlands during the years 2000-2005. Prevalence rates were compared between subgroups which had been divided according to risk factors: maternal ethnic origin, maternal age, parity, gender of child, inter-pregnancy interval, years of maternal education, smoking, alcohol use, and periconceptional folate use. RESULTS: The total prevalence of major congenital anomalies among liveborn children in the ABCD cohort was as expected based on the figures from the Eurocat registration. Digestive anomalies were reported significantly less frequently (n = 1) than expected (n = 10). Mothers of Surinam descent more frequently reported a child with a musculoskeletal anomaly. Older mothers were more likely to report congenital anomalies. No significant trends regarding other risk factors were observed. CONCLUSIONS: No significant trends regarding ethnicity and congenital anomalies were detected. The interpretation of the other results was hampered by methodological differences between the ABCD study and Eurocat. Nationwide registration with active case detection of congenital anomalies is therefore recommended.

Survival and health in liveborn infants with transposition of great arteries--a population-based study.

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.