Maternal occupational exposure to solvents and gastroschisis in offspring-National Birth Defects Prevention Study 1997-2011

Objectives: The aim of this study was to assess the association between maternal occupational exposure to solvents and gastroschisis in offspring. Methods: We used data from the National Birth Defects Prevention Study, a large population-based case-control study of major birth defects conducted in 10 US states from 1997 to 2011. Infants with gastroschisis were ascertained by active birth defects surveillance systems. Control infants without major birth defects were selected from vital records or birth hospital records. Self-reported maternal occupational histories were collected by telephone interview. Industrial hygienists reviewed this information to estimate exposure to aromatic, chlorinated and petroleum-based solvents from 1 month before conception through the first trimester of pregnancy. Cumulative exposure to solvents was estimated for the same period accounting for estimated exposure intensity and frequency, job duration and hours worked per week. ORs and 95% CIs were estimated to assess the association between exposure to any solvents or solvent classes, and gastroschisis risk. Results: Among 879 cases and 7817 controls, the overall prevalence of periconceptional solvent exposure was 7.3% and 7.4%, respectively. Exposure to any solvent versus no exposure to solvents was not associated with gastroschisis after adjusting for maternal age (OR 1.00, 95% CI 0.75 to 1.32), nor was an association noted for solvent classes. There was no exposure-response relationship between estimated cumulative solvent exposure and gastroschisis after adjusting for maternal age. Conclusion: Our study found no association between maternal occupational solvent exposure and gastroschisis in offspring. Further research is needed to understand risk factors for gastroschisis

Prevention of congenital malformations and other adverse pregnancy outcomes with 4.0 mg of folic acid : community-based randomized clinical trial in Italy and the Netherlands

Background: In 2010 a Cochrane review confirmed that folic acid (FA) supplementation prevents the first- and second-time occurrence of neural tube defects (NTDs). At present some evidence from observational studies supports the hypothesis that FA supplementation can reduce the risk of all congenital malformations (CMs) or the risk of a specific and selected group of them, namely cardiac defects and oral clefts. Furthermore, the effects on the prevention of prematurity, foetal growth retardation and pre-eclampsia are unclear.Although the most common recommendation is to take 0.4 mg/day, the problem of the most appropriate dose of FA is still open.The aim of this project is to assess the effect a higher dose of peri-conceptional FA supplementation on reducing the occurrence of all CMs. Other aims include the promotion of pre-conceptional counselling, comparing rates of selected CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age, abruptio placentae.Methods/Design: This project is a joint effort by research groups in Italy and the Netherlands. Women of childbearing age, who intend to become pregnant within 12 months are eligible for the studies. Women are randomly assigned to receive 4 mg of FA (treatment in study) or 0.4 mg of FA (referent treatment) daily. Information on pregnancy outcomes are derived from women-and-physician information.We foresee to analyze the data considering all the adverse outcomes of pregnancy taken together in a global end point (e.g.: CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age). A total of about 1,000 pregnancies need to be evaluated to detect an absolute reduction of the frequency of 8%. Since the sample size needed for studying outcomes separately is large, this project also promotes an international prospective meta-analysis.Discussion: The rationale of these randomized clinical trials (RCTs) is the hypothesis that a higher intake of FA is related to a higher risk reduction of NTDs, other CMs and other adverse pregnancy outcomes. Our hope is that these trials will act as catalysers, and lead to other large RCTs studying the effects of this supplementation on CMs and other infant and maternal outcomes.Trial registration: Italian trial: ClinicalTrials.gov Identifier: NCT01244347.Dutch trial: Dutch Trial Register ID: NTR3161

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

Objective: To evaluate the prevalence of the awareness of and the behaviour towards folic acid in 2003 and the trend of folic acid use among pregnant Dutch women between 1995 and 2003 with regard to socio-economic status (SES). Method: We conducted 2-yearly cross-sectional studies among pregnant women who filled in a questionnaire during the first or second antenatal visit. The highest achieved level of education was taken as a proxy for SES. Results: In 2003 the general level of folic acid awareness was high but with significant differences relating to SES; a quarter of the lower educated women did not know about folic acid before pregnancy. Of the subjects with a lower SES 20% knew the correct period of use compared with nearly 50% in the higher SES group. The reported correct use of folic acid among the lower educated women has decreased over the past 3 years (22% in 2003), while it has increased for the higher SES groups (59% in 2003), implying larger differences in health. Conclusion: In 2003, 8 years after a mass media campaign, awareness and use of folic acid were increased considerably in comparison with the start of the campaign. However, differences in knowledge and use of folic acid with respect to the level of education had never been so impressive in the Netherlands as in 2003. A once-only campaign has a short-term effect especially for lower educated women. Implementing strategies to promote folic acid use in daily structural health care systems are needed. Copyright (c) 2007 S. Karger AG, Basel

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. Copyright (C) 2010 John Wiley & Sons, Ltd

Cost-effectiveness of periconceptional supplementation of folic acid

Background: Supplementation of folic acid prior to and in the beginning of pregnancy may prevent neural tube defects (NTDs) in newborns - such as spina bifida - and possibly other congenital malformations. Objective. To estimate cost effectiveness of periconceptional supplementation of folk: acid using pharmaco-economic model calculation. Method Probabilities for NTDs, risk reductions through periconceptional supplementation of folic acid and lifetime costs of care for children with spina bifida were estimated using Dutch registrations and international literature. Main outcome measure: Cost effectiveness was expressed in net costs per discounted life-year gained. Cost effectiveness was calculated in the baseline and in sensitivity analysis. Results: Estimated cost effectiveness of periconceptional supplementation of folic acid amounts to NLG 3900(1800) In the base case. In sensitivity analysis cost effectiveness mostly remains below NLG 10.000(4500). Conclusion: Periconceptional supplementation of folic acid shows a favorable cost effectiveness. From pharmaco-economic point of view this justifies further stimulation of folic-acid supplementation prior to pregnancy. This can be done through targeted education by health-care workers, such as pharmacists

Disease-modifying antirheumatic drugs in pregnancy - Current status and implications for the future

Drug use during pregnancy is sometimes unavoidable, especially in chronic inflammatory diseases such as rheumatoid arthritis (RA). The use of disease-modifying antirheumatic drugs (DMARDs) often starts in the early stage of RA; therefore, women of reproductive age are at risk for exposure to a DMARD at time of conception as well as during pregnancy. The aim of this paper was to review recent literature about DMARDs used for rheumatic diseases in pregnancy and to describe the type of study designs and results reported. Twenty-nine studies; eight on hydroxychloroquine/chloroquine, thirteen on methotrexate, three on sulfasalazine and six on azathioprine were identified. With respect to hydroxychloroquine, most studies concluded that it could be safely used in systemic lupus erythematosus or RA. The same conclusions were drawn from the azathioprine studies, but the available evidence is scarce. Although the evidence regarding the safety of methotrexate during pregnancy is conflicting, a high rate of pregnancy losses indicates a risk to the fetus. For each individual case it must be decided whether the benefits outweigh the potential risks. No major teratogenic effects of sulfasalazine were seen although teratogenic effects still can not be excluded. For all other DMARDs, the information on their use in pregnancy was limited. This review underscores the gross absence of data on safety and risks of DMARD use during conception and pregnancy. While young women use these drugs in pregnancy, this review stresses the importance of good monitoring and further research