Improving care for rare genetic neurodevelopmental disorders: A systematic review and critical appraisal of clinical practice guidelines using AGREE II.

PURPOSE: Rare genetic neurodevelopmental disorders associated with intellectual disability require lifelong multidisciplinary care. Clinical practice guidelines may support healthcare professionals in their daily practice, but guideline development for rare conditions can be challenging. In this systematic review, the characteristics and methodological quality of internationally published recommendations for this population are described to provide an overview of current guidelines and inform future efforts of European Reference Network ITHACA (Intellectual disability, TeleHealth, Autism, and Congenital Anomalies). METHODS: MEDLINE, Embase, and Orphanet were systematically searched to identify guidelines for conditions classified as "rare genetic intellectual disability" (ORPHA:183757). Methodological quality was assessed using the Appraisal of Guidelines, Research, and Evaluation II tool. RESULTS: Seventy internationally published guidelines, addressing the diagnosis and/or management of 28 conditions, were included. The methodological rigor of development was highly variable with limited reporting of literature searches and consensus methods. Stakeholder involvement and editorial independence varied as well. Implementation was rarely addressed. CONCLUSION: Comprehensive, high-quality guidelines are lacking for many rare genetic neurodevelopmental disorders. Use and transparent reporting of sound development methodologies, active involvement of affected individuals and families, robust conflict of interest procedures, and attention to implementation are vital for enhancing the impact of clinical practice recommendations.

Should secondary pharmacogenomic variants be actively screened and reported when diagnostic genome-wide sequencing is performed in a child?

This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream's Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a genetic cause of their condition. We discuss actively searching for and reporting pharmacogenetic/genomic variants in pediatric patients, different methods of returning secondary pharmacogenomic findings to the patient/parents and/or treating clinicians, maintaining these data in the patient's health record over time, decision supports to assist using pharmacogenetic results in future treatment decisions, and sharing information in public databases to improve the clinical interpretation of pharmacogenetic variants identified in other children. We conclude by presenting a series of points to consider for clinicians and policymakers regarding whether, and under what circumstances, routine screening and return of pharmacogenomic variants unrelated to the indications for testing is appropriate in children who are undergoing genome-wide sequencing to assist in the diagnosis of a suspected genetic disease.

Perceptions of reproductive healthcare providers regarding their involvement in offering expanded carrier screening in fertility clinics: a qualitative study.

RESEARCH QUESTION: What are the main arguments of reproductive healthcare providers in favour or against their involvement in offering expanded carrier screening (ECS) for recessive disorders at fertility clinics in the Netherlands? DESIGN: Semi-structured interview study with 20 reproductive healthcare providers between May 2020 and January 2021. Participants included 11 gynaecologists, seven fertility doctors, one nurse practitioner and one clinical embryologist, recruited from academic medical centres (n = 13), peripheral facilities associated with academic centres (n = 4), and independent fertility treatment centres (n = 3) in the Netherlands. An interview guide was developed, and thematic content analysis was performed using ATLAS.ti software. RESULTS: Arguments of reproductive healthcare providers in favour of their potential involvement in offering ECS included: (i) opportunities offered by the setting; (ii) motivation to assist in reproduction and prevent suffering; and (iii) to counter unwanted commercialization offers. Arguments against involvement included: (i) lack of knowledge and familiarity with offering ECS; (ii) insufficient staff and resources, and potential high costs for clinics and/or couples; (iii) the emotional impact it may have on couples; (iv) perceived complexity of counselling and expected elongation of waiting lists; and (v) expected low impact on reducing the burden of diseases. Participants felt that more evidence and research on the costs-benefits, implications and demand are needed prior to their involvement. CONCLUSION: While agreeing that the field of medically assisted reproduction provides a unique opportunity to offer ECS, reproductive healthcare workers feel a lack of capability and limited motivation to offer ECS to all or a selection of couples at their fertility clinics.

Does non-invasive prenatal testing affect the livebirth prevalence of Down syndrome in the Netherlands? A population-based register study.

OBJECTIVE: To evaluate if non-invasive prenatal testing (NIPT) affects livebirth (LB) prevalence of Down syndrome (DS) in the Netherlands. METHOD: Data from clinical genetics laboratories and the Working Party on Prenatal Diagnosis and Therapy (2014-2018) and previous published data (1991-2013) were used to assess trends for DS LB prevalence and reduction percentage (the net decrease in DS LBs resulting from selective termination of pregnancies). Statistics Netherlands provided general population data. RESULTS: DS LB prevalence increased from 11.6/10,000 in 1991 to 15.9/10,000 in 2002 (regression coefficient 0.246 [95% CI: 0.105-0.388; p = 0.003]). After 2002, LB prevalence decreased to 11.3/10,000 in 2014 and further to 9.9/10,000 in 2018 (regression coefficient 0.234 (95% CI: -0.338 to -0.131; p < 0.001). The reduction percentage increased from 26% in 1991 to 55.2% in 2018 (regression coefficient 0.012 (95% CI: 0.010-0.013; p < 0.001)). There were no trend changes after introducing NIPT as second-tier (2014) and first-tier test (2017). CONCLUSIONS: Introducing NIPT did not change the decreasing trend in DS LB prevalence and increasing trend in reduction percentage. These trends may be caused by a broader development of more prenatal testing that had already started before introducing NIPT.

Uptake of fetal aneuploidy screening after the introduction of the non-invasive prenatal test: A national population-based register study.

INTRODUCTION: The introduction of the non-invasive prenatal test (NIPT) has shifted the prenatal screening landscape. Countries are exploring ways to integrate NIPT in their national prenatal screening programs, either as a first- or second-tier test. This study aimed to describe how the uptake of fetal aneuploidy screening changed after the introduction of NIPT as a second-tier and as a first-tier test within the national prenatal screening program of the Netherlands. MATERIAL AND METHODS: A population-based register study in the Netherlands, recording uptake of fetal aneuploidy screening. Data from all pregnant women choosing to have the first-trimester combined test (FCT) or first-tier NIPT between January 2007 and March 2019 were retrospectively collected using national registration systems. Uptake percentages for fetal aneuploidy screening (FCT and NIPT) were calculated and stratified by region and maternal age. Statistical significance was determined using trend analysis and chi-squared tests. RESULTS: Between 2007 and 2013 FCT uptake increased from 14.8% to 29.5% (P = .004). In April 2014 NIPT was introduced as a second-tier test for high-risk women after FCT (TRIDENT-1 study). FCT uptake rose from 29.5% in 2013 to 34.2% in 2015 (P < .0001). After the introduction of NIPT as a first-tier test for all women in April 2017 (TRIDENT-2 study), FCT uptake declined significantly from 35.8% in 2016 to 2.6% in 2018 (P < .0001). NIPT uptake increased to 43.4% in 2018. Regionally, NIPT uptake ranged from 31.8% to 67.9%. Total uptake (FCT and NIPT) between 2007 and 2018 increased significantly from 14.8% to 45.9% (P < .0001). However, total uptake stabilized at 46% for both years of TRIDENT-2 (April 2017-March 2019). CONCLUSIONS: An increase in total fetal aneuploidy screening uptake up to 45.9% was observed after the introduction of NIPT. Uptake appears to have stabilized within a year after introducing first-tier NIPT.

Genome-wide sequencing in acutely ill infants: genomic medicine's critical application?

Diagnostic genome-wide sequencing (exome or genome sequencing and data analysis for high-penetrance disease-causing variants) in acutely ill infants appears to be clinically useful, but the value of this diagnostic test should be rigorously demonstrated before it is accepted as a standard of care. This white paper was developed by the Paediatric Task Team of the Global Alliance for Genomics and Health's Regulatory and Ethics Work Stream to address the question of how we can determine the clinical value of genome-wide sequencing in infants in an intensive care setting. After reviewing available clinical and ethics literature on this question, we conclude that evaluating diagnostic genome-wide sequencing as a comprehensive scan for major genetic disease (rather than as a large panel of single-gene tests) provides a practical approach to assessing its clinical value in acutely ill infants. Comparing the clinical value of diagnostic genome-wide sequencing to chromosomal microarray analysis, the current evidence-based standard of care, per case of serious genetic disease diagnosed provides a practical means of assessing clinical value. Scientifically rigorous studies of this kind are needed to determine if clinical genome-wide sequencing should be established as a standard of care supported by healthcare systems and insurers for diagnosis of genetic disease in seriously ill newborn infants.

The Gen-Equip Project: evaluation and impact of genetics e-learning resources for primary care in six European languages.

PURPOSE: Genetic advances mean patients at risk of genetic conditions can be helped through testing, clinical screening, and preventive treatment, but they must first be identified to benefit. Ensuring quality of genetic care for patients requires genetic expertise in all health services, including primary care. To address an educational shortfall, a series of e-learning resources was developed in six languages to equip primary care professionals with genetic skills relevant for practice. The purpose of the study was to evaluate these resources using Kirkpatrick's framework for educational outcomes. METHODS: Mixed methods (qualitative and quantitative) were used over four phases of the study. RESULTS: A high level of satisfaction with the resources was reported. Knowledge and skills improved significantly after using the education material. Participants reported changes in confidence and practice behavior, including family history taking, seeking advice from specialists and referring patients. The resources helped users to learn how to explain genetics. Many visited the resources repeatedly and some used them to educate colleagues or students. CONCLUSION: Gen-Equip modules are effective in improving genetic knowledge, skills, and attitudes for primary care professionals. They provide both continuing professional development and just-in-time learning for a potentially large global audience at a practical level.

Correction: The Gen-Equip Project: evaluation and impact of genetics e-learning resources for primary care in six European languages.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.

Experiences of a High-Risk Population with Prenatal Hemoglobinopathy Carrier Screening in a Primary Care Setting: a Qualitative Study.

Carrier screening for hemoglobinopathies (HbPs; sickle cell disease and thalassemia) aims to facilitate autonomous reproductive decision-making. In the absence of a Dutch national HbP carrier screening program, some primary care midwives offer screening on an ad hoc basis. This qualitative descriptive study explores how pregnant women perceive an offer of HbP carrier screening by their midwife. Semi-structured interviews (n = 26) were conducted with pregnant women at risk of being a HbP carrier, and whom were offered screening at their booking appointment in one of two midwifery practices in Amsterdam. The results showed that half of the respondents were familiar with HbPs. Generally, women perceived the offer of HbP carrier screening as positive, and most women (n = 19) accepted screening. Seven declined, of whom two already knew their carrier status. Important reasons to accept screening were to obtain knowledge about their own carrier status and health of their unborn child, and the ease of the procedure. A multistep process of decision-making was observed, as many women did not give follow-up testing (e.g. partner, invasive diagnostics) much consideration while deciding on accepting or declining HbP screening. Women experienced information overload, and preferred receiving the information at a different moment (e.g. before the intake by a leaflet, or preconceptionally). In conclusion, while prenatal HbP carrier screening is perceived as positive, informed decision-making seems to be suboptimal, and both the content and timing of the information provided needs improvement.

Factors for successful implementation of population-based expanded carrier screening: learning from existing initiatives.

Background: Carrier screening for autosomal recessive disorders aims to facilitate reproductive decision-making by identifying couples with a 1-in-4 risk in every pregnancy of having an affected child. Except for a few countries or regions, carrier screening is not widely offered and is mostly ancestry-based. Technological advances enable carrier screening for multiple diseases simultaneously allowing universal screening regardless of ancestry (population-based expanded carrier screening). It is important to study how this can be successfully implemented. This study therefore aims to identify critical factors involved in successful implementation, from a user perspective, by learning from already implemented initiatives. Methods: Factors associated with successful implementation were identified by: (i) a literature review and (ii) two case studies; studying experiences with carrier screening in two high-risk communities (a Dutch founder population and the Ashkenazi Jewish population), including a survey among community members. Results: Factors identified were familiarity with (specific) genetic diseases and its availability, high perceived benefits of screening (e.g. screening avoids much suffering), acceptance of reproductive options, perceived risk of being a carrier and low perceived social barriers (e.g. stigmatization). In contrast to the Jewish community, the initial demand for screening in the Dutch founder population did not entirely come from the community itself. However, the large social cohesion of the community facilitated the implementation process. Conclusion: To ensure successful implementation of population-based expanded carrier screening, efforts should be made to increase knowledge about genetic diseases, create awareness and address personal benefits of screening in a non-directive way.

Stakeholder perspectives on the implementation of genetic carrier screening in a changing landscape.

BACKGROUND: In most countries, genetic carrier screening is neither offered, nor embedded in mainstream healthcare. Technological developments have triggered a two-fold transition in carrier screening: the expansion from screening one single disorder to many disorders simultaneously, and offering screening universally, regardless of ancestry. This study aims to identify general and population-specific barriers and needs reflected by stakeholders regarding the implementation of carrier screening in a changing landscape. METHODS: Seventeen semi-structured interviews were conducted with Dutch key stakeholders working in the practical and scientific field of carrier screening. The constellation approach was used to categorise barriers and needs into three levels: culture, structure and practice. RESULTS: Barriers on a cultural level include: undecidedness about the desirability of carrier screening, and a lack of priority of screening in mainstream healthcare. On a structural level barriers included: need for organisational structures in healthcare for embedding carrier screening, need for guidelines, financial structures, practical tools for overcoming challenges during counselling, and a need for training and education of both professionals and the public. A lack of demand for screening by the public, and a need for a division of responsibilities were barriers on a practical level. CONCLUSION: The absence of a collective sense of urgency for genetic carrier screening, a lack of organisational structures, and uncertainty or even disagreement about the responsibilities seem to be important barriers in the implementation of carrier screening. Stakeholders therefore suggest that change agents should be formally acknowledged to strategically plan broadening of current initiatives and attune different stakeholders.

Implementing non-invasive prenatal testing for aneuploidy in a national healthcare system: global challenges and national solutions.

BACKGROUND: Since the introduction of non-invasive prenatal testing (NIPT) in 2011, mainly by commercial companies, a growing demand for NIPT from the public and healthcare professionals has been putting pressure on the healthcare systems of various countries. This study identifies the challenges of establishing a responsible implementation of NIPT for aneuploidy in prenatal healthcare, by looking at the Netherlands. METHODS: A mixed methods approach involving 13 stakeholder interviews, document analysis and (participatory) observations of the Dutch NIPT Consortium meetings were used. The Diffusion of Innovation Theory and a Network of Actors model were used to interpret the findings. RESULTS: Implementation of NIPT was facilitated by several factors. The set-up of a national NIPT Consortium enabled discussion and collaboration between stakeholders. Moreover, it led to the plan to offer NIPT through a nationwide research setting (TRIDENT studies), which created a learning phase for careful implementation. The Dutch legal context was perceived as a delaying factor, but eventually gave room for the parties involved to organise themselves and their practices. CONCLUSIONS: This study shows that implementing advanced technologies with profound effects on prenatal care benefit from a learning phase that allows time to carefully evaluate the technical performance and women's experiences and to enable public debate. Such a coordinated learning phase, involving all stakeholders, will stimulate the process of responsible and sustainable implementation.

What Do Parents of Children with Down Syndrome Think about Non-Invasive Prenatal Testing (NIPT)?

This study explores the attitudes of parents of children with Down syndrome towards non-invasive prenatal testing (NIPT) and widening the scope of prenatal screening. Three focus groups (n = 16) and eleven individual interviews with Dutch parents (and two relatives) of children with Down syndrome were conducted. Safety, accuracy and earlier testing were seen as the advantages of NIPT. Some participants were critical about the practice of screening for Down syndrome, but acknowledged that NIPT enables people to know whether the fetus is affected and to prepare without risking miscarriage. Many feared uncritical use of NIPT and more abortions for Down syndrome. Concerns included the consequences for the acceptance of and facilities for children with Down syndrome, resulting in more people deciding to screen. Participants stressed the importance of good counseling and balanced, accurate information about Down syndrome. Testing for more disorders might divert the focus away from Down syndrome, but participants worried about "where to draw the line". They also feared a loss of diversity in society. Findings show that, while parents acknowledge that NIPT offers a better and safer option to know whether the fetus is affected, they also have concerns about NIPT's impact on the acceptance and care of children with Down syndrome.

Changing to NIPT as a first-tier screening test and future perspectives: opinions of health professionals.

OBJECTIVE: The aim of this study was to investigate health professionals' opinions toward offering noninvasive prenatal testing (NIPT) as first-tier screening test regardless of pregnant women's risk, and toward a potential broader range of disorders. METHODS: A questionnaire completed by obstetric health professionals (n = 240) after an in-service NIPT training in the West and North of the Netherlands. RESULTS: The majority (72%) of respondents favored replacing first-trimester combined test (FCT) by NIPT, although 43% preferred to maintain nuchal translucency measurement. Many respondents believed that replacing FCT by NIPT would only have advantages (57%), would lead to more pregnant women opting for prenatal testing (69%), and would simplify counseling (47%). Differences in attitudes toward counseling between health professionals were observed. When considering NIPT to screen for broader range of disorders, the majority (92%) thought that this should include disorders characterized by neonatal death, whereas 52% of the respondents favored testing for fetomaternal risk factors. Overall, 46% thought screening should be offered as a fixed list of disorders. CONCLUSION: Most health professionals favor NIPT instead of FCT but prefer to maintain nuchal translucency measurement. If NIPT becomes available as a first-tier screening test, attention remains necessary to ensure that pregnant women make well-informed decisions in line with the aim of prenatal screening.

Effects of a simple educational intervention in well-baby clinics on women's knowledge about and intake of folic acid supplements in the periconceptional period: a controlled trial.

OBJECTIVE: To test the hypothesis that a concise intervention to promote the preconception use of folic acid (FA) supplements among mothers who visit a well-baby clinic (WBC) for the 6-month check-up of their youngest child is effective. Effectiveness was measured as intention to use or actual use of FA supplements before a next pregnancy among women who expected to be pregnant within 0-12 months. DESIGN: Controlled intervention study with independent samples of intervention and control mothers. The intervention took place at the 6-month visit. A post-intervention measurement was done in the intervention group and a comparable measurement in the control group at the 11-month check-up visit. SETTING: The intervention, verbal and in writing, was implemented in four Dutch WBC and given by the WBC physician to the mothers who visited the WBC. SUBJECTS: All mothers visiting the WBC were eligible for inclusion, unless they were unable to complete a questionnaire. The intervention group consisted of 198 (68 %) mothers recruited from 291 6-month intervention visits and the control group of 215 (84%) mothers recruited from 255 11-month normal visits. RESULTS: In mothers who expected to be pregnant within 0-12 months, the proportion using or intending to use FA was 65% in the intervention group (n 49) v. 42% in the control group (n 43; difference 23%, 95% CI 4, 43%, P<0·05). CONCLUSIONS: Health education intervention at the 6-month WBC visit is an effective means to promote the use of FA supplements or the intention to do so.

Consanguinity and endogamy in the Netherlands: demographic and medical genetic aspects.

This paper reviews what is currently known about the presence of consanguinity and endogamy in the Netherlands, in the past and today, and concludes with a discussion of medical genetic aspects. First geographic characteristics, the demographic history, the genetic make-up of the native population, legal aspects and the public opinion are reviewed. Then data on the prevalence of consanguinity in the native population are presented for marriages since 1840, followed by data on consanguineous marriages among immigrants from countries with a tradition of close-kin marriages. It is estimated that approximately 1% of at-risk consanguineous couples are referred to clinical genetic centres for prospective genetic counselling in the Netherlands. This picture will change dramatically if and when next-generation sequencing is introduced to identify couples at ≥ 25% risk prospectively.

Effectiveness of oncogenetics training on general practitioners' consultation skills: a randomized controlled trial.

PURPOSE: General practitioners are increasingly called upon to deliver genetic services and could play a key role in translating potentially life-saving advancements in oncogenetic technologies to patient care. If general practitioners are to make an effective contribution in this area, their genetics competencies need to be upgraded. The aim of this study was to investigate whether oncogenetics training for general practitioners improves their genetic consultation skills. METHODS: In this pragmatic, blinded, randomized controlled trial, the intervention consisted of a 4-h training (December 2011 and April 2012), covering oncogenetic consultation skills (family history, familial risk assessment, and efficient referral), attitude (medical ethical issues), and clinical knowledge required in primary-care consultations. Outcomes were measured using observation checklists by unannounced standardized patients and self-reported questionnaires. RESULTS: Of 88 randomized general practitioners who initially agreed to participate, 56 completed all measurements. Key consultation skills significantly and substantially improved; regression coefficients after intervention were equivalent to 0.34 and 0.28 at 3-month follow-up, indicating a moderate effect size. Satisfaction and perceived applicability of newly learned skills were highly scored. CONCLUSION: The general practitioner-specific training proved to be a feasible, satisfactory, and clinically applicable method to improve oncogenetics consultation skills and could be used as an educational framework to inform future training activities with the ultimate aim of improving medical care.

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy.

STUDY QUESTION: How has the interface between genetics and assisted reproduction technology (ART) evolved since 2005? SUMMARY ANSWER: The interface between ART and genetics has become more entwined as we increase our understanding about the genetics of infertility and we are able to perform more comprehensive genetic testing. WHAT IS KNOWN ALREADY: In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and ART and published an extended background paper, recommendations and two Editorials. STUDY DESIGN, SIZE, DURATION: An interdisciplinary workshop was held, involving representatives of both professional societies and experts from the European Union Eurogentest2 Coordination Action Project. PARTICIPANTS/MATERIALS, SETTING, METHODS: In March 2012, a group of experts from the European Society of Human Genetics, the European Society of Human Reproduction and Embryology and the EuroGentest2 Coordination Action Project met to discuss developments at the interface between clinical genetics and ART. MAIN RESULTS AND THE ROLE OF CHANCE: As more genetic causes of reproductive failure are now recognized and an increasing number of patients undergo testing of their genome prior to conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and PGD may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from RCTs to substantiate that the technique is both effective and efficient. Whole genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. LIMITATIONS, REASONS FOR CAUTION: The legal landscape regarding assisted reproduction is evolving, but still remains very heterogeneous and often contradictory. The lack of legal harmonization and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe, and beyond. WIDER IMPLICATIONS OF THE FINDINGS: This continually evolving field requires communication between the clinical genetics and IVF teams and patients to ensure that they are fully informed and can make well-considered choices. STUDY FUNDING/COMPETING INTERESTS: Funding was received from ESHRE, ESHG and EuroGentest2 European Union Coordination Action project (FP7 - HEALTH-F4-2010-26146) to support attendance at this meeting.

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.

Factors associated with not using folic acid supplements preconceptionally.

OBJECTIVE: Neural tube defects are among the most common birth defects worldwide. Folic acid intake from one month before to three months after conception reduces the likelihood of neural tube defects by at least 50%. Since 1995, several campaigns have been organised in the Netherlands which resulted in 51% of pregnant women using folic acid supplements during the entire recommended period in the northern part of the Netherlands in 2005. Our research question was to gain insight into the current prevalence and factors associated with inadequate pregnancy-related use of folic acid supplements. DESIGN: Data from the DELIVER study were used, which is a population-based cohort study. SETTING: Twenty midwifery practices across the Netherlands in 2009 and 2010. SUBJECTS: In total 5975 pregnant women completed a questionnaire covering items on sociodemographic and lifestyle factors, including folic acid intake. RESULTS: Of our study population, 55·5% (3318/5975) used folic acid supplements before conception. Several sociodemographic and lifestyle factors were associated with no preconception use of folic acid, of which non-Western ethnicity and not having a partner had the largest effect size. CONCLUSIONS: In the Netherlands, the folic acid intake before conception is suboptimal and has not improved over recent years. Fortification of staple foods with folic acid should be reconsidered as it would provide a more effective means of ensuring an adequate intake, especially for those groups of women who are unlikely to plan their pregnancies or to receive or respond to health promotion messages.