Review ArticleFolic acid supplementation during the preconception period: A systematic review and meta-analysis
Introduction
Neural tube defects (NTDs) result from failure of the neural tube to close at approximately 3–4 weeks gestation, and can result in infant mortality or long-term disability (Greene and Copp, 2014; Flores et al., 2015). Most NTDs are preventable by sufficient intake of folate or its synthetic form, folic acid (Greene and Copp, 2014; Czeizel et al., 2013). Although the exact mechanisms are unclear, folate may play an important role in neural tube closure by regulating processes such as nucleotide biosynthesis and methylation reactions (Greene and Copp, 2014). Evidence from observational studies indicated lower rates of NTDs in offspring of women who supplemented with folic acid before pregnancy (Mulinsky et al., 1989; Mulinare et al., 1988). Subsequently, randomized controlled trials (RCTs) indicated meaningful reductions in NTDs following folic acid supplementation (Wald and Sneddon, 1991; Czeizel and Dudas, 1992). For example, a 72% protective effect of folic acid was reported by a seven-country study (Wald and Sneddon, 1991). Based on this evidence, the United States (US) government has recommended since 1992 that all women of childbearing age should supplement with 0.4 mg of folic acid daily (MMWR., 1992; Crider et al., 2011). The World Health Organization (WHO) similarly recommends that all women attempting to become pregnant supplement with 0.4 mg of folic acid daily (World Health Organization, 2017). Supplementation is recommended before conception, rather than after confirmation of pregnancy, because neural tube closure may occur before many women are aware of their pregnancy (Greene and Copp, 2014; Government of Canada, 2016).
Many countries (e.g., Canada, the US) have mandated fortification of grain products with folic acid (Centers for Disease Control and Prevention, 2010), resulting in increased levels of serum folate and decreased incidence of NTDs (Crider et al., 2011; Canfield et al., 2005). However, large scale studies of reproductive aged women suggest that folic acid supplementation remains necessary even in countries with mandatory grain fortification (e.g., 22% in Canada have sub-optimal blood serum folate concentrations for NTD prevention (Colapinto et al., 2011) and 22% in the US do not meet folate requirements from diet alone (Bailey et al., 2010)). Ultimately, mandatory fortification has not changed the recommendation for folic acid supplementation before pregnancy (Crider et al., 2011; World Health Organization, 2017).
Despite recommendations, there is considerable room for improvement in uptake of folic acid supplements. Among studies from countries with ‘very high human development’ (designated by the United Nations' human development index (United Nations Development Programme, 2015)), the prevalence of any preconception folic acid supplementation varies considerably and can be <10% (Toivonen et al., 2017). Even in a population-based study of 35,351 US women planning a pregnancy within the next year, only 54.3% reported taking folic acid supplements daily (Chuang et al., 2011).
To better understand how preconception folic acid supplementation rates compare to recommendations, there is a need to synthesize estimates of supplementation and examine potential factors associated with use. Ray et al. (2004) systematically reviewed preconceptional/periconceptional folic acid use worldwide but did not provide estimates by country or region. They observed a slight increase in use over time; reported greater likelihood of use among women with higher education, older age, non-immigrant status, partners, and planned pregnancies; but characterized overall use as generally suboptimal. Peake et al. (2013) published a systematic review and meta-analysis of periconceptional folic acid use among women of different ethnicities within the United Kingdom (UK), concluding that supplementation was nearly three times as prevalent among Caucasians relative to non-Caucasians. However, their meta-analytic estimates were based on only three studies for which adequate data were available (Peake et al., 2013). A scoping review by Toivonen et al. (2017) examined several preconception health behaviours, including folic acid use, however they only included countries with “very high human development” and did not synthesize prevalence estimates through meta-analysis. The present systematic review and meta-analysis provides an update to the review conducted by Ray et al. (2004), and is the first known study to provide national prevalence estimates of any preconception folic acid use where available. Potential sources of heterogeneity such as sample characteristics, methodology, and country fortification policy were examined. Additionally, the impact of study quality indicators on supplementation rates was investigated because low methodological quality can impact internal validity and bias the results (Stroup et al., 2000).
Because significant heterogeneity in supplementation estimates was expected among different countries, a single global prevalence estimate would not be meaningful. Therefore, the primary aim of this review was to estimate preconception folic acid supplementation prevalence by country. Secondary aims included: (1) examining supplementation prevalence by country grain fortification policies; (2) determining whether supplementation prevalence differed before and after implementation of mandatory grain fortification, among countries with mandatory fortification; and (3) examining supplementation prevalence by participant characteristics (e.g., maternal age), methodological factors (e.g., self-reports vs interviews), and study quality factors (e.g., whether inclusion/exclusion criteria were explicitly reported). This review defines the preconception period as any time before conception (among studies of women who retrospectively reported while pregnant or after a live birth), or the current time period (among women planning pregnancy within six months). Given the scarcity of data on objectively measured serum folate levels, and the inaccuracy of folate levels estimated from self-reported diet, the outcome of interest was use of folic acid supplementation as opposed to serum folate or estimated folate intake from food.
Section snippets
Methods
The present systematic review was performed according to a predetermined protocol (PROSPERO registration ID: CRD42016052774) and in accordance with MOOSE (Meta-Analyses of Observational Studies in Epidemiology) reporting guidelines (Stroup et al., 2000).
Study identification
Progress through stages of screening is summarized in a flow diagram (Fig. 1). The initial search yielded 3372 citations and 722 were included in full-text review. In total, 105 articles describing 106 prevalence estimates among different countries were included in the present review and meta-analysis (one article described prevalence estimates in two countries, thus they were treated as two separate estimates). See Appendix B for references of included studies. Of the 34 countries represented,
Discussion
The lowest pooled estimates (0%) were observed in Uganda and Nigeria (represented by one and two studies, respectively). The Ugandan government has published guidelines on maternal nutrition that recommend preconception folic acid intake (Ministry of Health, 2010), and women typically receive folic acid upon their first antenatal visit in both countries (Lawal and Adeleye, 2014; Bannink et al., 2015), though the first antenatal visit is often after the end of the first trimester (Lawal and
Conclusion
The present systematic review reported variable pooled prevalence estimates for preconception folic acid supplementation among different countries worldwide for which data were available. Estimates were highest among countries within North America (32–51%) and Europe (9–78%), and lowest in parts of Africa (0%). In light of scarce or non-existent data available in many regions and entire continents, there is a need for more widespread monitoring of preconception folic acid supplementation.
Acknowledgements
K. Toivonen is supported by a Canadian Institutes of Health Research Doctoral Award.
Conflicts of interest
The authors have no conflicts of interest to disclose.
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2022, The Lancet Global HealthCitation Excerpt :Health-care providers can generally only prescribe prenatal vitamin supplements when the pregnancy is discovered, typically after the fourth completed week of gestation, at which point it is too late to prevent spina bifida and anencephaly. Supplement programmes also require sustained external funding and continuous educational campaigns; they typically depend on individual behaviours and have low adherence rates.6 The solution is to provide adequate folic acid to women of reproductive age in a way that is timely, effective, equitable, and economical; large-scale food fortification meets all these criteria.7