Research Article: Folic Acid Supplementation and Spontaneous Preterm Birth: Adding Grist to the Mill?

Date Published: May 12, 2009

Publisher: Public Library of Science

Author(s): Leonie Callaway, Paul B. Colditz, Nicholas M. Fisk

Abstract: Nicholas Fisk and colleagues discuss a new study reporting that additional voluntary folic acid supplementation was associated with a major reduction in very preterm births.

Partial Text: Preterm birth is increasing, and complicates 12% of deliveries in the United States. It is the dominant cause of neonatal mortality. Preterm birth also accounts for one in three children with vision impairment, one in five with mental retardation, and almost half with cerebral palsy [1]. Babies born weighing under 2,500 g are at heightened risk in adulthood of diabetes and cardiovascular disease [1]. These short- and long-term sequelae make the prevention of preterm birth a public health priority.

Although some preterm births are indicated for maternal or fetal complications, most are spontaneous. Yet there is no licensed tocolytic agent available in the US to treat early-onset contractions, no treatment for threatened preterm labor that improves neonatal outcome, and no new class of drug under development [2]. In the face of such therapeutic nihilism, attention has turned instead to prophylaxis. There is encouraging evidence that prophylactic progesterone in women at increased risk (shortened cervix, previous history) reduces the incidence of very preterm birth [3],[4]. Enthusiasm for this approach has been dampened by two setbacks. First, progesterone does not work in all pregnancies at risk of preterm labor (specifically twins). Second, 17-hydroxyprogesterone caproate recently failed to win approval from the US Food and Drug Administration due to safety concerns about fetal death rates in monkeys and humans [5],[6].

Poor periconceptional nutrition is implicated in idiopathic preterm labor in both animal models and human studies. As with the progesterone story, there is renewed interest in decades-old suggestions that folic acid may reduce preterm birth [7]–[9]. Because of poor compliance with recommendations to take periconceptional folate supplements to prevent neural tube defects (NTDs), more than 50 countries have already introduced mandatory wheat flour fortification [10]–[12]. In California, this was associated with a modest reduction in low birthweight and preterm birth [13].

These tantalizing findings add further impetus to the study of preconceptional factors and interventions that impact on duration of pregnancy. The ultimate evidence as to whether folic acid prevents spontaneous preterm birth will require a randomized controlled trial, but conducting such a trial may prove challenging on several fronts. First, there are robust reasons to encourage all women to take folic acid. Second, one third of the world already has mandatory folic acid fortification [11]. Third are the ethical difficulties with a control group, although these might be surmounted in geographical areas where prepregnancy supplementation is not yet supported. One practical way forward would be a randomized controlled trial of ongoing folic acid supplementation in mothers with a previous very preterm birth, ideally with high-dose and low-dose arms compared to standard care to dissect out dose versus duration effects.

There is increasing evidence that recommended supplementation levels are inadequate to optimize pregnancy outcome. Studies from North and South America show that low-level fortification of flour prevents at most only 40% of NTDs, because such fortification provides only a quarter of the recommended daily intake [16],[17]. Bukowski and colleagues’ study confirms that fewer than 20% of women follow recommendations for additional folate, while in settings without mandatory fortification of flour, such as most of Europe, as few as 5% of women take the recommended 400 µg dose in the three months prior to conception [10]. Higher daily doses result in higher folate levels, and there is a continuous dose–response relationship between early pregnancy folate levels and NTD prevention [18]. Compelling arguments have been made to increase mandatory flour fortification levels 2–4 fold and pre-pregnancy folic acid tablets to 4–5 mg per day, aiming to prevent around 85% of NTDs [17]. There is little downside, now that earlier concerns about folic acid unmasking vitamin B12 deficiency appear resolved, and the evidence on whether folate supplementation increases twinning remains inconclusive [19],[20].



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