Effectiveness of folic acid supplementation in pregnancy on reducing the risk of small‐for‐gestational age neonates: a population study, systematic review and meta‐analysis

<jats:sec><jats:title>Objectives</jats:title><jats:p>To assess the effect of timing of folic acid (<jats:styled-content style="fixed-case">FA</jats:styled-content>) supplementation during pregnancy on the risk of the neonate being small for gestational age (<jats:styled-content style="fixed-case">SGA</jats:styled-content>).</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>A population database study and a systematic review with meta‐analysis including the results of this population study.</jats:p></jats:sec><jats:sec><jats:title>Setting and data sources</jats:title><jats:p>A <jats:styled-content style="fixed-case">UK</jats:styled-content> regional database was used for the population study and an electronic literature search (from inception until August 2013) for the systematic review.</jats:p></jats:sec><jats:sec><jats:title>Participants and included studies</jats:title><jats:p>Singleton live births with no known congenital anomalies; 111 736 in population study and 188 796 in systematic review.</jats:p></jats:sec><jats:sec><jats:title>Outcome measures, data extraction and analysis</jats:title><jats:p>The main outcome was SGA based on customised birthweight centile. Associations are presented as odds ratios (OR) and adjusted odds ratios (<jats:styled-content style="fixed-case">aOR</jats:styled-content>), adjusted for maternal and pregnancy‐related characteristics.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Of 108 525 pregnancies with information about FA supplementation, 92 133 (84.9%) had taken FA during pregnancy. Time of commencement of supplementation was recorded in 39 416 pregnancies, of which FA was commenced before conception in 10 036, (25.5%) cases. Preconception commencement of FA supplementation was associated with reduced risk of SGA <10th centile (<jats:styled-content style="fixed-case">aOR</jats:styled-content> 0.80, 95% CI 0.71–0.90, <jats:italic>P</jats:italic> < 0.01) and SGA <5th centile (<jats:styled-content style="fixed-case">aOR</jats:styled-content> 0.78, 95% CI 0.66–0.91, <jats:italic>P </jats:italic>< 0.01). This result was reproduced when the data were pooled with other studies in the systematic review, showing a significant reduction in SGA (<5th centile) births with preconception commencement of FA (<jats:styled-content style="fixed-case">aOR</jats:styled-content> 0.75, 95% CI 0.61–0.92, <jats:italic>P </jats:italic>< 0.006). In contrast, postconception folate had no significant effect on SGA rates.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Supplementation with <jats:styled-content style="fixed-case">FA</jats:styled-content> significantly reduces the risk of <jats:styled-content style="fixed-case">SGA</jats:styled-content> at birth but only if commenced preconceptually independent of other risk factors.</jats:p></jats:sec><jats:sec><jats:title>Systematic review registration</jats:title><jats:p>This systematic review was prospectively registered with <jats:styled-content style="fixed-case">PROSPERO</jats:styled-content> number <jats:styled-content style="fixed-case">CRD</jats:styled-content>42013004895.</jats:p></jats:sec>