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Am Fam Physician. 2015;92(3):222-223

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Clinical Question

What is the effect of multimicronutrient supplementation on birth outcomes in pregnant women?

Evidence-Based Answer

A multimicronutrient supplement is an oral tablet containing the recommended daily allowance of several vitamins and minerals: vitamin A, vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folic acid, vitamin C, vitamin D, vitamin E, iron, copper, selenium, and zinc. The use of multimicronutrient supplements in pregnant women reduces rates of low birth weight (by 11% to 14%) and small-for-gestational-age infants (by 9% to 17%). However, the World Health Organization does not recommend multimicronutrient supplementation because of the potential for increased neonatal mortality in some situations. (Strength of Recommendation: C, based on expert opinion and heterogeneous subgroup analyses.)

Evidence Summary

Five meta-analyses have evaluated the effects of multimicronutrient supplementation during pregnancy (eTable A).

Outcomes
YearNumber of RCTs included (patients)Control interventionLow birth weight (95% CI)Small for gestational age (95% CI)Comments
2009A1 13 (61,705)Placebo, or iron and folateRR = 0.81 (0.73 to 0.91) vs. placeboNo difference
RR = 0.83 (0.74 to 0.93) vs. iron and folate
2009A2 12 (27,676)Iron and folateRR = 0.89 (0.83 to 0.97)*RR = 0.91 (0.84 to 0.99)*Increased rates of small-for-gestational-age births
2011A3 14 (67,213)Iron and folateNRRR = 0.91 (0.86 to 0.96)Increased neonatal mortality in areas with more than 60% home births
2012A4 21 (75,785)Iron and folateRR = 0.89 (0.83 to 0.94)RR = 0.87 (0.81 to 0.95)Decreased neonatal mortality if started after 20 weeks' gestation
2012A5 16 (61,972)Less than three micronutrients (usually iron and folate)RR = 0.86 (0.81 to 0.91)RR = 0.83 (0.73 to 0.95)Increased neonatal mortality if started after first trimester

A Cochrane meta-analysis included 21 randomized controlled trials with nearly 76,000 pregnant women from developed and developing countries who were randomized to receive multimicronutrient supplements vs. iron/folate supplements. Multimicronutrient supplementation significantly decreased the number of low-birth-weight and small-for-gestational-age infants (by 11% and 13%, respectively).1 There were no significant effects on rates of preterm birth, miscarriage, maternal mortality, perinatal mortality, stillbirth, or overall neonatal mortality (relative risk [RR] = 1.01; 95% confidence interval [CI], 0.89 to 1.2).

A large international meta-analysis found a significant reduction in the incidence of low-birth-weight and small-for-gestational-age infants whose mothers received multi-micronutrient supplements (14% and 17%, respectively).2 Another large international meta-analysis found reductions in the incidence of low-birth-weight infants, but not in small-for-gestational-age infants.3 In both studies, overall neonatal mortality was unchanged. Two additional meta-analyses using studies from less-developed countries found reductions in small-for-gestational-age infants (9% in each), and one study evaluating low birth weight found a similar reduction (11%).4,5

One meta-analysis found no difference in the incidence of large-for-gestational-age infants in women who received multimicronutrient supplements (12 trials, N = 27,676; odds ratio = 1.1; 95% CI, 1.0 to 1.3).5 Overall mortality was not changed, but subgroup analyses in three of these studies suggested that supplementation may affect neonatal mortality in some situations.1,2,4 The Cochrane review found a decrease in neonatal mortality when supplementation was started after 20 weeks' gestation (three trials, N = 41,347; RR = 0.88; 95% CI, 0.8 to 0.97); however, the authors noted significant heterogeneity across the studies.1 Another meta-analysis found an increased risk of neonatal death when supplementation began after the first trimester (five trials, N = 7,835; RR = 1.4; 95% CI, 1.1 to 1.8)2; however, this meta-analysis excluded data from a large trial (n = 31,209) that was included in the Cochrane subanalysis. A third meta-analysis found an increased risk of neonatal mortality in studies in which more than 60% of births occurred at home (four trials, N = 11,583; RR = 1.5; 95% CI, 1.1 to 1.9).4

A separate meta-analysis evaluated the micronutrient intakes of pregnant women in developed countries and compared them with relevant national nutritional recommendations.6 Sixty-two studies were included, with nearly 109,000 pregnant women. Pregnant women in the United States consumed the most micronutrients at levels above national recommendations (vitamin A, vitamin B1, vitamin B2, niacin, vitamin B12, vitamin C, calcium, magnesium, and zinc), although intake of folate, iron, and vitamin D was below national recommendations.

Recommendations from Others

The World Health Organization recommends iron and folate supplementation in pregnant women.7 It acknowledges that multimicronutrient supplementation reduces the risk of low birth weight, but does not recommend it for general use because of neonatal mortality data. The Centers for Disease Control and Prevention recommends multivitamin supplementation in pregnant women who do not consume an adequate diet.8 In addition, it recommends that all women of reproductive age consume 0.4 mg of folic acid per day via fortified foods or supplements.

Copyright Family Physicians Inquiries Network. Used with permission.

Clinical Inquiries provides answers to questions submitted by practicing family physicians to the Family Physicians Inquiries Network (FPIN). Members of the network select questions based on their relevance to family medicine. Answers are drawn from an approved set of evidence-based resources and undergo peer review. The strength of recommendations and the level of evidence for individual studies are rated using criteria developed by the Evidence-Based Medicine Working Group (https://www.cebm.net).

The complete database of evidence-based questions and answers is copyrighted by FPIN. If interested in submitting questions or writing answers for this series, go to https://www.fpin.org or email: questions@ fpin.org.

This series is coordinated by John E. Delzell Jr., MD, MSPH, associate medical editor.

A collection of FPIN’s Clinical Inquiries published in AFP is available at https://www.aafp.org/afp/fpin.

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