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Multivitamin use and adverse birth outcomes in high-income countries: a systematic review and meta-analysis

American Journal of Obstetrics and Gynecology, October 2017, Volume 217, Issue 4, Pages 404.e1-404.e30

Editor’s comment: Prof. Yves Ville: An ounce of prevention is worth a pound of cure
(Editor's comment relates to the AJOG articles below)

The fall issues of AJOG are rich in preventive measures.(1,2)

Multivitamins (3 or more vitamins or minerals in tablets or capsules) in pregnancy are often regarded to be at best a more palatable way to deliver folic acid and iron in pregnancy. A systematic review and meta-analysis gives us more incentive to encourage supplementation.(2)

The risk of giving birth to a small baby for gestational age (SGA) is reduced with multivitamin use. (RR :0.77 (95% CI, 0.63-0.93, I2 1⁄4 43%). However, the risk was unchanged for preterm birth and low-birth-weight.

This also applies to 4 different congenital birth defects (NTDs, (RR, 0.59 [95% CI, 0.36–0.96]); cardiovascular defects (RR,0.83 (95% CI, 0.70–0.98, I2 = 56%) ;  urinary tract defects (RR, 0.60 (95% CI, 0.46–0.78, I2 = 0%);  and limb deficiencies (RR, 0.68 (95% CI, 0.52–0.89, I2 = 0%).

This enthusiasm should be mitigated by several potential pitfalls that make interference with causality rather difficult:

  1. Whether these vitamins are taken from the periconceptional period or later is barely known and therefore the pathway towards prevention of embryonic defects is unclear.
  2.  The fact that the 35 eligible studies and 98,926 women are not that many when addressing low-risk populations. There were very few RCTs, resulting in a low degree of clinical evidence but for the recurrence of NTDs.
  3. Also none of the studies compared the use of folic acid and iron vs the use of multivitamins, nor did they describe possible side effects associated with multivitamins.
  4. pooled unadjusted estimates, so we could not account for other covariates possibly associated with preeclampsia/eclampsia, such as maternal age and body mass index (BMI). 

The recent consecration of aspirin as the current champion against the development of severe preeclampsia had unfairly shadowed the rising interest in Metformin in pregnancy. (3)

Metformin (dimethylbiguanide hy- drochloride) has been known as herbal medicine since antiquity. Standard of care in type diabetes mellitus, metformin reaced first-line treatment status in gestational diabetes unsettled with diet in the early 8O’s. It has been shown superior to insulin in the reduction of maternal weight gain during pregnancy and in the frequency of gestational hypertension. However, metformin did not change the frequency of large-for- gestational-age (LGA) or small-for- gestational-age (SGA) fetuses.

Owing to the interconnection between gestational as well as type 2 diabetes with maternal obesity, evidence has rapidly accumulated that metformin might reduce the prevalence of preeclampsia and LGA in non-diabetic obese patients. Two RCT’s performed in the UK concurred to conclude on the lack of reduction of LGA but came up with opposite conclusions on its preventive effect on preeeclampsia and maternal weight gain. Significant methodological biases may explain the negative results including too low a definition of obesity and poor observance to too late and low a dosage of metformin. Therefore it seems appropriate to propose metformin to women with a BMI over 35, starting before 18 weeks with incremental dosage from 1 g/day, increased by 0.5 g/week to a maximum dose of 3 g/day.

Metformin reduces the rate of gestational hypertension because of its effects on endothelial function and its decrease in the production of reactive oxygen species. Current evidence suggests that metformin’s wide-ranging beneficial effects are mediated by at least 2 primary mecha- nisms: suppression of intracellular metabolic activity of mitochondria and the cellular nutrient-sensing system mediated by mTOR.  There is more to come within and outside opur field since metformin has been associated with cancer prevention, control of polycystic ovary syndrome, as well as a benefit in congestive heart failure, chronic liver disease, renal tubulointerstitial fibrosis, and nonalcoholic fatty liver disease. The authors of this elegant and captivating review has already crowned metformin the aspirin of the 21st century. (3)


  1. Benjamin Franklin
  2. Wolf HT et al. Multivitamin use and adverse birth outcomes in high-income countries: a systematic review and meta-analysis
  3. Romero R et al. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity



In high-income countries, a healthy diet is widely accessible. However, a change toward a poor-quality diet with a low nutritional value in high-income countries has led to an inadequate vitamin intake during pregnancy.


We conducted a systematic review and meta-analysis to evaluate the association between multivitamin use among women in high-income countries and the risk of adverse birth outcomes (preterm birth [primary outcome], low birthweight, small for gestational age, stillbirth, neonatal death, perinatal mortality, and congenital anomalies without further specification).


We searched electronic databases (MEDLINE, Embase, Cochrane, Scopus, and CINAHL) from inception to June 17, 2016, using synonyms of pregnancy, study/trial type, and multivitamins. Eligible studies were all studies in high-income countries investigating the association between multivitamin use (3 or more vitamins or minerals in tablets or capsules) and adverse birth outcomes. We evaluated randomized, controlled trials using the Cochrane Collaboration tool. Observational studies were evaluated using the Newcastle-Ottawa Scale. Meta-analyses were applied on raw data for outcomes with data for at least 2 studies and were conducted using RevMan (version 5.3). Outcomes were pooled using the random-effect model. The quality of evidence was assessed using the Grades of Research, Assessment, Development and Evaluation approach.


We identified 35 eligible studies including 98,926 women. None of the studies compared the use of folic acid and iron vs the use of multivitamins. The use of multivitamin did not change the risk of the primary outcome, preterm birth (relative risk, 0.84 [95% confidence interval, 0.69-1.03]). However, the risk of small for gestational age (relative risk, 0.77 [95% confidence interval, 0.63-0.93]), neural tube defects (relative risk, 0.67 [95% confidence interval, 0.52-0.87]), cardiovascular defects (relative risk, 0.83 [95% confidence interval, 0.70-0.98]), urine tract defects (relative risk, 0.60 [95% confidence interval, 0.46-0.78]), and limb deficiencies (relative risk, 0.68 [95% confidence interval, 0.52-0.89]) was decreased. Of the 35 identified studies, only 4 were randomized, controlled trials. The degree of clinical evidence according to the Grades of Research, Assessment, Development, and Evaluation system was low or very low for all outcomes except for recurrence of neural tube defects in which a moderate degree of clinical evidence was found.


Routine multivitamin use in high-income countries can be recommended but with caution because of the low quality of evidence. Randomized, controlled trials or well-performed, large prospective cohort studies are needed.

Copyright © 2017 Elsevier Inc. All rights reserved.


adverse birth outcome; congenital birth defects; meta-analysis; multivitamin; pregnancy; systematic review


The authors report no conflict of interest.