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Original Investigation
September 2018

Association of Antenatal Micronutrient Supplementation With Adolescent Intellectual Development in Rural Western China: 14-Year Follow-up From a Randomized Clinical Trial

Author Affiliations
  • 1Department of Epidemiology and Biostatistics, School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
  • 2Department of Nutrition and Food Safety Research, School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
  • 3United Nations Children’s Fund, China Office, Beijing, China
  • 4Nutrition and Food Safety Engineering Research Center of Shaanxi Province, Xi’an, Shaanxi, China
  • 5Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, London, United Kingdom
  • 6Department of Clinic Science, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
  • 7Department of International Public Health, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
  • 8The Sydney School of Public Health, Faculty of Medicine, The University of Sydney, New South Wales, Australia
JAMA Pediatr. 2018;172(9):832-841. doi:10.1001/jamapediatrics.2018.1401
Key Points

Question  What is the long-term association of micronutrient supplementation during pregnancy with adolescent offspring intellectual development?

Findings  In this follow-up study of 2118 adolescent offspring of mothers who received supplementation in a randomized clinical trial in rural China, micronutrient supplementation during pregnancy was associated with a significant increase in intellectual development for teenaged children compared with folic acid or folic acid plus iron supplements.

Meaning  These findings suggest that multiple micronutrients need to be considered in the current guidelines revision of antenatal supplementation.


Importance  The association of micronutrient supplementation during pregnancy with the intellectual development of adolescent offspring is unknown.

Objective  To assess the long-term association of antenatal micronutrient supplementation with adolescent intellectual development.

Design, Setting, and Participants  This 14-year follow-up study of a randomized clinical trial of micronutrient supplementation in pregnancy was conducted in 2 counties in rural western China in 2118 adolescent offspring (aged 10 to 14 years) of mothers who were randomized to take a daily capsule of either folic acid, folic acid plus iron, or multiple micronutrients from August 1, 2002, through February 28, 2006. Follow-up was conducted from June 1, 2016, through December 31, 2016. Data analyses took place from April 1, 2017, to June 20, 2017.

Main Outcomes and Measures  Adolescent full-scale intelligence quotient and aspects of verbal comprehension, working memory, perceptual reasoning, and processing speed indexes were assessed by the Wechsler Intelligence Scale for Children.

Results  Of 2118 adolescent offspring, 1252 (59.1%) were boys and 866 (40.9%) were girls, with a mean (SD) age of 11.7 (0.87) years, representing 47.2% of the 4488 single live births that were eligible to participate. Compared with folic acid supplementation, multiple micronutrient supplementation was associated with a 1.13-point higher full-scale intelligence quotient (95% CI, 0.15-2.10) and a 2.03-point higher verbal comprehension index (95% CI, 0.61-3.45); similar results were found in comparison with folic acid plus iron. When mothers initiated supplementation early (<12 weeks of gestation) and had an adequate dose (≥180 capsules), multiple micronutrient capsules were associated with a 2.16-point higher full-scale intelligence quotient (95% CI, 0.41-3.90) and 4.29-point higher verbal comprehension index (95% CI, 1.33-7.24) compared with folic acid capsules. The mean test scores were lower in the substratum of supplementation initiated late (≥12 weeks of gestation) and with an inadequate dose (<180 capsules). The multiple micronutrient group had higher scores than the other 2 treatment groups, and significant differences were observed for full-scale intelligence quotient (adjusted mean difference, 2.46; 95% CI, 0.98-3.94) when compared with the folic acid plus iron group.

Conclusions and Relevance  Compared with folic acid plus iron or folic acid capsules supplementation, antenatal multiple micronutrient supplementation appeared to be associated with increased adolescent intellectual development; initiating supplementation in the first trimester and then continuing for at least 180 days were associated with the greatest rewards.

Trial Registration  isrctn.org Identifier: ISRCTN08850194