Emily R Smith1, Anuraj H Shankar2, Lee S-F Wu3, Said Aboud4, Seth Adu-Afarwuah5, Hasmot Ali3, Rina Agustina6, Shams Arifeen7, Per Ashorn8, Zulfiqar A Bhutta9, Parul Christian3, Delanjathan Devakumar10, Kathryn G Dewey11, Henrik Friis12, Exnevia Gomo13, Piyush Gupta14, Pernille Kæstel12, Patrick Kolsteren15, Hermann Lanou16, Kenneth Maleta17, Aissa Mamadoultaibou18, Gernard Msamanga19, David Osrin10, Lars-Åke Persson20, Usha Ramakrishnan21, Juan A Rivera22, Arjumand Rizvi23, H P S Sachdev24, Willy Urassa4, Keith P West3, Noel Zagre25, Lingxia Zeng26, Zhonghai Zhu26, Wafaie W Fawzi27, Christopher R Sudfeld28. 1. Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA. 2. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Summit Institute of Development, Mataram, Indonesia. 3. The JiVitA Project, Johns Hopkins University in Bangladesh, Gaibandha, Bangladesh; Center for Human Nutrition, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 4. Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania. 5. Department of Nutrition and Food Science, University of Ghana, Legon, Accra, Ghana. 6. Summit Institute of Development, Mataram, Indonesia; Department of Nutrition, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia. 7. International Centre for Diarrhoeal Diseases Research Bangladesh (ICDDR,B), Dhaka, Bangladesh. 8. Centre for Child Health Research and Department of Paediatrics, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland. 9. Center for Global Child Health, Hospital for Sick Children, Toronto, ON, Canada; Center of Excellence in Women and Child Health, The Aga Khan University, Karachi, Pakistan. 10. UCL Institute for Global Health, London, UK. 11. Department of Nutrition and Program in International and Community Nutrition, University of California-Davis, Davis, CA, USA. 12. Department of Nutrition Exercise and Sports, University of Copenhagen, Copenhagen, Denmark. 13. College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe. 14. Department of Pediatrics, University College of Medical Sciences, Delhi, India. 15. Nutrition and Child Health Unit, Department of Public Health, Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium; Faculty of Bio-science engineering, Ghent University, Belgium. 16. Institut de Recherche en Sciences de la Santé, Ministry of Scientific Research and Innovation, Ouagadougou, Burkina Faso. 17. School of Public Health and Family Medicine, University of Malawi College of Medicine, Blantyre, Malawi. 18. Food and Agriculture Organization of the United Nations, Libreville, Gabon. 19. Department of Community Health, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania. 20. Department of Women's and Children's Health, International Maternal and Child Health, Uppsala University, Uppsala, Sweden. 21. Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, USA. 22. Instituto Nacional de Salud Publica, Cuernavaca, Mexico. 23. Center of Excellence in Women and Child Health, The Aga Khan University, Karachi, Pakistan. 24. Pediatric and Clinical Epidemiology Unit, Sitar am Bhartia Institute of Science and Research, New Delhi, India. 25. UNICEF Regional Office for West and Central Africa, Dakar, Senegal. 26. Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi Province, China. 27. Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 28. Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: csudfeld@hsph.harvard.edu.
Abstract
BACKGROUND: Micronutrient deficiencies are common among women in low-income and middle-income countries. Data from randomised trials suggest that maternal multiple micronutrient supplementation decreases the risk of low birthweight and potentially improves other infant health outcomes. However, heterogeneity across studies suggests influence from effect modifiers. We aimed to identify individual-level modifiers of the effect of multiple micronutrient supplements on stillbirth, birth outcomes, and infant mortality in low-income and middle-income countries. METHODS: This two-stage meta-analysis of individual patient included data from 17 randomised controlled trials done in 14 low-income and middle-income countries, which compared multiple micronutrient supplements containing iron-folic acid versus iron-folic acid alone in 112 953 pregnant women. We generated study-specific estimates and pooled subgroup estimates using fixed-effects models and assessed heterogeneity between subgroups with the χ2 test for heterogeneity. We did sensitivity analyses using random-effects models, stratifying by iron-folic acid dose, and exploring individual study effect. FINDINGS: Multiple micronutrient supplements containing iron-folic acid provided significantly greater reductions in neonatal mortality for female neonates compared with male neonates than did iron-folic acid supplementation alone (RR 0·85, 95% CI 0·75-0·96 vs 1·06, 0·95-1·17; p value for interaction 0·007). Multiple micronutrient supplements resulted in greater reductions in low birthweight (RR 0·81, 95% CI 0·74-0·89; p value for interaction 0·049), small-for-gestational-age births (0·92, 0·87-0·97; p=0·03), and 6-month mortality (0·71, 0·60-0·86; p=0·04) in anaemic pregnant women (haemoglobin <110g/L) as compared with non-anaemic pregnant women. Multiple micronutrient supplements also had a greater effect on preterm births among underweight pregnant women (BMI <18·5 kg/m2; RR 0·84, 95% CI 0·78-0·91; p=0·01). Initiation of multiple micronutrient supplements before 20 weeks gestation provided greater reductions in preterm birth (RR 0·89, 95% CI 0·85-0·93; p=0·03). Generally, the survival and birth outcome effects of multiple micronutrient supplementation were greater with high adherence (≥95%) to supplementation. Multiple micronutrient supplements did not significantly increase the risk of stillbirth or neonatal, 6-month, or infant mortality, neither overall or in any of the 26 examined subgroups. INTERPRETATION: Antenatal multiple micronutrient supplements improved survival for female neonates and provided greater birth-outcome benefits for infants born to undernourished and anaemic pregnant women. Early initiation in pregnancy and high adherence to multiple micronutrient supplements also provided greater overall benefits. Studies should now aim to elucidate the mechanisms accounting for differences in the effect of antenatal multiple micronutrient supplements on infant health by maternal nutrition status and sex. FUNDING: None.
BACKGROUND: Micronutrient deficiencies are common among women in low-income and middle-income countries. Data from randomised trials suggest that maternal multiple micronutrient supplementation decreases the risk of low birthweight and potentially improves other infant health outcomes. However, heterogeneity across studies suggests influence from effect modifiers. We aimed to identify individual-level modifiers of the effect of multiple micronutrient supplements on stillbirth, birth outcomes, and infant mortality in low-income and middle-income countries. METHODS: This two-stage meta-analysis of individual patient included data from 17 randomised controlled trials done in 14 low-income and middle-income countries, which compared multiple micronutrient supplements containing iron-folic acid versus iron-folic acid alone in 112 953 pregnant women. We generated study-specific estimates and pooled subgroup estimates using fixed-effects models and assessed heterogeneity between subgroups with the χ2 test for heterogeneity. We did sensitivity analyses using random-effects models, stratifying by iron-folic acid dose, and exploring individual study effect. FINDINGS: Multiple micronutrient supplements containing iron-folic acid provided significantly greater reductions in neonatal mortality for female neonates compared with male neonates than did iron-folic acid supplementation alone (RR 0·85, 95% CI 0·75-0·96 vs 1·06, 0·95-1·17; p value for interaction 0·007). Multiple micronutrient supplements resulted in greater reductions in low birthweight (RR 0·81, 95% CI 0·74-0·89; p value for interaction 0·049), small-for-gestational-age births (0·92, 0·87-0·97; p=0·03), and 6-month mortality (0·71, 0·60-0·86; p=0·04) in anaemic pregnant women (haemoglobin <110g/L) as compared with non-anaemic pregnant women. Multiple micronutrient supplements also had a greater effect on preterm births among underweight pregnant women (BMI <18·5 kg/m2; RR 0·84, 95% CI 0·78-0·91; p=0·01). Initiation of multiple micronutrient supplements before 20 weeks gestation provided greater reductions in preterm birth (RR 0·89, 95% CI 0·85-0·93; p=0·03). Generally, the survival and birth outcome effects of multiple micronutrient supplementation were greater with high adherence (≥95%) to supplementation. Multiple micronutrient supplements did not significantly increase the risk of stillbirth or neonatal, 6-month, or infant mortality, neither overall or in any of the 26 examined subgroups. INTERPRETATION: Antenatal multiple micronutrient supplements improved survival for female neonates and provided greater birth-outcome benefits for infants born to undernourished and anaemic pregnant women. Early initiation in pregnancy and high adherence to multiple micronutrient supplements also provided greater overall benefits. Studies should now aim to elucidate the mechanisms accounting for differences in the effect of antenatal multiple micronutrient supplements on infant health by maternal nutrition status and sex. FUNDING: None.
Authors: Paulo A R Neves; Marcia C Castro; Clariana V R Oliveira; Maira B Malta; Bárbara H Lourenço; Marly A Cardoso Journal: Eur J Nutr Date: 2018-12-17 Impact factor: 5.614
Authors: Lidwina Priliani; Elizabeth L Prado; Restuadi Restuadi; Diana E Waturangi; Anuraj H Shankar; Safarina G Malik Journal: J Nutr Date: 2019-08-01 Impact factor: 4.798
Authors: Mary K Quinn; Emily R Smith; Paige L Williams; Willy Urassa; Joy Shi; Gernard Msamanga; Wafaie W Fawzi; Christopher R Sudfeld Journal: J Nutr Date: 2020-02-01 Impact factor: 4.798