Preconception maternal nutrition: a multi-site randomized controlled trial

K Michael Hambidge, Nancy F Krebs, Jamie E Westcott, Ana Garces, Shivaprasad S Goudar, Balachandra S Kodkany, Omrana Pasha, Antoinette Tshefu, Carl L Bose, Lester Figueroa, Robert L Goldenberg, Richard J Derman, Jacob E Friedman, Daniel N Frank, Elizabeth M McClure, Kristen Stolka, Abhik Das, Marion Koso-Thomas, Shelly Sundberg, Preconception Trial Group, K Michael Hambidge, Nancy F Krebs, Jamie E Westcott, Ana Garces, Shivaprasad S Goudar, Balachandra S Kodkany, Omrana Pasha, Antoinette Tshefu, Carl L Bose, Lester Figueroa, Robert L Goldenberg, Richard J Derman, Jacob E Friedman, Daniel N Frank, Elizabeth M McClure, Kristen Stolka, Abhik Das, Marion Koso-Thomas, Shelly Sundberg, Preconception Trial Group

Abstract

Background: Research directed to optimizing maternal nutrition commencing prior to conception remains very limited, despite suggestive evidence of its importance in addition to ensuring an optimal nutrition environment in the periconceptional period and throughout the first trimester of pregnancy.

Methods/study design: This is an individually randomized controlled trial of the impact on birth length (primary outcome) of the time at which a maternal nutrition intervention is commenced: Arm 1: ≥ 3 mo preconception vs. Arm 2: 12-14 wk gestation vs. Arm 3: none.192 (derived from 480) randomized mothers and living offspring in each arm in each of four research sites (Guatemala, India, Pakistan, Democratic Republic of the Congo). The intervention is a daily 20 g lipid-based (118 kcal) multi-micronutient (MMN) supplement. Women randomized to receive this intervention with body mass index (BMI) <20 or whose gestational weight gain is low will receive an additional 300 kcal/d as a balanced energy-protein supplement. Researchers will visit homes biweekly to deliver intervention and monitor compliance, pregnancy status and morbidity; ensure prenatal and delivery care; and promote breast feeding. The primary outcome is birth length. Secondary outcomes include: fetal length at 12 and 34 wk; incidence of low birth weight (LBW); neonatal/infant anthropometry 0-6 mo of age; infectious disease morbidity; maternal, fetal, newborn, and infant epigenetics; maternal and infant nutritional status; maternal and infant microbiome; gut inflammatory biomarkers and bioactive and nutritive compounds in breast milk. The primary analysis will compare birth Length-for-Age Z-score (LAZ) among trial arms (independently for each site, estimated effect size: 0.35). Additional statistical analyses will examine the secondary outcomes and a pooled analysis of data from all sites.

Discussion: Positive results of this trial will support a paradigm shift in attention to nutrition of all females of child-bearing age.

Trial registration: ClinicalTrials.gov NCT01883193.

Figures

Figure 1
Figure 1
Consort diagram (subject numbers are for each independent site).
Figure 2
Figure 2
Blood collection and analyses for maternal longitudinal samples.
Figure 3
Figure 3
Organizational chart for month-to-month supervision of project.
Figure 4
Figure 4
Organization of individual research sites.

References

    1. Piwoz E, Sundberg S, Rooke J. Promoting healthy growth: what are the priorities for research and action? Adv Nutr. 2012;3(2):234–241. doi: 10.3945/an.111.001164.
    1. Victora CG, Adair L, Fall C, Hallal PC, Martorell R, Richter L, Sachdev HS. Maternal and child undernutrition: consequences for adult health and human capital. Lancet. 2008;371(9609):340–357. doi: 10.1016/S0140-6736(07)61692-4.
    1. Victora CG, de Onis M, Hallal PC, Blossner M, Shrimpton R. Worldwide timing of growth faltering: revisiting implications for interventions. Pediatrics. 2010;125(3):e473–e480. doi: 10.1542/peds.2009-1519.
    1. Bhutta ZA, Das JK, Rizvi A, Gaffey MF, Walker N, Horton S, Webb P, Lartey A, Black RE. Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? Lancet. 2013;382(9890):452–477. doi: 10.1016/S0140-6736(13)60996-4.
    1. Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull WHO. 1987;65:663–737.
    1. Bukowski R, Smith GC, Malone FD, Ball RH, Nyberg DA, Comstock CH, Hankins GD, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, D'Alton ME. Fetal growth in early pregnancy and risk of delivering low birth weight infant: prospective cohort study. BMJ. 2007;334(7598):836. doi: 10.1136/.
    1. Smith GC. First-trimester determination of complications of late pregnancy. JAMA. 2010;303(6):561–562. doi: 10.1001/jama.2010.102.
    1. Mook-Kanamori DO, Steegers EA, Eilers PH, Raat H, Hofman A, Jaddoe VW. Risk factors and outcomes associated with first-trimester fetal growth restriction. JAMA. 2010;303(6):527–534. doi: 10.1001/jama.2010.78.
    1. Neufeld LM, Haas JD, Grajeda R, Martorell R. Changes in maternal weight from the first to second trimester of pregnancy are associated with fetal growth and infant length at birth. Am J Clin Nutr. 2004;79(4):646–652.
    1. Persson LA, Arifeen S, Ekstrom EC, Rasmussen KM, Frongillo EA, Yunus M. Effects of prenatal micronutrient and early food supplementation on maternal hemoglobin, birth weight, and infant mortality among children in Bangladesh: the MINIMat randomized trial. JAMA. 2012;307(19):2050–2059.
    1. Frith AL, Naved RT, Persson LA, Rasmussen KM, Frongillo EA. Early participation in a prenatal food supplementation program ameliorates the negative association of food insecurity with quality of maternal-infant interaction. J Nutr. 2012;142(6):1095–1101. doi: 10.3945/jn.111.155358.
    1. Wu G, Imhoff-Kunsch B, Girard AW. Biological mechanisms for nutritional regulation of maternal health and fetal development. Paediatr Perinat Epidemiol. 2012;26(Suppl 1):4–26.
    1. Ramakrishnan U, Grant F, Goldenberg T, Zongrone A, Martorell R. Effect of women’s nutrition before and during early pregnancy on maternal and infant outcomes: a systematic review. Paediatr Perinat Epidemiol. 2012;26(Suppl 1):285–301.
    1. Martorell R, Zongrone A. Intergenerational influences on child growth and undernutrition. Paediatr Perinat Epidemiol. 2012;26(Suppl 1):302–314.
    1. Bogin B, Smith P, Orden AB, Varela Silva MI, Loucky J. Rapid change in height and body proportions of Maya American children. Am J Hum Biol. 2002;14(6):753–761. doi: 10.1002/ajhb.10092.
    1. McMillen IC, MacLaughlin SM, Muhlhausler BS, Gentili S, Duffield JL, Morrison JL. Developmental origins of adult health and disease: the role of periconceptional and foetal nutrition. Basic Clin Pharmacol Toxicol. 2008;102(2):82–89. doi: 10.1111/j.1742-7843.2007.00188.x.
    1. Rasmussen KM, Habicht JP. Maternal supplementation differentially affects the mother and newborn. J Nutr. 2010;140(2):402–406. doi: 10.3945/jn.109.114488.
    1. Huybregts L, Roberfroid D, Lanou H, Menten J, Meda N, Van Camp J, Kolsteren P. Prenatal food supplementation fortified with multiple micronutrients increases birth length: a randomized controlled trial in rural Burkina Faso. Am J Clin Nutr. 2009;90(6):1593–1600. doi: 10.3945/ajcn.2009.28253.
    1. Berngard SC, Berngard JB, Krebs NF, Garces A, Miller LV, Westcott J, Wright LL, Kindem M, Hambidge KM. Newborn length predicts early infant linear growth retardation and disproportionately high weight gain in a low-income population. Early Hum Dev. 2013;89(12):967–972. doi: 10.1016/j.earlhumdev.2013.09.008.
    1. McKay JA, Mathers JC. Diet induced epigenetic changes and their implications for health. Acta Physiol (Oxf) 2011;202(2):103–118. doi: 10.1111/j.1748-1716.2011.02278.x.
    1. Segars JH, Aagaard-Tillery KM. Epigenetics in reproduction. Semin Reprod Med. 2009;27(5):349–350. doi: 10.1055/s-0029-1237422.
    1. Suter M, Bocock P, Showalter L, Hu M, Shope C, McKnight R, Grove K, Lane R, Aagaard-Tillery K. Epigenomics: maternal high-fat diet exposure in utero disrupts peripheral circadian gene expression in nonhuman primates. FASEB J. 2011;25(2):714–726. doi: 10.1096/fj.10-172080.
    1. Cox J, Williams S, Grove K, Lane RH, Aagaard-Tillery KM. A maternal high-fat diet is accompanied by alterations in the fetal primate metabolome. Am J Obstet Gynecol. 2009;201(3):281. e281-289.
    1. Cooper WN, Khulan B, Owens S, Elks CE, Seidel V, Prentice AM, Belteki G, Ong KK, Affara NA, Constancia M, Dunger DB. DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: results of a pilot randomized controlled trial. FASEB J. 2012;26(5):1782–1790. doi: 10.1096/fj.11-192708.
    1. Shrimpton R. Global policy and programme guidance on maternal nutrition: what exists, the mechanisms for providing it, and how to improve them? Paediatr Perinat Epidemiol. 2012;26(Suppl 1):315–325.
    1. Goudar SS, Carlo WA, McClure EM, Pasha O, Patel A, Esamai F, Chomba E, Garces A, Althabe F, Kodkany B, Sami N, Derman RJ, Hibberd PL, Liechty EA, Krebs NF, Hambidge KM, Buekens P, Moore J, Wallace D, Jobe AH, Koso-Thomas M, Wright LL, Goldenberg RL. The maternal and newborn health registry study of the global network for women’s and children's health research. Intl J Gyn Obst. 2012;118(3):190–193. doi: 10.1016/j.ijgo.2012.04.022.
    1. Mazariegos M, Krebs NF, Kindem M, Tshefu A, Sami N, Chomba E, Wright L, Hambidge KM. PAS 2011E-PAS20113530.3. Denver, CO; 2011. Predictors of stunting in 6 month olds in 4 diverse settings in developing countries.
    1. Krebs NF, Mazariegos M, Chomba E, Sami N, Pasha O, Tshefu A, Carlo WA, Goldenberg RL, Bose CL, Wright LL, Koso-Thomas M, Goco N, Kindem M, McClure EM, Westcott J, Garces A, Lokangaka A, Manasyan A, Imenda E, Hartwell TD, Hambidge KM. Randomized controlled trial of meat compared with multimicronutrient-fortified cereal in infants and toddlers with high stunting rates in diverse settings. Am J Clin Nutr. 2012;96(4):840–847. doi: 10.3945/ajcn.112.041962.
    1. Coates J, Swindale A, Bilinisky P. Household Food Insecurity Access Scale for Measurement of Household Food Access: Indicator Guide. Washington, DC: Food and Nutrition Technical Assistance Project, Academy for Educational Development; 2007.
    1. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press; 2011.
    1. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc. Washington, DC: National Academy Press; 2001.
    1. Cheikh Ismail L, Knight HE, Bhutta Z, Chumlea WC. Anthropometric protocols for the construction of new international fetal and newborn growth standards: the INTERGROWTH-21st project. BJOG. 2013;120(Suppl 2):42–47.
    1. Saker M, Soulimane Mokhtari N, Merzouk SA, Merzouk H, Belarbi B, Narce M. Oxidant and antioxidant status in mothers and their newborns according to birthweight. Eur J Obstet Gynecol Reprod Biol. 2008;141(2):95–99. doi: 10.1016/j.ejogrb.2008.07.013.
    1. Sifakis S, Akolekar R, Kappou D, Mantas N, Nicolaides KH. Maternal serum placental growth hormone at 11-13 weeks' gestation in pregnancies delivering small for gestational age neonates. J Matern Fetal Neona. 2012;25(9):1796–1799. doi: 10.3109/14767058.2012.663834.
    1. Kyriakakou M, Malamitsi-Puchner A, Militsi H, Boutsikou T, Margeli A, Hassiakos D, Kanaka-Gantenbein C, Papassotiriou I, Mastorakos G. Leptin and adiponectin concentrations in intrauterine growth restricted and appropriate for gestational age fetuses, neonates, and their mothers. Eur J Endocrinol. 2008;158(3):343–348. doi: 10.1530/EJE-07-0692.
    1. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474(7351):327–336. doi: 10.1038/nature10213.
    1. Young BE, Johnson SL, Krebs NF. Biological determinants linking infant weight gain and child obesity: current knowledge and future directions. Adv Nutr. 2012;3(5):675–686. doi: 10.3945/an.112.002238.
    1. Wendt A, Gibbs CM, Peters S, Hogue CJ. Impact of increasing inter-pregnancy interval on maternal and infant health. Paediatr Perinat Epidemiol. 2012;26(Suppl 1):239–258.

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