Ajcn029033 916..924

Background: Although prenatal multiple micronutrients can improve fetal growth, their benefit on postnatal health remains uncertain. Objective: We assessed the effect of the UNICEF/WHO/United Nations University multiple micronutrient supplement for pregnant and lactating women (UNIMMAP) compared with the usual iron and folic acid supplement (IFA) on survival, growth, and morbidity during infancy. Design: In a double-blind, randomized trial, we followed 1294 singleton newborns whose mothers had prenatally received either the UNIMMAP or IFA. We assessed monthly anthropometric measures and health variables up to age 12 mo. Children were assessed again at a mean age of 30 mo. Mixed-effects models accounted for repeated measurements. Results: The UNIMMAP resulted in a 27% (HR: 0.73; 95% CI: 0.60, 0.87; P = 0.002) reduction in the rate of stunting in 15,261 infant-months with a higher length-for-age z score of 0.13 (95% CI: 0.02, 0.24; P = 0.02) over the whole observation period. However, by age 30 mo, this difference was not observed. An effect of the UNIMMAP on weight-for-length (P-interaction = 0.004) and head circumference–for-age (P-interaction = 0.03) became apparent by the end of the first year of life. By the age of 30 mo, children from the UNIMMAP group had a higher weight-for-height z score of 0.20 (95% CI: 0.06, 0.34; P = 0.004). No difference in mortality or morbidity was identified in groups, except a 14% reduction in reported episodes of fever (95% CI: 1%, 28%; P = 0.04). Conclusions: Improved linear fetal growth with continuation into early life and enhanced postnatal growth were 2 mechanisms that mediated the effect of the prenatal UNIMMAP on infant nutritional status. Additional follow-up to assess long-term effects is warranted. This trial was registered at clinicaltrials.gov as NCT00642408. Am J Clin Nutr 2012;95:916–24. INTRODUCTION The deleterious effects of an LBW (weight,2500 g) on child morbidity and survival in developing countries have been well described (1). Therefore, it is expected that improved fetal growth will prevent such negative effects and result in improved growth during infancy. Because multiple micronutrient deficiencies might contribute to LBW (2), UNICEF, WHO, and United Nations University formulated the UNIMMAP, which contains one Recommended Dietary Allowance of 15 micronutrients (Table 1) (3, 4). In a remarkable coordination of international research, the evidence base on the UNIMMAP grew rapidly (5). Over the past decade, randomized controlled trials that compared the UNIMMAP with the usual IFA supplement have been carried out in Bangladesh (6), China (7), Indonesia (8, 9), Nepal (10), Pakistan (11), Burkina Faso (12), Guinea-Bissau (13), and Niger (14). Most of these trials have reported a positive effect of the UNIMMAP on birth weight (pooled estimate: +22.4 g; 95% CI: 8.3, 36.4 g; P = 0.002) and a reduction in the prevalence of LBW (pooled OR: 0.89; 95% CI: 0.81, 0.97; P = 0.01) (15). In contrast, there is extremely little information about whether such prenatal effects translate into long-term growth and health benefits. A follow-up of the Nepalese study reported that, at a mean age of 2.5 y, children of women who had taken the UNIMMAP were heavier by 204 g (95% CI: 27, 381 g; P, 0.05) and had a slightly lower systolic blood pressure than did control subjects, but rates of underweight, stunting, or wasting were not significantly different between the 2 groups (16). In Bangladesh, the prevalence of vitamin B-12 deficiency at 6 mo was lower in the UNIMMAP group (26.1%) than in the IFA group (36.5%) (17), but no difference in the motor development of infants could be observed between the 2 groups when it was evaluated at the age of 7 mo (6). The most striking postnatal effect of the UNIMMAP was observed in the largest UNIMMAP trial carried out in Indonesia, in which infants of women who consumed the UNIMMAP had an 18% reduction in early infant mortality (deaths ,90 d postpartum) compared with infants whose mothers had received an IFA supplement (35.5 deaths/1000 live 1 From the Child Health and Nutrition Unit, Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium (DR and PK); the Center Muraz, Ministry of Health, Bobo-Dioulasso, Burkina Faso (HL, M-CH, and NM); the Institute of Research in Health Sciences, Ministry of Research, Ouagadougou, Burkina Faso (HL and LO); and the Department of Food Safety and Food Quality, Ghent University, Ghent, Belgium (PK and LH). 2 Supported by Nutrition Third World and the Belgian Ministry of Development. 3 Address correspondence to D Roberfroid, Child Health and Nutrition Unit, Department of Public Health, Institute of Tropical Medicine, 155, Nationalestraat, 2000 Antwerp, Belgium. E-mail: [email protected]. 4 Abbreviations used: IFA, iron and folic acid; LBW, low birth weight; MUAC, midupper arm circumference; UNIMMAP, UNICEF/WHO/United Nations University multiple micronutrient supplement for pregnant and lactating women. Received October 18, 2011. Accepted for publication January 5, 2012. First published online February 29, 2012; doi: 10.3945/ajcn.111.029033. 916 Am J Clin Nutr 2012;95:916–24. Printed in USA. 2012 American Society for Nutrition by gest on A uust 5, 2017 ajcn.trition.org D ow nladed fom births compared with 43 deaths/1000 live births, respectively; RR: 0.82; 95% CI: 0.70, 0.95; P = 0.010) (9). In contrast, no effect on mortality in the first 2 y of life was identified in Guinea-Bissau, but this study was not powered for the assessment of such an outcome and suffered from an important proportion of loss to follow-up (18). None of these studies assessed infant growth and nutritional status longitudinally. In 2008, we published the results of an individually randomized, double-blind, controlled trial in Burkina Faso that compared the UNIMMAP to IFA (12). After adjustment for gestational age at delivery, birth weight (52 g; 95% CI: 4, 100 g; P = 0.03), birth length (3.6 mm; 95% CI: 0.8, 6.3 mm; P = 0.01), arm circumference (1.2 mm; 95% CI: 0.2, 2.3 mm; P = 0.02), and chest circumference (2.8 mm; 95% CI: 0.1, 5.6 mm; P = 0.02) were all significantly higher in the UNIMMAP group. The aim of this study was to assess whether these differences at birth persist in the postnatal period. SUBJECTS AND METHODS Subjects and measurements From March 2004 to February 2006, 1426 pregnant women in the catchment area of 2 health centers in the Houndé district, Burkina Faso, were randomly assigned to receive daily either IFA or the UNIMMAP up to delivery (12). Participants were also randomly assigned to receive either 300 mg chloroquine once per week, or intermittent, preventive treatment with sulfadoxine (1500 mg) and pyrimethamine (75mg) (once in the second and third trimesters) for malaria prevention. All participants also received albendazole (400 mg) during the second and third trimester for deworming. Twenty-five locally trained home visitors visited every mother of childbearing age monthly for early pregnancy detection. The study purpose and procedures were explained to the mothers in 1 of the 3 local languages (Bwamu, Moré, or Dioula, as appropriate). A unique randomization code generated by a computer program in permuted blocks of 4 was allocated to consenting women. The trial’s staff, health workers, and mothers remained blinded to the treatment allocation until data analysis. UNIMMAP and IFA tablets were identical in appearance (Scanpharm). The daily supplement intake was directly observed by the project home visitors, whose work was assessed every month on a random day, by using a lot quality survey (19). After delivery, mothers were invited to monthly visits at the nearest health center for assessment of infant growth and health during the first year of life. In the case of a missed appointment, a home visit was organized to encourage the mother to attend. Lost to follow-up was defined as any living infant who could not be visited 1 y of age. This event usually occurred because the mother had left the area. In such cases, data up to the last visit were used in the analysis. After the 12-mo follow-up period of the last newborn had been completed, every family was visited one more time to ascertain the vital status of subjects who had been lost to follow-up and to measure growth variables of all study children (weight, length, and MUAC). Infant length and weight were measured to the nearest 1 mm by using a SECA 207 scale (SECA) and to the nearest 10 g by using a SECA 725 scale (SECA), respectively. For infants 6 mo of age, weight was measured to the nearest 100 g by using a SECA UNISCALE (SECA). Infant occipitofrontal head circumference, thoracic circumference, and MUAC were measured to the nearest 1 mm by using a SECA Girth Measuring Tape (SECA) or a SECA 402 Baby Band (SECA). Head circumference was taken at the maximum occipito-frontal measurement. The MUAC was measured midway between the tip of the olecranon process and the acromion process. The chest was measured at the level of the nipples, midway between inspiration and expiration during quiet breathing. To ensure reliability, all anthropometric variables were measured twice, once by clinic staff and a second time by an anthropometrist hired by the project. The average of the 2 measures was used for analysis. If there was a large discrepancy between the 2 measurements (.200 g for weight or .5 mm for other measurements), the file was reviewed by a supervisor for a consistency check and ascertainment of the valid measurements, if any. All weighing scales were calibrated daily. The accuracy and precision of measurements were established monthly through a standardization session (20) with immediate feedback to the assessors. At each encounter, we also collected information on diarrhea, which was defined as 3 watery stools per 24 h, fever, and cough episodes that had occurred in the 2 wk before the visit. Recommendations about exclusive breastfeeding and, in due time, optimal complementary foods were provided to every woman. Every child was vaccinated according to the national schedule and received vitamin A at 6 mo (100,000 IU) and at 12 mo (200,000 IU). Infants who were sick and/or had lost weight since the previous visit were referred to curative services for appropriate clinical management. The study was approved by the ethics committees of the Center Muraz, Bobo-Dioulasso, Burkina Faso, and the Institute of Tropical Medicine, Antwerp, Belgium. Statistical analysis Intent-to-treat analyses included all singletons born alive who had at least one set of anthropometric measurement taken at or after delivery. TABLE 1 Composition of the UNIMMAP and IFA supplement Nutrient Form IFA amount UNIMMAP