Hermann Lanou

Prenatal food supplementation fortified with multiple micronutrients increases birth length: a randomized controlled trial in rural Burkina Faso

BACKGROUND Prenatal multiple micronutrient (MMN) or balanced energy and protein supplementation has a limited effect on birth size of the offspring. OBJECTIVE The objective was to determine whether a prenatal MMN-fortified food supplement (FFS) improves anthropometric measures at birth compared with supplementation with an MMN pill alone. DESIGN We conducted a nonblinded, individually randomized controlled trial in 1296 pregnant women in 2 villages in rural Burkina Faso. Supplements were provided on a daily basis, and compliance was closely verified by using a community-based network of home visitors. RESULTS Anthropometric measures at birth were available for analysis for 87% of the 1175 live singleton deliveries enrolled. After adjustment for gestational age at birth, the FFS group had a significantly higher birth length (+4.6 mm; P = 0.001). FFS supplementation resulted in a modestly higher birth weight (+31 g; P = 0.197). Subgroup analyses showed clinically important treatment effects on birth length (+12.0 mm; P = 0.005) and on birth weight (+111 g; P = 0.133) for underweight [body mass index (in kg/m(2)) <18.5] pregnant women. Women with early pregnancy anemia who received FFS gave birth to longer newborns (+7.3 mm; P = 0.002) than did those who received MMN supplementation. CONCLUSIONS The provision of FFS to pregnant women resulted in higher birth length than did MMN supplementation. For women with a suboptimal prepregnancy nutritional status, MMN supplementation should be complemented with a balanced energy and protein supplement to produce a clinical effect on birth size. The trial was registered at clinicaltrials.gov as NCT00909974.

Impact of prenatal multiple micronutrients on survival and growth during infancy: a randomized controlled trial

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.

Randomized controlled trial of 2 prenatal iron supplements: is there a dose-response relation with maternal hemoglobin?

BACKGROUND The most appropriate dose of iron to prevent maternal anemia is still unclear. OBJECTIVE We assessed the dose-response relation between maternal hemoglobin and 2 prenatal iron supplements. DESIGN An intention-to-treat, double-blind, randomized controlled trial compared 30 mg Fe + folic acid and 13 other micronutrients (UNIMMAP; UNICEF/WHO/UNU multiple micronutrient supplement for pregnant and lactating women) with 60 mg Fe + folic acid (IFA) only in rural Burkina Faso. Home visitors directly observed tablet intake. Mixed-effects models were used for the data analysis. RESULTS At inclusion, 43.2% of the 1268 participants were anemic. On average, the hemoglobin concentration decreased over gestation by 0.019 g/dL (95% CI: 0.012, 0.025 g/dL) per week in the IFA and UNIMMAP groups. An increment in hemoglobin concentration per micronutrient tablet [β (±SE) = 0.006 ± 0.001 g/dL; P < 0001] was observed only in women who were anemic at inclusion, whereas a decrease was observed in the other mothers (-0.003 ± 0.001 g/dL; P = 0.002, P for interaction < 0.0001); the finding was similar in both the IFA and UNIMMAP groups. Women with baseline anemia achieved the same hemoglobin concentration (mean ± SD: 11.1 ± 0.64 g/dL) as their counterparts who received ±180 tablets of either UNIMMAP or IFA. Despite this, micronutrient intake did not significantly prevent anemia (51.0% in the third trimester). It was, however, a risk factor for hemoconcentration (odds ratio per tertile of tablet intake: 2.10; 95% CI: 1.12, 3.94), independently of supplement type or initial hemoglobin concentration. CONCLUSIONS UNIMMAP triggered the same hemoglobin dose response with half the amount of iron as provided by IFA treatment. The benefit of iron supplements in nonanemic women is unclear. Despite micronutrient supplementation, anemia remained highly prevalent during gestation, partly because of physiologic hemodilution. This trial was registered at clinicaltrials.gov as NCT00642408.

Prenatal Micronutrient Supplements Cumulatively Increase Fetal Growth

Prenatal multiple micronutrients (UNIMMAP) improve fetal growth only moderately compared to iron and folic acid alone (IFA). Whether this is due to insufficient amounts of UNIMMAP or to IFA being in reality an active control is unknown. We assessed the association between cumulative micronutrient intake (CMI) and fetal growth by secondary analysis of a randomized controlled trial in Burkina Faso where tablet intake was directly observed. We applied 2-part residual regression models adjusted for main confounders. Among the 1056 single pregnancies included, the mean CMI (± SD) was 124 ± 54 tablets. The odds of delivering a small-for-gestational-age baby was reduced by 21% [(95%CI: 5, 35); P = 0.013] for each additional tertile of CMI. The association between CMI and birth weight was positively modified by gestational age at enrollment (P-interaction = 0.001). Each unit of CMI was associated with a 1.6-g [(95%CI: 0.3, 3.1); P = 0.019] higher birth weight at a mean-centered gestational age at enrollment, with a higher gradient observed later in pregnancy. Maternal BMI at enrollment was also a positive modifying factor (P-interaction = 0.02), with no association of CMI with birth weight for low BMI. There was no evidence of an effect modification by group allocation; i.e., we observed the same change in birth weight per unit of CMI with either IFA or UNIMMAP. Yet UNIMMAP increased birth weight by 69 g [(95%CI: 58, 81); P < 0.001] relative to IFA. We found similar results for thoracic and cephalic circumferences. In conclusion, for both IFA and UNIMMAP, the effect on fetal growth is cumulative. The supplementation should therefore begin as early as possible in pregnancy, even if the growth increment per CMI is higher in late than in early pregnancy. Women with a low BMI should also receive extra energy.

Effect of maternal multiple micronutrient supplements on cord blood hormones: a randomized controlled trial

BACKGROUND Fetal growth improves in pregnant women who take daily maternal multiple micronutrients [United Nations International Multiple Micronutrient Preparation (UNIMMAP)] rather than iron and folic acid (IFA) alone. OBJECTIVE Our objective was to test whether such an effect was mediated by changes in concentrations of cord hormones. DESIGN In a double-blind, controlled trial carried out in Burkina Faso, we randomly assigned 1426 pregnant women to receive UNIMMAP or IFA supplements. We measured concentrations of insulin-like growth factor I (IGF-I), leptin, insulin, free thyroxine, and cortisol in cord serum in a subsample of 294 live single newborns. We performed mediation analysis with an Aroian test. RESULTS UNIMMAP supplementation had no significant effect on cord hormone concentrations. However, UNIMMAP supplementation significantly affected concentrations of IGF-I (+30%; 95% CI: 8%, 52%; P = 0.009) and leptin in male newborns. In these infants, 51.1% (P = 0.08) of the effect of UNIMMAP supplementation on birth weight was mediated through IGF-I, whereas for female newborns, this proportion was negligible. UNIMMAP supplementation also increased cortisol concentrations by 36% (P = 0.009) in cord blood in primiparae (P for interaction = 0.02). Growth-retarded infants had 41.2% lower IGF-I (P < 0.0001) and 27.3% lower leptin (P = 0.04) than did infants with normal growth. Offspring of primiparae had reduced IGF-I and insulin concentrations, and their cortisol concentrations were 25% higher (P = 0.05). Male newborns had lower concentrations of IGF-I, leptin, and insulin than did female newborns. CONCLUSIONS UNIMMAP supplementation had sex-specific effects on cord IGF-I and leptin concentrations that were of unclear clinical significance. Other pathways may have been involved in the action of UNIMMAP on fetal growth. The specific hormonal pattern in primiparae could be related to constrained fetal growth. Confirmatory studies are warranted. This trial was registered at clinicaltrials.gov as NCT00642408.

Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality: a meta-analysis of individual patient data from 17 randomised trials in low-income and middle-income countries

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.

Prenatal Lipid-Based Nutrient Supplements Increase Cord Leptin Concentration in Pregnant Women from Rural Burkina Faso

In developing countries, prenatal lipid-based nutrient supplements (LNSs) were shown to increase birth size; however, the mechanism of this effect remains unknown. Cord blood hormone concentrations are strongly associated with birth size. Therefore, we hypothesize that LNSs increase birth size through a change in the endocrine regulation of fetal development. We compared the effect of daily prenatal LNSs with multiple micronutrient tablets on cord blood hormone concentrations using a randomized, controlled design including 197 pregnant women from rural Burkina Faso. Insulin-like growth factors (IGF) I and II, their binding proteins IGFBP-1 and IGFBP-3, leptin, cortisol, and insulin were quantified in cord sera using immunoassays. LNS was associated with higher cord blood leptin mainly in primigravidae (+57%; P = 0.02) and women from the highest tertile of BMI at study inclusion (+41%; P = 0.02). We did not find any significant LNS effects on other measured cord hormones. The observed increase in cord leptin was associated with a significantly higher birth weight. Cord sera from small-for-gestational age newborns had lower median IGF-I (-9 μg/L; P = 0.003), IGF-II (-79 μg/L; P = 0.003), IGFBP-3 (-0.7 μg/L; P = 0.007), and leptin (-1.0 μg/L; P = 0.016) concentrations but higher median cortisol (+18 μg/L; P = 0.037) concentrations compared with normally grown newborns. Prenatal LNS resulted in increased cord leptin concentrations in primigravidae and mothers with higher BMI at study inclusion. The elevated leptin concentrations could point toward a higher neonatal fat mass.

Effectiveness of facility-based personalized maternal nutrition counseling in improving child growth and morbidity up to 18 months: A cluster-randomized controlled trial in rural Burkina Faso

The period from conception to 24 months of age is a crucial window for nutrition interventions. Personalized maternal counseling may improve childbirth outcomes, growth, and health. We assessed the effectiveness of facility-based personalized maternal nutrition counseling (from pregnancy to 18 months after birth) in improving child growth and health in rural Burkina Faso. We conducted a paired cluster randomized controlled trial in a rural district of Burkina Faso with 12 primary health centers (clusters). Healthcare providers in the intervention centers received patient-centered communication and nutrition counseling training. Pregnant women in the third trimester living in the center catchment areas and intending to stay for the next 2 years were prospectively included. We followed 2253 mother-child pairs quarterly until the child was aged 18 months. Women were interviewed about counseling experiences, dietary practices during pregnancy, and their child’s feeding practices and morbidity history. Anthropometric measurements were taken at each visit using standardized methods. The primary outcomes were the cumulative incidence of wasting, and changes in child weight-for-height z-score (WHZ). Secondary outcomes were the women’s prenatal dietary practices, early breastfeeding practices, exclusive breastfeeding, timely introduction of complementary food, child’s feeding frequency and dietary diversity, children’s mean birth weight, endpoint prevalence of stunting, and cumulative incidence of diarrhea, fever, and acute respiratory infection. All analyses were by intention-to-treat using mixed effects models. The intervention and control arms each included six health centers. Mothers in the intervention arm had a significantly higher exposure to counseling with 11.2% for breastfeeding techniques to 75.7% for counseling on exclusive breastfeeding. Mothers of infants below 6 months of age in the intervention arm were more likely to exclusively breastfeed (54.3% vs 42.3%; Difference of Proportion (DP) 12.8%; 95% CI: 2.1, 23.6; p = 0.020) as compared to the control arm. Between 6 and 18 months of age, more children in the intervention arm benefited from the required feeding frequency (68.8% vs 53.4%; DP 14.1%; 95% CI: 9.0, 19.2; p<0.001) and a larger proportion had a minimum dietary diversity (28.6% vs 22.0%; DP 5.9%; 95% CI: 2.7, 9.2; p<0.001). Birth weight of newborns in the intervention arm was on average 84.8 g (p = 0.037) larger compared to the control arm. However, we found no significant differences in child anthropometry or morbidity between study arms. Facility-based personalized maternal nutrition counseling was associated with an improved prenatal dietary practices, Infant and Young Child Feeding practices, and child birth weight. Complementary strategies are warranted to obtain meaningful impact on child growth and morbidity. This includes strategies to ensure good coverage of facility-based services and effective nutrition/care practices in early childhood.