Effects of Prenatal Multiple Micronutrient Supplementation on Fetal Growth Factors: A Cluster-Randomized, Controlled Trial in Rural Bangladesh

<div><p>Prenatal multiple micronutrient (MM) supplementation improves birth weight through increased fetal growth and gestational age, but whether maternal or fetal growth factors are involved is unclear. Our objective was to examine the effect of prenatal MM supplementation on intrauterine growth factors and the associations between growth factors and birth outcomes in a rural setting in Bangladesh. In a double-blind, cluster-randomized, controlled trial of MM vs. iron and folic acid (IFA) supplementation, we measured placental growth hormone (PGH) at 10 weeks and PGH and human placental lactogen (hPL) at 32 weeks gestation in maternal plasma (n = 396) and insulin, insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) in cord plasma (n = 325). Birth size and gestational age were also assessed. Early pregnancy mean (SD) BMI was 19.5 (2.4) kg/m² and birth weight was 2.68 (0.41) kg. There was no effect of MM on concentrations of maternal hPL or PGH, or cord insulin, IGF-1, or IGFBP-1. However, among pregnancies of female offspring, hPL concentration was higher by 1.1 mg/L in the third trimester (95% CI: 0.2, 2.0 mg/L; p = 0.09 for interaction); and among women with height <145 cm, insulin was higher by 59% (95% CI: 3, 115%; p = 0.05 for interaction) in the MM vs. IFA group. Maternal hPL and cord blood insulin and IGF-1 were positively, and IGFBP-1 was negatively, associated with birth weight z score and other measures of birth size (all p<0.05). IGF-1 was inversely associated with gestational age (p<0.05), but other growth factors were not associated with gestational age or preterm birth. Prenatal MM supplementation had no overall impact on intrauterine growth factors. MM supplementation altered some growth factors differentially by maternal early pregnancy nutritional status and sex of the offspring, but this should be examined in other studies.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT00860470?term=NCT00860470" target="_blank">NCT00860470</a></p></div

Association between fetal growth hormones and birth size in rural Bangladesh, 2009–2010¹.

<p>¹ hPL, human placental lactogen; PGH, placental growth hormone; IGF-1, insulin like growth factor; IGFBP-1, IGF-1 binding protein; MUAC, mid-upper arm circumference. Linear regression models adjusted for maternal BMI, height, parity, age, education, and supplementation group (multiple micronutrient or iron and folic acid). Insulin, IGF-1, and IGFBP-1 were standardized to have mean = 0 and SD = 1. Exposures were standardized to have mean = 0 and SD = 1. β's represent mean increase in placental weight or other birth size outcome for each standard deviation increase in exposure.</p><p>² Sex- and gestational age-specific z scores were calculated by a Canadian National Growth Reference [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137269#pone.0137269.ref023" target="_blank">23</a>].</p><p>³ p<0.05</p><p>⁴ p<0.01</p><p>Association between fetal growth hormones and birth size in rural Bangladesh, 2009–2010<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137269#t004fn004" target="_blank">¹</a>.</p

Effect of prenatal multiple micronutrient supplementation compared to iron and folic acid on plasma concentrations of growth factors by maternal and fetal characteristics in rural Bangladesh, 2009–2010¹.

<p>¹ hPL, human placental lactogen; PGH, placental growth hormone; IGF-1, insulin like growth factor; IGFBP-1, insulin like growth factor—1 binding protein. For insulin, IGF-1, and IGFBP-1, n = 70 & 255 for height groups; n = 129 & 196 for BMI groups; n = 162 &163 for age groups; n = 120 & 205 for parity groups; and n = 174 for males and n = 151 for females.</p><p>² Mean difference in supplement groups from linear regression models with generalized estimating equations (GEE) to account for cluster randomization.</p><p>³ p<0.10 for interaction.</p><p>⁴ p<0.05.</p><p>Effect of prenatal multiple micronutrient supplementation compared to iron and folic acid on plasma concentrations of growth factors by maternal and fetal characteristics in rural Bangladesh, 2009–2010<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137269#t003fn001" target="_blank">¹</a>.</p

CONSORT flow diagram showing maternal and infant participation through the study.

<p>There were 16 clusters in the folic-acid group and 15 clusters in the multiple micronutrient group. Some mothers were not met at 32 weeks, but were met at birth for cord blood collection.</p

Effect of prenatal multiple micronutrient supplementation compared to iron and folic acid on fetal growth factors in maternal and cord plasma, rural Bangladesh, 2009–2010¹.

<p>¹ hPL, human placental lactogen; PGH, placental growth hormone; IGF-1, insulin like growth factor; IGFBP-1, IGF-1 binding protein.</p><p>² Linear regression models with generalized estimating equations (GEE) to account for cluster randomization. Results did not meaningfully differ when using ln transformed outcomes for PGH and IGFBP-1 so untransformed data were modeled. For insulin, mean difference is percent change.</p><p>³ hPL and PGH at 32 weeks gestation; PGH Δ is the concentration at 32 weeks–concentration at 10 weeks.</p><p>⁴ p = 0.05 for unadjusted difference.</p><p>Effect of prenatal multiple micronutrient supplementation compared to iron and folic acid on fetal growth factors in maternal and cord plasma, rural Bangladesh, 2009–2010<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137269#t002fn001" target="_blank">¹</a>.</p

Effect of multiple micronutrient supplementation compared to iron and folic acid on a) human placental lactogen, by infant sex (p = 0.09 for interaction), and b) cord plasma insulin, by maternal stature (p = 0.04 for interaction).

<p>Solid line for multiple micronutrient group; dashed line for iron and folic acid group.</p

Micronutrient deficiencies are common in 6- to 8-year-old children of rural Nepal, with prevalence estimates modestly affected by inflammation.

Subclinical micronutrient deficiencies remain a hidden aspect of malnutrition for which comprehensive data are lacking in school-aged children. We assessed the micronutrient status of Nepalese children, aged 6 to 8 y, born to mothers who participated in a community-based antenatal micronutrient supplementation trial from 1999 to 2001. Of 3305 participants, plasma indicators were assessed in a random sample of 1000 children. Results revealed deficiencies of vitamins A (retinol &lt;0.70 μmol/L, 8.5%), D (25-hydroxyvitamin D &lt;50 nmol/L, 17.2%), E (α-tocopherol &lt;9.3 μmol/L, 17.9%), K (decarboxy prothombin &gt;2 μg/L, 20%), B-12 (cobalamin &lt;150 pmol/L, 18.1%), B-6 [pyridoxal-5'-phosphate (PLP) &lt;20 nmol/L, 43.1%], and β-carotene (41.5% &lt;0.09 μmol/L), with little folate deficiency (6.2% &lt;13.6 nmol/L). Deficiencies of iron [ferritin &lt;15 μg/L, 10.7%; transferrin receptor (TfR) &gt;8.3 mg/L, 40.1%; TfR:ferritin &gt;500 μg/μg, 14.3%], iodine (thyroglobulin &gt;40 μg/L, 11.4%), and selenium (plasma selenium &lt;0.89 μmol/L, 59.0%) were observed, whereas copper deficiency was nearly absent (plasma copper &lt;11.8 μmol/L, 0.7%). Hemoglobin was not assessed. Among all children, 91.7% experienced at least 1 micronutrient deficiency, and 64.7% experienced multiple deficiencies. Inflammation (α-1 acid glycoprotein &gt;1 g/L, C-reactive protein &gt;5 mg/L, or both) was present in 31.6% of children, affecting the prevalence of deficiency as assessed by retinol, β-carotene, PLP, ferritin, TfR, selenium, copper, or having any or multiple deficiencies. For any nutrient, population deficiency prevalence estimates were altered by ≤5.4% by the presence of inflammation, suggesting that the majority of deficiencies exist regardless of inflammation. Multiple micronutrient deficiencies coexist in school-aged children in rural Nepal, meriting more comprehensive strategies for their assessment and prevention