Effects of Prenatal Multiple Micronutrient Supplementation on Fetal Growth Factors: A Cluster-Randomized, Controlled Trial in Rural Bangladesh
Alison D. GernandKerry SchulzeAshika Nanayakkara‐BindMargia ArguelloAbu Ahmed ShamimHasmot AliLee WuKeith P. WestParul Christian
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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. Trial Registration ClinicalTrials.gov NCT00860470Keywords:
Human placental lactogen
Placental lactogen
Cord blood
The cell-free translation product of human placental lactogen mRNA is a precursor molecule larger than the mature hormone that circulates in plasma. To determine the structure of pre-placental lactogen, the poly(A)-rich RNA fraction of term placenta was isolated and translated in a wheat germ cell-free system. The mRNA programmed the synthesis of a major protein, 3000 daltons larger than placental lactogen, that was specifically precipitated by hormone antibodies. The immunoprecipitated protein was labeled separately with 20 radioactive amino acids and subjected to sequence analysis. The results showed the synthesis of pre-placental lactogen in which an extra piece 25 residues long preceded the NH2 terminus of the mature protein. The structure of the extra piece is as follows: Met-Pro-Gly-Ser-Arg-Thr-Ser-Leu-Leu-Ala-Phe-Ala-Leu-Leu-Cys-Leu-Pro-Trp-Leu-Gln-Glu-Ala-Gly-Ala-. Met1 is the initiator residue because only initiator [35S]Met-tRNAMet1, but not internal [35S]Met-tRNA2Met, donated NH2-terminal methionine. The structure of the extra piece showed little homology with that of unrelated hormones but striking homology (64%) with the extra piece of rat pre-growth hormone. Most amino acid substitutions involved a single base change in the codon. Mature human placental lactogen and rat growth hormone have 59% homology in sequence. Thus, our findings provide additional evidence to support the common evolutionary origin of these hormones, not only of the mature proteins but also of the extra piece segments.
Placental lactogen
Human placental lactogen
Protein primary structure
Homology
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Studies were carried out with human placental lactogen (hPL) to elucidate its role in regulation of steroidogenesis (progesterone and estrogens) during early pregnancy in humans. Our in vitro studies with early pregnancy placenta under different doses of hPL demonstrated that this hormone could stimulate the synthesis of progesterone as well as estrogens (estrone and estradiol) from their respective precursors.
Human placental lactogen
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Antibodies raised against purified ovine placental lactogen were used to demonstrate the cellular localization of the hormone in tissues of the ewe placenta and chorionic membranes by immunofluorescence and immunoperoxidase techniques. Although binucleate cells have been shown to appear as early as Day 16 of pregnancy, ovine placental lactogen was not detected in the trophoblast until Day 22, and in substnatial numbers of cells until Day 80, of gestation. In the more mature placenta, lactogen-immunoreactive material was demonstrated in (a) binucleate cells of the fetal trophoblast, (b) uninucleate cells associated with the maternal epithelium syncytium and (c) binucleate cells of the chorionic membranes.
Placental lactogen
Human placental lactogen
Trophoblast
Immunoperoxidase
Syncytium
Langhans giant cell
Syncytiotrophoblasts
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Human placental lactogen
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Progestogen
Estriol
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A prospective study has been carried out of placental lactogen levels in pregnancy complicated by diabetes mellitus. The levels were higher than those in normal pregnant subjects; the higher levels were related to increased placental and fetal weight but more closely to the former; and lower levels were found when there was clinical evidence of placental dysfunction. Those patients requiring the largest insulin increment for the control of their diabetes in the pregnancy have placental lactogen levels in the higher range.
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Human placental lactogen
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SUMMARY The intravenous administration of ovine placental lactogen to pregnant and non-pregnant sheep produced significant acute decreases in plasma free fatty acid, glucose and amino nitrogen concentrations. Plasma insulin concentrations decreased 1 h after administration of ovine placental lactogen and then increased significantly above baseline concentrations. The results suggest that, like human placental lactogen, ovine placental lactogen is important in the modulation of intermediary metabolism during pregnancy. The sheep is an excellent animal model for the investigation of the physiology of placental lactogen.
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Human placental lactogen
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Placental lactogen
Human placental lactogen
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The anaemia and thrombocytopenia of hypophysectomized (Hypox) rats could be corrected readily by daily treatment with human placental lactogen. Spontaneous DNA synthesis in the bone marrow of Hypox rats was grossly impaired, which was also normalized by placental lactogen. Human placental lactogen exerted a direct mitogenic effect on rat bone marrow cells in vitro. These results indicate that placental lactogen is a potent haemopoietic hormone.
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Placental lactogen
Human placental lactogen
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