Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis.

<h4>Background</h4>Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT dat...

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Autores principales:	William D Thompson, Jessica Tyrrell, Maria-Carolina Borges, Robin N Beaumont, Bridget A Knight, Andrew R Wood, Susan M Ring, Andrew T Hattersley, Rachel M Freathy, Debbie A Lawlor
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2019
Materias:	Medicine R
Acceso en línea:	https://doaj.org/article/bdf6673a81dd40a3ac26519e7ac355fe
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spelling	oai:doaj.org-article:bdf6673a81dd40a3ac26519e7ac355fe2021-12-02T19:55:40ZAssociation of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis.1549-12771549-167610.1371/journal.pmed.1002828https://doaj.org/article/bdf6673a81dd40a3ac26519e7ac355fe2019-06-01T00:00:00Zhttps://doi.org/10.1371/journal.pmed.1002828https://doaj.org/toc/1549-1277https://doaj.org/toc/1549-1676<h4>Background</h4>Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight.<h4>Methods and findings</h4>We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 × 10-9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy.<h4>Conclusions</h4>Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments.William D ThompsonJessica TyrrellMaria-Carolina BorgesRobin N BeaumontBridget A KnightAndrew R WoodSusan M RingAndrew T HattersleyRachel M FreathyDebbie A LawlorPublic Library of Science (PLoS)articleMedicineRENPLoS Medicine, Vol 16, Iss 6, p e1002828 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R
spellingShingle	Medicine R William D Thompson Jessica Tyrrell Maria-Carolina Borges Robin N Beaumont Bridget A Knight Andrew R Wood Susan M Ring Andrew T Hattersley Rachel M Freathy Debbie A Lawlor Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis.
description	<h4>Background</h4>Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight.<h4>Methods and findings</h4>We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 × 10-9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy.<h4>Conclusions</h4>Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments.
format	article
author	William D Thompson Jessica Tyrrell Maria-Carolina Borges Robin N Beaumont Bridget A Knight Andrew R Wood Susan M Ring Andrew T Hattersley Rachel M Freathy Debbie A Lawlor
author_facet	William D Thompson Jessica Tyrrell Maria-Carolina Borges Robin N Beaumont Bridget A Knight Andrew R Wood Susan M Ring Andrew T Hattersley Rachel M Freathy Debbie A Lawlor
author_sort	William D Thompson
title	Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis.
title_short	Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis.
title_full	Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis.
title_fullStr	Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis.
title_full_unstemmed	Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis.
title_sort	association of maternal circulating 25(oh)d and calcium with birth weight: a mendelian randomisation analysis.
publisher	Public Library of Science (PLoS)
publishDate	2019
url	https://doaj.org/article/bdf6673a81dd40a3ac26519e7ac355fe
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Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis.

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