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

Background 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. Methods and findings 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. Conclusions 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 Thompson and colleagues, using mendelian randomisation methods, reveal no association between levels of maternal circulating vitamin D and birth weight of newborns.
Author summary Why was this study done? Birth weight that is lower or higher than average has been associated with poor health outcomes across the life span, including infant mortality, cardiovascular disease, and type 2 diabetes. If we can identify modifiable maternal factors in pregnancy that are causally related to birth weight, we may be able to reduce the number of babies that are born with lower or higher than optimal birth weight. This may in turn help to reduce the associated poor health outcomes. Previous studies have suggested that higher maternal 25(OH)D and calcium in pregnancy are associated with higher birth weight. However, many of those studies used conventional multivariable regression in observational studies and may be subject to residual confounding. Few of them estimated the size of the effect of either maternal 25(OH)D or calcium levels on birth weight. What did the researchers do and find? We estimated the effects of maternal gestational 25(OH)D and calcium levels on offspring birth weight using mendelian randomisation, a method that uses genetic data to overcome certain limitations of traditional observational studies—for example, residual confounding. We analysed genetic data on 190,406 women from the UK Biobank who reported the birth weight of their first child, along with the results from published studies of genetic associations with 25(OH)D and calcium levels in 122,123 and 61,275 individuals, respectively. We checked that the results were not biased by offspring genotype using data from two UK birth cohorts, the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4,576 mother–child pairs) and Exeter Family Study of Childhood Health (EFSOCH; n = 647 mother–child pairs), respectively. To strengthen our causal understanding, we triangulated the mendelian randomisation results with findings from randomised controlled trials in which we used randomised status (to vitamin D or calcium supplementation) as an instrumental variable to estimate the effect of 25(OH)D or calcium on birth weight. We found no evidence of a strong effect of maternal 25(OH)D on birth weight. We found inconsistent evidence of effects of maternal calcium on birth weight. What do these findings mean? Our findings do not support using vitamin D supplementation during pregnancy or preconceptually to influence offspring birth weight. The effect of calcium on birth weight is still unclear and needs further investigation in well-powered genetic studies and/or well-conducted randomised controlled trials.