Date Published: June 18, 2019
Publisher: Public Library of Science
Author(s): 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, Jenny E Myers
Abstract: BackgroundSystematic 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 findingsWe 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.ConclusionsOur 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.
Partial Text: Infants with lower or higher birth weight (BW) than average are at an increased risk of neonatal mortality and morbidity . BW is also inversely associated with some adverse adult health outcomes, including coronary heart disease , type 2 diabetes , poor cognitive ability , and several types of cancer , with most of these associations being linear across most of the BW distribution. BW is an indicator of conditions in utero and may be influenced by modifiable factors in the maternal circulation. For example, there is evidence that higher maternal fasting glucose is causally related to greater fetal growth and higher BW [6,7], which increases the risk of complications during delivery. However, relatively little is known about the causal influences of other maternal factors. More evidence is required on how modifying the in utero environment might influence BW and associated health outcomes.
The analyses plan was developed by RMF, DAL, WDT, and MCB, prior to any analyses beginning. It was acted on by WDT and MCB. The analysis plan has not been published but was informally recorded in meeting notes. We made one change to the overall study plans after completing analyses; we undertook risk-of-bias assessment of the RCTs with a focus on factors that might mean instrumental variable assumptions were violated. This was motivated by differences in results comparing MR to instrumental variables in RCTs, particularly in relation to the effects of calcium on BW. We made one change to the plan following reviewers’ comments; we undertook two multivariable MR analyses to adjust for potential confounders. These were (1) multivariable MR of the association of 25(OH)D with BW adjusting (genetically) for maternal height and (2) partial multivariable MR of the association of calcium with BW adjusting (genetically) for maternal educational level.
The characteristics of included participants from UKB, ALSPAC, and EFSOCH are shown in Table 1. The SNP-outcome associations for UKB, ALSPAC, and EFSOCH are shown in S5, S6 and S7 Tables.
This study triangulated two approaches (two-sample MR and instrumental variables applied to RCTs) assessing the effects of maternal circulating 25(OH)D and calcium on BW. Across the main and all sensitivity MR analyses, we found no evidence that maternal 25(OH)D has an important effect on BW, but applying instrumental variable analyses to RCTs, there was evidence of a weak positive effect. Findings for maternal circulating calcium were inconsistent across methods and sensitivity analyses, making it difficult for us to conclude from the data used here what the effect of maternal circulating calcium on BW is.