Association between micronutrient supplementation during pregnancy and preterm birth: evidence from a large-scale children survey and Mendelian randomization study

Liwen Ding^1*Yiliang Liu²Xiaona Yin³Guomin Wen³Dengli Sun³Danxia Xian³Yafen Zhao³Maolin Zhang¹Weikang Yang³Wei-Qing Chen^1,4*

• ¹Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
• ²Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
• ³Independent researcher, Shenzhen, China
• ⁴Xinhua College of Sun Yat-sen University, Guangzhou, China

Background: Preterm birth (PTB) is a leading cause of neonatal mortality and under-five mortality worldwide, with long-term health impacts. While micronutrient supplementation shows promise in preventing PTB, its effectiveness remains controversial due to confounding factors. This study aims to elucidate the association between micronutrient supplementation and PTB risk by analyzing a large-scale children survey and employing Mendelian Randomization (MR) to address confounding factors. Methods: This study recruited 66,728 mother-child dyads in Longhua District, Shenzhen, China in 2021. Participants provided information on micronutrient supplementation (multinutrient, folic acid, calcium, and iron) through a structured questionnaire. Logistic regression assessed the association between micronutrient supplementation and PTB in crude, adjusted, and full-inclusion models. MR analysis used summary-level GWAS data from the UK Biobank and FinnGen consortiums. The main MR analyses employed inverse variance weighting (IVW), with sensitivity analyses including MR Egger regression, weighted median, weighted mode, simple mode, and MR-PRESSO.Results: Observational analysis indicated folic acid (OR=0.80, 95%CI: 0.72-0.89), calcium (OR=0.88, 95%CI: 0.80-0.96), and iron (OR=0.92, 95%CI: 0.86-0.98) as protective factors against PTB, especially in co-supplementation, while multinutrient supplementation showed no significant effect. MR analysis indicating a consistent protective effect of calcium (ORIVW=0.04, 95% CI: 0.004-0.42, p<0.01, pFDR<0.05). Sensitivity analyses supported these findings, detecting no bias or pleiotropy.Conclusion: Combining observational data with genetic causal inference, our study confirms the protective roles of folic acid, calcium, and iron against PTB, with MR particularly highlighting calcium's causal association with reduced PTB risk. These findings provide a comprehensive understanding and underscore the importance of targeted nutritional interventions, especially calcium, in prenatal care for PTB prevention. However, given the limitations of the self-reported data and the lack of information on doses used in our study, future prospective studies with more detailed micronutrient information are needed to provide more comprehensive evidence.