Periconceptional maternal supplement intake and human embryonic growth, development, and birth outcomes: the Rotterdam Periconception Cohort.

study questionIs periconceptional multiple-micronutrient supplement (MMS) use including folic acid (FA) compared to FA use only associated with increased embryonic growth, development, and birth weight in a high-risk population? SUMMARY ANSWER: Women with MMS intake show no significant differences in first-trimester morphological embryo development, but increased first-trimester embryonic growth trajectories and fewer neonates born small for gestational age (SGA), less than the 3rd percentile (<p3), compared to women using only FA. WHAT IS KNOWN ALREADY: Periconceptional maternal FA intake in the general population is associated with increased embryonic and fetal growth, and reduced risks of neural tube defects, other congenital malformations, low birth weight, and neonates born SGA. STUDY DESIGN, SIZE, DURATION: A prospective tertiary hospital-based cohort study (the Rotterdam Periconceptional Cohort) was conducted from January 2010 to December 2020. PARTICIPANTS/MATERIALS, SETTING,

methodsWe included 1076 women from the Rotterdam Periconceptional Cohort, before 10 weeks of pregnancy with follow-up until delivery. Embryonic growth was assessed by measurement of crown-rump length (CRL) and embryonic volume (EV), and embryonic morphology was described by Carnegie stages using longitudinal three-dimensional ultrasound scans and virtual reality techniques. Birth outcomes were extracted from medical records. General characteristics and supplement use were extracted from research questionnaires. MAIN RESULTS AND THE ROLE OF CHANCE: This study showed increased embryonic growth trajectories (adjusted models, CRL: β = 0.052, 95% CI 0.012-0.090, EV: β = 0.022, 95% CI 0.002-0.042) in women using MMS compared to those using only FA. Moreover, a 45% reduced risk of a neonate-born SGA (<p3) was shown in women using MMS compared to FA users (adjusted OR = 0.546, 95% CI 0.308, 0.969). Embryonic morphological development (Carnegie stages) and the occurrence of miscarriages did not differ between women using MMS or solely FA. LIMITATIONS, REASONS FOR CAUTION: Following the heterogeneity of the composition and dose of MMS preparations, it is unclear which specific micronutrient, combination, or dose explains the increased embryonic growth trajectory and reduction in risk for SGA. This also hampers the possibility of differentiating between the effects of FA alone or as a component of MMS. WIDER IMPLICATIONS OF THE

findingsOur findings emphasize the importance of periconceptional maternal MMS use as a potential preventative intervention against reduced embryonic growth and neonates born SGA. Therefore, we recommend the periconceptional use of MMS in women at risk of inadequate micronutrient intake. However, awareness of potentially harmful side effects of high doses and combinations of micronutrients is essential, therefore the optimal composition and dose need to be investigated, and careful surveillance is recommended. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands, and the ZonMw grant Open Competition 2018 (09120011910046). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: NTR4356.