First-trimester maternal folate and vitamin B12 concentrations and their associations with first-trimester placental growth: the Rotterdam Periconception Cohort.

study questionAre maternal folate and vitamin B12 concentrations associated with first-trimester placental growth? SUMMARY ANSWER: Maternal folate concentrations and commencement of folic acid supplements prior to conception, as compared to following conception, are positively associated with first-trimester placental volume (PV), whereas no associations were found for maternal vitamin B12 concentrations. WHAT IS KNOWN ALREADY: Besides the protective effect of folic acid supplement use against neural tube defects and other adverse birth outcomes, the preconceptional commencement of folic acid supplements is positively associated with postpartum placental size, although conflicting outcomes have been reported. Studies in mice show an association with vitamin B12 deficiency and decreased placental weight postpartum. STUDY DESIGN, SIZE, DURATION: Between January 2010 and December 2020, 480 pregnancies (727 longitudinal ultrasound measurements) with known maternal folate and/or vitamin B12 blood concentrations in the first trimester and 875 pregnancies (1430 longitudinal ultrasound measurements) with known timing of folic acid supplement initiation were included in the Rotterdam Periconception Cohort, a prospective, hospital-based observational cohort. PARTICIPANTS/MATERIALS, SETTING,

methodsRed blood cell (RBC) folate and serum vitamin B12 concentrations were determined in first-trimester maternal blood, and the timing of folic acid supplement use was collected using validated questionnaires. PV was measured from serial 3-dimensional ultrasounds performed at 7, 9, and 11 weeks of gestation. Linear mixed models were used to assess the associations between maternal folate and vitamin B12 concentrations with first-trimester PVs. Analyses were adjusted for gestational age at ultrasound, maternal age, BMI, geographical background, education level, parity, smoking, mode of conception, and the other B vitamins. For validation, the association between the timing of folic acid supplement initiation (pre- or postconception) and PV was assessed. MAIN RESULTS AND THE ROLE OF CHANCE: The median RBC folate concentration was 1395 nmol/l (IQR 1169-1588) and the median serum vitamin B12 concentration was 314 pmol/l (IQR 241-391). For RBC folate, the smallest PVs were found in women in the lowest quartile, with the largest difference as compared to women in the fourth quartile: 3√PV (β = -0.141, 95% CI = -0.249 to -0.033, P = 0.010), corresponding to a 1.79 cm3 (-18.7%) and a 6.99 cm3 (-9.9%) smaller PV at 7 and 11 weeks of gestation, respectively. Additionally, PV was significantly smaller in women who initiated folic acid supplements following rather than prior to conception: 3√PV (β=-0.129, 95% CI = -0.207 to -0.051, P = 0.001) corresponding to a 1.69 cm3 (-16.9%) and a 6.62 cm3 (-8.9%) smaller PV at 7 and 11 weeks of gestation, respectively. We found no significant association between maternal serum vitamin B12 concentrations and PV. LIMITATIONS, REASONS FOR CAUTION: The observational design of this study does not exclude residual confounding, and our hospital-based study population, with mostly adequate RBC folate and serum vitamin B12 concentrations, could limit the generalizability of our results. WIDER IMPLICATIONS OF THE

findingsOur results emphasize the importance of the preconceptional commencement of folic acid supplements to achieve adequate maternal RBC folate concentrations, which could support optimal placental growth during the first trimester and also protect against neural tube defects and other adverse birth outcomes. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Department of Obstetrics and Gynecology and the Department of Developmental Biology of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands. K.D.S. was in receipt of funding from the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/K017810/1). The authors declare that they have no conflict of interests. TRIAL REGISTRATION NUMBER: NTR4356.