Preconception One-Carbon Metabolism Nutrient Levels in Preparing for Pregnancy Couples and Spontaneous Pregnancy Loss: A Prospective Cohort Study

Abstract

Spontaneous pregnancy loss (SPL) remains an important yet poorly understood pregnancy outcome. One-carbon metabolism (OCM) nutrients play an essential role in embryonic development, but their relationship with SPL remains unclear. In this prospective cohort of 11,033 couples and 2862 unpaired mothers, we assessed associations between preconception parental one-carbon metabolism (OCM) nutrients and SPL risk. We used generalized linear models to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for fathers, mothers, and the combined parental population, respectively. Each 100 ng/mL increase in paternal and maternal red blood cell (RBC) folate was associated with a 19% (aRR = 0.81; 95% CI, 0.73–0.90) and an 8% (aRR = 0.92; 0.85–0.98) lower SPL risk, respectively. The risk was reduced by 64% (aRR = 0.36; 0.16–0.79) when both parents achieved levels ≥ 400 ng/mL, compared to neither. Exploratory case–control analysis suggested associations of parental serum betaine with increased risk of SPL (β [standard error]: 0.09 [0.11] for fathers; 0.02 [0.08] for mothers) and inverse associations for taurine (−0.09 [0.11] and −0.03 [0.08], respectively). These findings highlight paternal and maternal preconception RBC folate, and imbalances in OCM metabolites are associated with an increased SPL risk, offering novel insights into SPL etiology and have public health implications.

Keywords

cohort study / metabolite / one-carbon metabolism / preconception / red blood cell folate / spontaneous pregnancy loss

References

[1] G. B. D. Fertility and C. Forecasting, “Global Fertility in 204 Countries and Territories, 1950–2021, With Forecasts to 2100: A Comprehensive Demographic Analysis for the Global Burden of Disease Study 2021,” Lancet 403, no. 10440 (2024): 2057–2099.

[2] J. Qiao, Y. Wang, X. Li, et al., “A Lancet Commission on 70 Years of Women's Reproductive, Maternal, Newborn, Child, and Adolescent Health in China,” Lancet 397, no. 10293 (2021): 2497–2536.

[3] Y. Wei, Q. Xu, H. Yang, et al., “Preconception Diabetes Mellitus and Adverse Pregnancy Outcomes in over 6.4 Million Women: A Population-Based Cohort Study in China,” Plos Medicine 16, no. 10 (2019): e1002926.

[4] S. Quenby, I. D. Gallos, R. K. Dhillon-Smith, et al., “Miscarriage Matters: The Epidemiological, Physical, Psychological, and Economic Costs of Early Pregnancy Loss,” Lancet 397, no. 10285 (2021): 1658–1667.

[5] M. M. van Dijk, A. M. Kolte, J. Limpens, et al., “Recurrent Pregnancy Loss: Diagnostic Workup After Two or Three Pregnancy Losses? A Systematic Review of the Literature and Meta-Analysis,” Human Reproduction Update 26, no. 3 (2020): 356–367.

[6] H. W. Korsmo and X. Jiang, “One Carbon Metabolism and Early Development: A Diet-Dependent Destiny,” Trends in Endocrinology and Metabolism 32, no. 8 (2021): 579–593.

[7] M. Viswanathan, R. P. Urrutia, K. N. Hudson, et al., “Folic Acid Supplementation to Prevent Neural Tube Defects: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force,” JAMA 330, no. 5 (2023): 460–466.

[8] H. Chen, Y. Zhang, D. Wang, et al., “Periconception Red Blood Cell Folate and Offspring Congenital Heart Disease: Nested Case-Control and Mendelian Randomization Studies,” Annals of Internal Medicine 175, no. 9 (2022): 1212–1220.

[9] L. George, J. L. Mills, A. L. Johansson, et al., “Plasma Folate Levels and Risk of Spontaneous Abortion,” JAMA 288, no. 15 (2002): 1867–1873.

[10] T. Yamada, M. Morikawa, T. Yamada, et al., “First-Trimester Serum Folate Levels and Subsequent Risk of Abortion and Preterm Birth among Japanese Women With Singleton Pregnancies,” Archives of Gynecology and Obstetrics 287, no. 1 (2013): 9–14.

[11] P. Cavalle-Busquets, M. Ingles-Puig, J. D. Fernandez-Ballart, et al., “Moderately Elevated First Trimester Fasting Plasma Total Homocysteine Is Associated With Increased Probability of Miscarriage. The Reus-Tarragona Birth Cohort Study,” Biochimie 173 (2020): 62–67.

[12] A. Arcot, R. E. Walker, K. Gallagher, et al., “Maternal Vitamin B12 in Pregnancy and Placental Development,” Journal of Nutrition and Metabolism 2024 (2024): 3439995.

[13] R. Bala, R. Verma, P. Verma, et al., “Hyperhomocysteinemia and Low Vitamin B12 Are Associated with the Risk of Early Pregnancy Loss: A Clinical Study and Meta-Analyses,” Nutrition Research 91 (2021): 57–66.

[14] J. Hoek, M. P. H. Koster, S. Schoenmakers, et al., “Does the Father Matter? The Association Between the Periconceptional Paternal Folate Status and Embryonic Growth,” Fertility and Sterility 111, no. 2 (2019): 270–279.

[15] R. Lambrot, C. Xu, S. Saint-Phar, et al., “Low Paternal Dietary Folate Alters the Mouse Sperm Epigenome and Is Associated with Negative Pregnancy Outcomes,” Nature Communications 4 (2013): 2889.

[16] R. Oh and D. L. Brown, “Vitamin B12 Deficiency,” American Family Physician 67, no. 5 (2003): 979–986.

[17] X. Li, Y. M. Zeng, Y. D. Luo, et al., “Effects of Folic Acid and Folic Acid Plus Zinc Supplements on the Sperm Characteristics and Pregnancy Outcomes of Infertile Men: A Systematic Review and Meta-Analysis,” Heliyon 9, no. 7 (2023): e18224.

[18] A. M. Cordero, K. S. Crider, L. M. Rogers, et al., “Optimal Serum and Red Blood Cell Folate Concentrations in Women of Reproductive Age for Prevention of Neural Tube Defects: World Health Organization Guidelines,” Mmwr Morbidity and Mortality Weekly Report 64, no. 15 (2015): 421–423.

[19] L. E. Murphy, J. L. Mills, A. M. Molloy, et al., “Folate and Vitamin B12 in Idiopathic Male Infertility,” Asian Journal of Andrology 13, no. 6 (2011): 856–861.

[20] H. Y. Chen, Y. Zhang, D. M. Wang, et al., “Periconception Red Blood Cell Folate and Offspring Congenital Heart Disease Nested Case-Control and Mendelian Randomization Studies,” Annals of Internal Medicine (2022).

[21] J. Stephenson, N. Heslehurst, J. Hall, et al., “Before the Beginning: Nutrition and Lifestyle in the Preconception Period and Its Importance for Future Health,” Lancet 391, no. 10132 (2018): 1830–1841.

[22] A. C. Antony, “In Utero Physiology: Role of Folic Acid in Nutrient Delivery and Fetal Development,” American Journal of Clinical Nutrition 85, no. 2 (2007): 598S–603S.

[23] J. E. Schjenken and S. A. Robertson, “The Female Response to Seminal Fluid,” Physiological Reviews 100, no. 3 (2020): 1077–1117.

[24] H. W. Kim, Y. J. Choi, K. N. Kim, et al., “Effect of Paternal Folate Deficiency on Placental Folate Content and Folate Receptor Alpha Expression in Rats,” Nutrition Research and Practice 5, no. 2 (2011): 112–116.

[25] T. Podinic, A. MacAndrew, and S. Raha, “Trophoblast Syncytialization: A Metabolic Crossroads,” Results and Problems in Cell Differentiation 71 (2024): 101–125.

[26] J. M. Kim, K. Hong, J. H. Lee, et al., “Effect of Folate Deficiency on Placental DNA Methylation in Hyperhomocysteinemic Rats,” Journal of Nutritional Biochemistry 20, no. 3 (2009): 172–176.

[27] J. I. Rader, “Folic Acid Fortification, Folate Status and Plasma Homocysteine,” Journal of Nutrition 132, no. S8 (2002): 2466S–2470S.

[28] D. Wang, Y. Zhang, Y. Jiang, et al., “Shanghai Preconception Cohort (SPCC) for the Association of Periconceptional Parental Key Nutritional Factors With Health Outcomes of Children With Congenital Heart Disease: A Cohort Profile,” BMJ Open 9, no. 11 (2019): e031076.

[29] American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Gynecology. “ACOG Practice Bulletin No. 200: Early Pregnancy Loss,” Obstetrics and Gynecology 132, no. 5 (2018): e197–e207.

[30] Y. Wang, J. Mi, X. Y. Shan, et al., “Is China Facing an Obesity Epidemic and the Consequences? The Trends in Obesity and Chronic Disease in China,” International Journal of Obesity 31, no. 1 (2007): 177–188.

[31] Abortion GoCECoDaToS. "Consensus of Chinese Experts on Diagnosis and Treatment of Spontaneous Abortion," Chinese Journal of Practical Gynecology and Obstetrics 36, no. 11 (2020): 1082–1090.

[32] R. Bender Atik and O. B. Christiansen, “ESHRE Guideline: Recurrent Pregnancy Loss,” Human Reproduction Open 2018, no. 2 (2018): hoy004.

[33] E. N. Ugurlu, G. Ozaksit, A. Karaer, et al., “The Value of Vascular Endothelial Growth Factor, Pregnancy-Associated Plasma Protein-A, and Progesterone for Early Differentiation of Ectopic Pregnancies, Normal Intrauterine Pregnancies, and Spontaneous Miscarriages,” Fertility and Sterility 91, no. 5 (2009): 1657–1661.

[34] T. Gaster, C. M. Eggertsen, H. Stovring, et al., “Quantifying the Impact of Unmeasured Confounding in Observational Studies with the E Value,” BMJ Medicine 2, no. 1 (2023): e000366.

RIGHTS & PERMISSIONS

2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.