Association of Homocysteine Levels with Recurrent Pregnancy Loss: A Systematic Review
Homocysteine Levels with Recurrent Pregnancy Loss
DOI:
https://doi.org/10.54393/pjhs.v6i9.3511Keywords:
Homocysteine, Recurrent Pregnancy Loss, Hyperhomocysteinemia, Endothelial Dysfunction, Folate, Vitamin B12, MTHFR Polymorphism, Pregnancy OutcomeAbstract
Elevated homocysteine (Hcy) has been implicated in placental vascular dysfunction and adverse reproductive outcomes. Objective: To synthesize recent evidence on the association between Hcy levels and recurrent pregnancy loss (RPL), emphasizing methodological consistency and potential modifiers. Methods: Following PRISMA 2020, observational studies comparing Hcy in women with RPL versus controls were screened across PubMed, Scopus, and Cochrane. Reviews, pilots, case reports, abstracts, animal studies, and articles without quantitative Hcy data were excluded. Risk of bias was assessed using the Newcastle–Ottawa criteria; results were summarized with Synthesis Without Meta-analysis (SWiM). Results: Fourteen eligible studies across South Asia, the Middle East, Europe, and East Asia consistently reported higher Hcy among RPL cases, with typical mean differences =4–7 µmol/L and odds ratios ≈2–3, including studies adjusting for folate/B12 and MTHFR genotype. Heterogeneity stemmed from biospecimen type (serum/plasma), assay platform (HPLC vs immunoassay), fasting status, sampling time (preconception vs early pregnancy), and cut-offs (10–15 µmol/L). Emerging literature outside the included set supports endothelial mechanisms and gene nutrient interactions while highlighting reporting gaps and the need for interventional trials. Conclusions: Current evidence supports Hcy as a reproducible risk marker for RPL, plausibly mediated by endothelial and thrombo-inflammatory pathways and modified (but not fully explained) by folate/B12 status and genetic variants. Standardized measurement, rigorous adjustment, and randomized trials of targeted vitamin strategies are priorities.
References
Thakur P and Bhalerao A. High Homocysteine Levels During Pregnancy and Its Association with Placenta-Mediated Complications: A Scoping Review. Cureus. 2023 Feb; 15(2). doi: 10.7759/cureus.35244. DOI: https://doi.org/10.7759/cureus.35244
Kjaergaard AD, Wu Y, Ming WK, Wang Z, Kjaergaard MN, Ellervik C. Homocysteine and Female Fertility, Pregnancy Loss and Offspring Birthweight: A Two-Sample Mendelian Randomization Study. European Journal of Clinical Nutrition. 2022 Jan; 76(1): 40-7. doi: 10.1038/s41430-021-00898-2. DOI: https://doi.org/10.1038/s41430-021-00898-2
Ameri A, Khashei Varnamkhasti K, Parhoudeh S, Khashei Varnamkhasti S et al. Spontaneous Miscarriage Driven by Maternal Genetic Mutation at Position of PAI-1-844G/A: Shed Light on A Race-Specific Genetic Polymorphism. BioMed Central Research Notes. 2023 Dec; 16(1): 360. doi: 10.1186/s13104-023-06635-1. DOI: https://doi.org/10.1186/s13104-023-06635-1
Diao J, Luo L, Li J, Zhang S, Li Y, Qin J. Maternal Homocysteine and Folate Levels and Risk of Recurrent Spontaneous Abortion: A Meta‐Analysis of Observational Studies. Journal of Obstetrics and Gynaecology Research. 2020 Dec; 46(12): 2461-73. doi: 10.1111/jog.14500. DOI: https://doi.org/10.1111/jog.14500
Ledowsky C, Scarf V, Steel A. Health Professionals Require More Defined Protocols, Better Funding and Patient Resources to Support Couples with Recurrent Pregnancy Loss. Scientific Reports. 2025 Aug; 15(1): 28965. doi: 10.1038/s41598-025-13772-z. DOI: https://doi.org/10.1038/s41598-025-13772-z
Kozłowska-Wytyk M, Kurzawińska G, Ożarowski M, Mrozikiewicz AE, Olbromski P, Karpiński TM et al. The Importance of Gene Variants Related to Folate Uptake and Distribution in the Etiology of Recurrent Miscarriage and Intrauterine Fetal Demise. Applied Sciences. 2024 Dec; 14(24): 11847. doi: 10.3390/app142411847. DOI: https://doi.org/10.3390/app142411847
Jakubowski H and Witucki Ł. Homocysteine Metabolites, Endothelial Dysfunction, and Cardiovascular Disease. International Journal of Molecular Sciences. 2025 Jan; 26(2): 746. doi: 10.3390/ijms26020746. DOI: https://doi.org/10.3390/ijms26020746
Alfaleh A, Alkattan A, Mahmoud N, Alfaleh F, Almutair N, Alanazi A et al. The Association Between MTHFR C677T Gene Polymorphism and Repeated Pregnancy Loss in Arabic Countries: A Systematic Review and Meta-Analysis. Reproductive Sciences. 2023 Jul; 30(7): 2060-8. doi: 10.1007/s43032-023-01201-3. DOI: https://doi.org/10.1007/s43032-023-01201-3
Jian Q, Mu F, Wang K, Wang F. Risk Prediction Models for Pregnancy Outcomes in Recurrent Pregnancy Loss: A Narrative Systematic Review. Frontiers in Endocrinology. 2025 May; 16: 1582156. doi: 10.3389/fendo.2025.1582156. DOI: https://doi.org/10.3389/fendo.2025.1582156
Afaq E, Ali A, Jamil R, Waseem HF. Association of Plasma Folic Acid, Vitamin-B12 and Homocysteine with Recurrent Pregnancy Loss. “A Case Control Study”. Pakistan Journal of Medical Sciences. 2023 Sep; 39(5): 1280. doi: 10.12669/pjms.39.5.7432. DOI: https://doi.org/10.12669/pjms.39.5.7432
Sultana MN, Rahman S, Nira JA, Fatima P. Comparison of Blood Homocysteine Levels between Women with Recurrent Pregnancy Loss and Women with Normal Fertility. Journal of Enam Medical College. 2021; 11(1): 10-7. doi: 10.3329/jemc.v11i1.63168. DOI: https://doi.org/10.3329/jemc.v11i1.63168
Masuda Sultana P, Akhtar N, Saha M, Chowdhury N, Akhter P, Begum F. Association of Serum Homocysteine Level with Unexplained Recurrent Pregnancy Loss: A Case-Control Study. Obstetrics and Gynecology Research. 2023; 06(04). doi: 10.26502/ogr0150. DOI: https://doi.org/10.26502/ogr0150
Abd-Ellatef DM, Beteha GA, Hasan MM, Eid MA. The Relation Between Serum Homocystiene Level and Recurrent Abortion in Egyptian Women. The Egyptian Journal of Hospital Medicine. 2018 Jan; 70(5): 731-8. doi: 10.12816/0043975. DOI: https://doi.org/10.12816/0043975
D'Uva M, Di Micco P, Strina I, Alviggi C, Iannuzzo M, Ranieri A et al. Hyperhomocysteinemia in Women with Unexplained Sterility or Recurrent Early Pregnancy Loss from Southern Italy: A Preliminary Report. Thrombosis Journal. 2007 Jul; 5(1): 10. doi: 10.1186/1477-9560-5-10. DOI: https://doi.org/10.1186/1477-9560-5-10
Gaber KR, Farag MK, Soliman SE, Abd Al-Kaderm MA. Hyperhomocysteinemia in Recurrent Miscarriage. In Proceedings of the 9. International Conference for Nuclear Sciences and Applications. 2008 Jan; (No. INIS-EG—195): 6-6.
Mukhopadhyay I, Pruthviraj V, Rao PS, Biswas M. Hyperhomocysteinemia in Recurrent Pregnancy Loss and the Effect of Folic Acid and Vitamin B12 on Homocysteine Levels: A Prospective Analysis. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2017 Jun; 6(6): 2258-61. doi: 10.18203/2320-1770.ijrcog20172013. DOI: https://doi.org/10.18203/2320-1770.ijrcog20172013
Bhatia N and Hemanshu B. Hyperhomocysteinemia in Recurrent Pregnancy Loss. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2017 Jul; 6(7): 2919-22. doi: 10.18203/2320-1770.ijrcog20172907. DOI: https://doi.org/10.18203/2320-1770.ijrcog20172907
Qi L, Yang Y, Xie X, Xiang L, Zhang S, Li X et al. Elevated Homocysteine Levels and Endothelial Dysfunction in Unexplained Recurrent Spontaneous Abortion. International Journal of Women's Health. 2025 Dec: 429-37. doi: 10.2147/IJWH.S503677. DOI: https://doi.org/10.2147/IJWH.S503677
Dogan GO and Sahin O. Exploring the Association of Hyperhomocysteinemia with Early Pregnancy Losses: A Retrospective Case–Control Study in A Tertiary Clinic in Türkiye. Medicine. 2024 Aug; 103(32): e39101. doi: 10.1097/MD.0000000000039101. DOI: https://doi.org/10.1097/MD.0000000000039101
Lei F, Zhang L, Wang L, Wu W, Wang F. Association Between Early Spontaneous Abortion and Homocysteine Metabolism. Frontiers in Medicine. 2024 Mar; 11: 1310112. doi: 10.3389/fmed.2024.1310112. DOI: https://doi.org/10.3389/fmed.2024.1310112
Que TT, The NV, Trang VT, Truong LV, Van TT, Phuong DT. Exploring the Sophistications of Unexplained Recurrent Pregnancy Loss: A Case-Control Study. Women's Health. 2024 Nov; 20: 17455057241296608. doi: 10.1177/17455057241296608 DOI: https://doi.org/10.1177/17455057241296608
Annu MM, Govindaraju S, Imam SM, Vasudeva B, Savitha C. Estimation of Homocysteine in Recurrent Pregnancy Loss. Journal of cardiovascular Disease Research. 2024; 15(9).
Li J, Feng D, He S, Wu Q, Su Z, Ye H. Meta-Analysis: Association of Homocysteine with Recurrent Spontaneous Abortion. Women and Health. 2021 Aug 9;61(7):713-20. doi: 10.1080/03630242.2021.1957747. DOI: https://doi.org/10.1080/03630242.2021.1957747
Asanidze E, Kristesashvili J, Parunashvili N, Urjumelashvili M, Tsetskhladze Z, Asanidze A. Hyperhomocysteinemia and Pregnancy Outcomes in Women with Polycystic Ovary Syndrome: A Case-Control Study. International Journal of Reproductive Biomedicine. 2023 Mar; 21(2): 167. doi: 10.18502/ijrm.v21i2.12807. DOI: https://doi.org/10.18502/ijrm.v21i2.12807
MM XZ, MM LY, MM MW, MM XZ. Correlation of Folic Acid Metabolic Gene Polymorphisms, Homocysteine, Vitamin B12, and Red Blood Cell Folate with Adverse Pregnancy Outcomes. Alternative Therapies in Health and Medicine. 2024 May; 30(5): 284-8.
Jawad M and Abdulrasol EA. Comparison of Blood Homocysteine Levels in Women with Unexplained Infertility and Women with Normal fertility. Journal of Emergency Medicine, Trauma and Acute Care. 2024; 2024(5): 8. DOI: https://doi.org/10.5339/jemtac.2024.iscncm.8
Shibbl FA and Sharif YH. The Role of Hyperhomocystinemia in Recurrent Pregnancy Loss. Annals of the Romanian Society for Cell Biology. 2021; 25(6): 10129-37.
Elagab EA, Alshahrani MS, Alasmary MY, Ahmed OY, Seoudi MA, Aedh AI et al. Association Between Hyperhomocysteinemia and Recurrent Miscarriages: A Cross-Sectional Study Set in Saudi Arabia. Bahrain Medical Bulletin. 2022 Sep; 44(3).
Yang X, Tian X, Liu H, Wang J, Wang F. Homocysteine Increases Uterine Artery Blood Flow Resistance in Women with Pregnancy Loss. Journal of Gynecology Obstetrics and Human Reproduction. 2023 Feb; 52(2): 102533. doi: 10.1016/j.jogoh.2023.102533. DOI: https://doi.org/10.1016/j.jogoh.2023.102533
Naim Z, Auda MA, Saddam N. The Effect of Homocysteine, Some Vitamins in Women Who Suffer from Recurrent Miscarriage in Thi-Qar Province/Iraq. Annals of the Romanian Society for Cell Biology. 2021; 25(1): 4840-51.
Jin X, Meng M, Wang X. Comparative Analysis of Plasma Folate, Homocysteine and Erythrocyte Folate Levels in Pregnant Women After Folic Acid Administration During Different Pregnancies. Journal of Medical Biochemistry. 2025 Mar; 44(2): 295. doi: 10.5937/jomb0-52621. DOI: https://doi.org/10.5937/jomb0-52621
Bala R, Verma R, Verma P, Singh V, Yadav N, Rajender S et al. Hyperhomocysteinemia and Low Vitamin B12 Are Associated with the Risk of Early Pregnancy Loss: A Clinical Study and Meta-Analyses. Nutrition Research. 2021 Jul; 91: 57-66. doi: 10.1016/j.nutres.2021.05.002. DOI: https://doi.org/10.1016/j.nutres.2021.05.002
Zejnullahu VA, Zejnullahu VA, Kosumi E. The Role of Oxidative Stress in Patients with Recurrent Pregnancy Loss: A Review. Reproductive Health. 2021 Oct; 18(1): 207. doi: 10.1186/s12978-021-01257-x. DOI: https://doi.org/10.1186/s12978-021-01257-x
Hussain T, Murtaza G, Metwally E, Kalhoro DH, Kalhoro MS, Rahu BA et al. The role of Oxidative Stress and Antioxidant Balance in Pregnancy. Mediators of Inflammation. 2021; 2021(1): 9962860. doi: 10.1155/2021/9962860. DOI: https://doi.org/10.1155/2021/9962860
Qin XY, Ha SY, Chen L, Zhang T, Li MQ. Recent Advances in Folates and Autoantibodies Against Folate Receptors in Early Pregnancy and Miscarriage. Nutrients. 2023 Nov; 15(23): 4882. doi: 10.3390/nu15234882. DOI: https://doi.org/10.3390/nu15234882
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