**Background:** Placenta-mediated complications, including fetal growth restriction, preeclampsia, placental abruption, and recurrent pregnancy loss, complicate 5-15% of pregnancies and contribute significantly to maternal and perinatal morbidity and mortality. Homocysteine, a sulfur-containing amino acid produced from dietary methionine demethylation, has been implicated in placental vasculopathies through mechanisms involving endothelial dysfunction and oxidative stress. Normal pregnancy is associated with declining homocysteine levels due to increased glomerular filtration rate, hemodilution, and fetal uptake. Hyperhomocysteinemia (HHcy), defined as fasting values >15 μmol/L, results from genetic abnormalities in homocysteine metabolism enzymes or deficiencies of cofactor vitamins (folate, B12, B6). While individual studies have reported associations between elevated homocysteine and adverse pregnancy outcomes, results have been inconsistent, prompting this scoping review to synthesize available evidence and identify knowledge gaps.
**Methods:** This scoping review followed PRISMA-ScR and PRISMA-S guidelines. The research question was formulated using the Population, Concept, Context (PCC) format. A computerized search of PubMed and Google Scholar databases was conducted using keywords and medical subject headings related to homocysteine and placenta-mediated complications. Inclusion criteria encompassed cross-sectional studies, prospective cohort studies, case-control studies, systematic reviews, and meta-analyses published in English between 2010 and 2022. Studies were excluded if they were retrospective, non-controlled, or involved participants with chronic hypertension, renal disease, diabetes mellitus, or known causes of recurrent pregnancy loss (incompetent os, fibroid, congenital uterine anomalies). Of 149 articles initially retrieved, 28 duplicates were removed. Two independent reviewers screened titles and abstracts, with disagreements resolved by a third reviewer. Eighteen full-text articles were assessed, and 10 studies met final inclusion criteria. Data extraction captured author details, country, study design, instruments, objectives, participant characteristics, and summary findings.
**Key Results:** The 10 included studies demonstrated consistent associations between elevated homocysteine and placenta-mediated complications. Bibi et al. (2010) studied 332 pregnant women and found higher homocysteine levels in pregnancies affected by eclampsia and preeclampsia, with evidence that folate, vitamin B12, and B6 supplementation reduced homocysteine levels. Acilmis et al. (2011) compared 26 mild preeclampsia, 26 severe preeclampsia, and 26 normal pregnancies, finding significantly elevated maternal and fetal serum homocysteine in severe preeclampsia compared to mild preeclampsia and controls, suggesting homocysteine levels correlate with preeclampsia severity. Mascarenhas et al. (2014) studied 100 women at 8-12 weeks gestation and linked elevated first-trimester homocysteine to preterm birth, hypertensive disorders, history of miscarriages, low birth weight, oligohydramnios, and meconium-stained amniotic fluid. Wadhwani et al. (2015) prospectively followed 62 preeclampsia cases and 126 normotensive controls, finding elevated homocysteine throughout pregnancy in women with preeclampsia. Maru et al. (2016) studied 214 cases (32 eclampsia, 64 moderate preeclampsia, 50 severe preeclampsia, 68 controls) and demonstrated a clear statistical association between homocysteine levels and severity of hypertension and complications. Mukhopadhyay et al. (2017) found an association between hyperhomocysteinemia and recurrent pregnancy loss, with vitamin supplementation reducing homocysteine levels. Gaiday et al. (2018) conducted a systematic review of 1,287 studies, concluding that high homocysteine levels increased the likelihood of placental abruption by 5.3 times, though some findings did not support a correlation with abruption. Chaudhry et al. (2020) conducted the largest cohort study with 7,587 participants, finding that early to mid-second trimester maternal homocysteine elevation independently affected placenta-mediated pregnancy complications. Chamotra et al. (2020) studied 180 pregnant women (57 exposed, 123 unexposed), finding significantly higher mean homocysteine in the exposed group and increased rates of low APGAR scores and NICU admissions among neonates born to mothers with hyperhomocysteinemia. Oluwole et al. (2020) studied 200 participants in Lagos, Nigeria, reporting a relatively low rate of maternal hyperhomocysteinemia but associations with adverse pregnancy outcomes.
**Clinical Implications:** The review supports that elevated maternal homocysteine in early pregnancy is associated with placenta-mediated complications, particularly hypertensive disorders of pregnancy and adverse perinatal outcomes. Serum homocysteine testing is described as quick, simple, and potentially reliable as a predictive marker for pregnancy-induced hypertension and related complications. However, the authors note several limitations: heterogeneity in study designs, varying timing of homocysteine measurement across trimesters, lack of standardized cut-off values for specific complications, and absence of meta-analysis. The review identifies critical knowledge gaps including the need to determine optimal gestational timing for homocysteine screening (proposed at 10-14 weeks), establish complication-specific threshold values, investigate genetic components (particularly MTHFR gene mutations), and conduct larger-scale prospective studies across diverse populations. The authors conclude that while evidence supports the association between hyperhomocysteinemia and placenta-mediated complications, further research is necessary to translate these findings into clinical screening protocols and preventive interventions.