Klotho in placenta related pregnancy complications: A systematic review and meta-analysis

Background: Klotho is an anti aging protein implicated in oxidative stress regulation, endothelial protection, placental senescence, and fetal growth. Its role in placenta related pregnancy complications remains unclear. To systematically review the evidence on Klotho in placenta related pregnancy complications and to quantitatively synthesize eligible studies. Methods: This systematic review and meta-analysis was reported in accordance with the PRISMA 2020 statement. Of 54 records identified, 9 studies were included in the systematic review and 7 in the meta-analysis. Study quality was assessed using a structured tool for non randomized studies. Random-effects models with Hartung-Knapp adjustment were used to calculate pooled standardized mean differences as Hedges' g with 95% confidence intervals (CIs). Results: Most included studies suggested reduced Klotho expression in placenta related pathological pregnancies. Meta-analysis showed significantly lower serum Klotho levels in pregnancies complicated by intrauterine growth restriction, fetal growth restriction, and small for gestational age (Hedges'g = -1.07, 95% CI: -1.34 to -0.80) and in pregnancies with adverse fetal outcomes (Hedges'g = -1.13, 95% CI: -1.29 to -0.97). Placental Klotho levels were also significantly reduced in pregnancy complications (Hedges'g = -1.35, 95% CI: -1.80 to -0.90). By contrast, pooled associations for serum Klotho in preeclampsia and overall pregnancy complications were not statistically significant due to substantial heterogeneity. Conclusions: Reduced Klotho is consistently associated with placental dysfunction, particularly in pregnancies with fetal growth impairment and adverse fetal outcomes. Placental Klotho appears to provide a more stable signal than circulating Klotho.