Vitamin C Levels in Pregnant Women and the Efficacy of Vitamin C Supplements in Preventing Premature Rupture of Membranes: A Systematic Review and Meta-Analysis

Abstract

Background: Premature rupture of membranes (PROM) is defined as the leakage of amniotic fluid before the onset of labor and delivery contractions. Some studies found that women who experienced PROM had significantly lower vitamin C blood levels than those who did not, while others found no significant differences. Previous systematic reviews and meta-analyses on the efficacy of vitamin C in the prevention of PROM had conflicting results.

Aims: Conduct a systematic review and meta-analysis to determine if there was a significant difference in vitamin C blood levels in women who had PROM versus the control group who did not and to determine if vitamin C supplements could help prevent it.

Study design: Systematic review and meta-analysis.

Methods: We registered our protocol with PROSPERO (CRD42022371644). We searched PubMed/MEDLINE, Web of Science, and Scopus through February 15, 2024. Additionally, backward and forward citation searches were conducted. Studies were selected based on predetermined inclusion and exclusion criteria. Meta-Essentials: Workbooks for Meta-Analysis (version 1.5) was used for analysis.

Results: Twenty-five studies (26 reports) met all eligibility criteria, with 18 studies (18 reports) assessing vitamin C levels and seven studies (eight reports) evaluating efficacy. Women with PROM, whether preterm or term, had significantly lower vitamin C levels [Hedges’ g, -1.48; 95% confidence interval (CI): -2.82, -0.14; p = 0.020; I² = 94.08%) and specifically preterm PROM after removing the outlying study [Hedges’ g, -1.29; 95% CI: -1.85, -0.73; p < 0.001; I² = 87.35%). Vitamin C supplementation significantly reduced the risk of preterm or term PROM [risk ratio (RR), 0.57; 95% CI: 0.39, 0.81; p < 0.001; I² = 12.17%), particularly for preterm PROM (RR, 0.67; 95% CI: 0.45, 0.99; p = 0.001; I² = 0.00%). There were no significant differences in vitamin C levels between women with term PROM and controls, and there were no differences in the risk of developing term PROM between women taking vitamin C supplements and controls. Results were not robust in all sensitivity analyses.

Conclusion: Women with PROM, particularly those who developed it preterm, appear to have significantly lower vitamin C levels, and vitamin C supplementation appears to be effective in reducing the risk of PROM, particularly preterm PROM. More high-quality studies with low risk of bias, more homogenous, and larger samples are needed to confirm these findings.

Figure 1

Results of the search and selection process (PRISMA flow diagram). PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analysis.

Figure 2

Risk of bias assessment of efficacy studies according to RoB 2 tool. RoB, Risk of Bias 2.

Figure 3

Forest plots showing effect sizes of differences in vitamin C levels between women with PROM regardless of whether it was preterm or term, PPROM or TPROM and controls. PROM, Premature rupture of membranes; PPROM, preterm premature rupture of membranes; TPROM, term premature rupture of membranes; CI, confidence interval.

Figure 4

Forest plots showing effect sizes of the efficacy of vitamin C supplementation in prevention of PROM regardless of whether it was preterm or term, PPROM and TPROM. PROM, Premature rupture of membranes; PPROM, preterm premature rupture of membranes; TPROM, term premature rupture of membranes; CI, confidence interval.

Figure 5

Funnel plots with trim-and-fill analysis for comparisons of vitamin C levels between women with PROM regardless of whether it was preterm or term and controls and PPROM and controls. PROM, Premature rupture of membranes; PPROM, preterm premature rupture of membranes.