Do Antioxidants Prevent Premature Rupture of Membranes?
Abstract & Commentary
By Dónal P. O'Mathúna, PhD. Dr. O'Mathúna is Senior Lecturer in Ethics, Decision- Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship to this field of study.
Source: Spinnato JA II, et al. Antioxidant supplementation and premature rupture of the membranes: A planned secondary analysis. Am J Obstet Gynecol 2008;199: 433.e1-433.e8.
The purpose of this study was to determine if antioxidant supplementation during pregnancy reduces the incidence of premature rupture of the membranes (PROM). A placebo-controlled, double-blind trial was conducted. PROM and preterm PROM (PPROM) were planned secondary outcomes of the trial. Women between 12 and 19 weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were randomized to daily treatment with both vitamin C (1,000 mg) and E (400 IU) or placebo. Outcome data for PROM were available for 697 of 739 patients. The rates of PROM (37/349 [10.6%] vs 19/348 [5.5%]; adjusted risk ratio [RR], 1.89; 95.42% confidence interval [CI], 1.11-3.23; P = 0.015), and PPROM (16/349 [4.6%] vs 6/348 [1.7%]; RR, 2.68; CI, 1.07-6.71; P = 0.025) were increased in the antioxidant group. Contrary to expectations, vitamins C and E supplementation in this dose combination may be associated with an increased risk of PROM and PPROM.
Commentary
Preterm delivery occurs in approximately one of every eight births in the United States and has been on the increase in recent decades.1 Approximately one-third of preterm deliveries are preceded by premature rupture of the membranes (PROM). This is associated with higher risk of perinatal infection and compression of the umbilical cord. The acronym PPROM refers to preterm PROM, which occurs prior to 37 weeks of gestation. Much remains to be understood about the causes of PROM and PPROM, methods of prevention, and the optimal approaches to clinical assessment and management.1
Fetal membranes derive their strength and elasticity primarily from collagen. In 2001, based on evidence from previous studies, a hypothesis was put forward that PROM could result from interference with collagen integrity and strength caused by reactive oxygen species (ROS).2 This group of highly reactive chemicals is continuously generated in the body and plays an important role in destroying microorganisms. However, overproduction of ROS can damage healthy tissues. The body uses antioxidants to neutralize ROS and keep their levels within appropriate ranges. Several risk factors for PROM and PPROM are associated with increased ROS levels. These include infections, cigarette smoking, vaginal bleeding, and use of cocaine. While these factors may not directly impact collagen in fetal membranes, they can consume antioxidants, leaving fetal membranes more vulnerable to ROS.
Vitamins E and C are antioxidants and have been proposed to have a number of health-promoting benefits. Vitamin E inhibits the membrane-damaging effects of ROS and vitamin C stimulates and protects collagen synthesis and recycles vitamin E. The primary outcome of the randomized, double-blind clinical trial reviewed here was the development of preeclampsia. The women enrolled were 12-19 weeks pregnant and had been diagnosed with nonproteinuric chronic hypertension or had a history of preeclampsia in their most recent pregnancy that went beyond 20 weeks. The enrolled women were randomized to daily treatment with both vitamin E (400 IU) and C (1,000 mg) or placebo.
The results were not what were expected. According to the intention-to-treat analysis, the vitamin group was significantly more likely to have PROM (10.6% vs 5.5%; P = 0.015) and PPROM (4.6% vs 1.7%; P = 0.025). To check for compliance with protocol, participants were asked to return any unused pills. Those who returned less than 20% of the pills they were expected to consume were classified as compliant. In a subgroup analysis of the compliant patients, those taking vitamins had a significantly higher incidence of PROM (P = 0.029) but not PPROM (P = 0.16). The number of compliant participants with PPROM was small, with 10 in the vitamin group and 5 in the placebo group. No significant differences were found between the two groups for the frequency of stillbirth, preterm delivery, low birthweight, small for gestational age, or Apgar scores.
The unexpected findings from this study have to be examined in light of some of its limitations. The participants were at risk for preeclampsia, which may limit the applicability of the results to the general population. The study was conducted at four sites in Brazil, which may also limit its generalizability. The particular combination of antioxidants, dose, timing, or pharmaceutical preparation may have impacted the findings. One earlier randomized controlled trial found significantly reduced incidence of PROM in women taking 100 mg vitamin C during pregnancy.3
The combination of vitamins used in this study cannot be recommended for women at risk of preeclampsia or PROM. Other studies with different antioxidants and doses may be warranted, but should be conducted with caution given the increased risk of PROM and PPROM found in this study. This is not the first time that antioxidants proposed as having beneficial effects based on epidemiological or theoretical understandings were later found in randomized controlled trials to have no significant benefits or to put people at higher risk of adverse effects.4
References
1. ACOG Committee on Practice Bulletin-Obstetrics. ACOG Practice Bulletin No. 80: Premature rupture of the membranes. Clinical management guidelines for obstetrician-gynecologists. Obstet Gynecol 2007;109: 1007-1019.
2. Woods JR Jr, et al. Vitamins C and E: Missing links in preventing preterm premature rupture of membranes? Am J Obstet Gynecol 2001;185:5-10.
3. Casanueva E, et al. Vitamin C supplementation to prevent premature rupture of the chorioamniotic membranes: A randomized trial. Am J Clin Nutr 2005; 81:859-863.
4. Miller ER III, et al. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.
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