Vitamins C and E to Prevent Complications of Pregnancy Associated Hypertension James M. Roberts, M.D., Leslie Myatt, Ph.D.,et al. New England Journal of Medicine 2010;362 R3 Min Kyung Kim/Prof. Woo Shik Kim

Back ground Pregnancy associated Hypertension Clinical findings Chronic HTN* Gestational HTN Preeclamsia Time of onset HTN <20 weeks third trimester† ≥20 weeks Degree of HTN Mild or severe Mild Proteinuria‡ Absent Usually present Thrombocytopenia Severe disease Hepatic dysfunction *Before pregnancy of diagnosed before 20 weeks † Third trimester is from week 27 to the end of the pregnancy ‡Defined as ≥1+ by dipstick testing on two occasions or ≥ 300mg/24hrs Gestational age 0 day 20 weeks 27weeks delivery

Back ground Preeclampsia 16% of pregnancy-related deaths Preeclamsia: 10% of pregnancy Hypertensive disorders in pregnancy are most significant unsolved problems in obstetrics 2005% 2006% 전 체% Pregnancy associated hypertension 19.7 12.1 15.7 중증의 전자간증 8.2 4.5 6.3 상세불명의 전자간증 1.6 6 3.9 임신 자간증 4.9 1.5 3.1 산후 자간증 0.8 시기 상세불명의 자간증 3.3 Bleeding 26.2 27.3 26.8 Thromboembolism 21.3 13.6 17.3

Reactive oxygen species Preeecalmpsia: two stage disorder Abnormal placentation or perfusion  Inflammatory response Endothelial dysfunction characteristic maternal syndrome Cytokine ↑(TNF-α,IL-6) Oxidative stress: Reactive oxygen species

Back ground Antioxidant supplementation with vitamins C and E Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial Lancet 1999; 354: 810–16 Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease. But larger randomized trials involving women at high risk and women at low risk. None of these studies replicated the original positive findings. To detect a modest effect size in serious outcomes associated with preeclampsia among low risk women with treatment beginning early in the pregnancy

Methods Exclusion criteria Inclusion criteria 31,917 women 13,113 run in 10,154 randomization 4,993 Vitamins C and E 4,976 Placebo Period: 2003.07-2008.02 Double blind randomization Run in period 2wk Delivery Proteinuria, Uterine problems(ex.bleeding), fetal problems(ex.anomaly),in vitro ferilization, abuse of illicit drugs or alcohol Taking Vit C ≥ 150mg, ≥ 75IU vitamin E antiplatelet drugs, NSAIDs Inclusion criteria Screening: Singleton with GA<16wks 0d Randomization: 9wks 0d-16wks 6d

+ One or more of the following Preterm birth (<30wks) by HTN Fetal/neonatal death Primary outcome Severe pregnancy associated hypertension alone (Severe SBP≥160mmHg ,DBP≥110mmHg) Severe or mild pregnancy associated hypertension (mild:SBP 140-159, DBP 90-109) + One or more of the following Secondary outcome Pulmonary edema Thrombocytopenia < 100,000/m3 HELLP syndrome : -complication of severe preeclamasia -Hemolysis, Elevated liver enzyme, Low platelet Preeclamsia Mild Severe proteinuria 300mg/24hrs 5g/24hrs ≥ +2 dip stick oliguria Pro/Cr ≥ 0.35

Study population Taking a Vitamin at the time of randomization: 77% Compliance in both group: 88% Reported side effect (ex. Nausea, vomiting):  no significant deference

Pirmary outcome There was no significant between group difference in any component of the primary outcome

Secondary outcome No benefit of therapy

Results Neonatal outcome Rates of adverse neonatal outcomes also did not differ significantly between the groups

Summary and Conclusion Supplementation with vitamin C (at a dose of 1000 mg daily) and vitamin E (at a dose of 400 IU daily) did not reduce the rates of either serious adverse outcomes of pregnancy associated hypertension or preeclampsia among low-risk, nulliparous women. Previous studies have shown a similar lack of efficacy among high-risk women among women who were likely to have had a deficiency of vitamins C and E The findings of these several studies provide no support for the use of vitamin C and E supplementation in pregnancy to reduce the risk of preeclampsia or its complications