This randomized double-blind clinical trial was conducted in Iran in women with cervical intraepithelial neoplasia (CIN) I, as diagnosed with pap smear, colposcopy and biopsy. Women were between the ages of 18 to 55 and had proven CIN 1 based on pap smear cytology and then colposcopy and biopsy. Only those with biopsy proven CIN 1 were included. Women were excluded if they had a history of cervical cancer, other cancers of the lower genital tract, hysterectomy, past treatment of the cervix with cell destructive therapy (ex/ cryotherapy, cautery, conizations), pregnant women or if they were using anti-folate medications.
Women were randomly assigned to receive 5 mg/day of folate (n=29) or placebo (n=29) for 6 months. While the study reports “folate”, it does not clarify if it was in fact folic acid or a form of folate, however, compliance was assessed measuring plasma homocysteine levels. Women were advised not to change their diet or physical activity during the 6 months.
The primary outcome was histology proven CIN 1 and was determined through pap smear cytology, colposcopy and cervical biopsy. Secondary outcomes were glucose homeostasis, lipid profiles, inflammatory factors and biomarkers of oxidative stress.
Four women in the folate group and 5 in the placebo group did not complete the trial, although all 58 women were included in the final analysis. After 6 months of 5 mg/day of folate supplementation or placebo, a greater percentage of women in the folate group had a regression of their CIN 1. (83.3% vs. 52.0%). One patient in the each group progressed to CIN-II. Folate supplementation resulted in a significant decrease in serum insulin, homocysteine, HOMA-B and plasma malondialdehyde, and increased glutathione levels, but it did not affect lipids, reduce fasting glucose, or affect inflammatory or oxidative stress markers.
Commentary: CIN develops in a linear fashion and those with CIN are susceptible to cervical cancer, with greater risks for those who have higher grade lesions (CIN-II, CIN-III), and those with the high risk human papilloma virus (HPV) types, especially HPV 16 and 18. The current study reports that women taking folate (unknown form) at 5 mg/day for 6 months resulted in more women having regression of their CIN 1 to normal, than those in the placebo group. However, it is important to keep in mind that the rates of spontaneous regression of CIN 1, with no treatment, are between 60% and 85% within a 2-year time period. The question in my mind is: Were these results meaningful and due to folate supplementation or within the range of normal regression, whether folate or placebo? Select previous research has found an inverse association between folate levels in the serum and folate in the diet and CIN, while other research did not find a significant relationship. In controlled clinical studies, folic acid supplementation (10 mg/day) has resulted in the improvement or normalization of cytology smears in patients with cervical dysplasia. When patients were treated with folic acid, the regression-to-normal rate, as determined by colposcopy/biopsy examination, was observed to be 20% in one study, 63.7% in another, and 100% in yet another.
Given the totality of the research on folic acid, I will continue to use 5-10 mg/day. As part of my total treatment plan for CIN 1, I typically use 10 mg/day for 6 months, and if cytology/pathology results are then normal, I adjust the treatment plan, including reducing the folate to 5 mg/day for another 6 months. There is a small amount of evidence that women with MTHFR mutations that affect folate metabolism, may have higher risk of cervical cancer. Practitioners could consider testing MTHFR in those women with abnormal pap smears, to determine if supplementation with folic acid or the more expensive folate is an important part of the treatment plan based on MTHFR results.
Asemi Z, Vahedpoor Z, Jamilian M, et al. Effects of long-term folate supplementation on metabolic status and regression of cervical intraepithelial neoplasia: A randomized, double-blind, placebo-controlled trial. Nutrition 2016; 32 (6): 681-6