The goal of this randomized, double-blind, placebo-controlled clinical trial is to verify if 3-month oral supplementation with resveratrol can enhance the oocyte quality in advanced maternal age women undergoing in vitro fertilization (IVF).

Participants will take a daily capsule of resveratrol or placebo during the 3 months preceding their IVF treatment. They will then follow the same treatment protocol as non-participant patients.

The study will be conducted in the Reproductive Medicine Unit of an Academic Hospital.

Eligible participants who meet the inclusion and exclusion criteria will be randomly assigned to one of the following groups:

1. Resveratrol (study group) or
2. Placebo (control group).

Supplementation

Women in the study group will take a daily capsule of 200 mg Polygonum cuspidatum (Solgar®, Dietimport, Lisboa, Portugal) yielding 100 mg/day resveratrol (trans-3,5,4'-trihydroxystilbene). Women from control group will take a daily capsule of 400 mcg folic acid (Solgar®, Dietimport, Lisboa, Portugal), a vitamin widely prescribed to women who intend to achieve pregnancy for prevention of neural tube defects). Participants will be instructed to take the capsules by morning, every day during the 3 months preceding their IVF treatment. Oral intake of resveratrol/placebo will be discontinued after oocyte retrieval due to the potential adverse effects of resveratrol on endometrial decidualization. Package of resveratrol and placebo will be identical. Compliance of the participant to the intervention will be measured using capsule count. Participants will be asked to keep their usual lifestyle including nutrition and physical activity level.

Ovarian stimulation

GnRH antagonist protocol will be used in all the patients. On day 2 or 3 of the menstrual cycle, daily subcutaneous (SC) injections of rFSH are given up to the day of human chorionic gonadotropin (hCG) administration, when at least three leading follicles reached a mean diameter of 17 mm. Doses of rFSH range from 150 to 300 IU/day depending on the women's age, body mass index (BMI), AFC and AMH. Administration of a daily dose of 0.25 mg of gonadotropin releasing hormone antagonist (GnRHa) (Cetrotide ®, Merck, Netherlands; or Orgalutran ®, Organon, Netherlands) is initiated when the larger follicle reaches a mean diameter of 14 mm. Transvaginal oocyte retrieval is scheduled to 36 hours after choriogonadotropin alfa (α-hCG) administration. Luteal phase support with progesterone is initiated on the day of the oocyte retrieval with 200 mg of micronized intravaginal progesterone every 8 hours (Progeffik ®, EFIKK, France).

In vitro fertilization and embryo transfer

According to the couples's indication, IVF or ICSI is performed. Fertilization is assessed after 18 hours, and oocyte maturational stage is assessed and registered. Embryo cleavage is assessed every 24 hours. Embryo transfer is performed 5 days after oocyte retrieval under ultrasound guidance. All remaining good quality embryos will be vitrified and transferred in subsequent menstrual cycles. If fresh transfer is canceled for clinical reasons, frozen embryo transfer will also be scheduled. Before frozen embryo transfer, patients will start exogenous hormone therapy for endometrial preparation. This therapy is initiated on day 1 of menstrual cycle and consists of 150 mcg of estradiol transdermal patches (Dermestril®, BGP, Lisboa, Portugal) replaced every 3 days. On day 12-14, a pelvic ultrasound is performed to assess endometrial development. If the endometrial thickness is > 7 mm, 400 mg vaginal micronized progesterone (Cyclogest®, Gedeon Richter, Budapest, Hungria) twice daily was added to the treatment scheme. Fourteen days after oocyte retrieval a quantitative serum value of β-hCG is obtained and a transvaginal ultrasound is scheduled one week later in case of a positive result (biochemical pregnancy). Clinical pregnancy is established by the ultrasonography visualization of a gestational sac. Ongoing pregnancy was defined by a viable intrauterine pregnancy of at least 12 weeks duration confirmed on an ultrasound scan. The outcomes of fresh and vitrified-warmed embryo transfer will be analyzed. Live birth was defined as the delivery of one or more live babies. Miscarriage was defined by a spontaneous pregnancy termination before the gestational age of 12 weeks.

Inclusion Criteria:

• Women with infertility undergoing IVF/ICSI
• Ovarian stimulation with GnRH-antagonist protocol
• Age 35-40 years old

Exclusion Criteria:

• Severe male factor (oligospermia or azoospermia)
• Low ovarian reserve (AMH < 1.1. ng/mL)
• Poor response to ovarian stimulation (< 3 oocytes)
• Polycystic ovarian syndrome (Rotterdam criteria)
• Ovarian endometriosis (endometrioma > 30 mm)
• Uterine anomalies (congenital or acquired)
• Diabetes Mellitus
• Concurrent use of any vitamin (except folic acid)

Patients, physicians, and embryologists will be blinded to group assignments of the participants in the trial.