Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility
Overview
- Phase
- Phase 3
- Intervention
- Moderate physical activity
- Conditions
- Infertility, Female
- Sponsor
- Yale University
- Enrollment
- 379
- Locations
- 10
- Primary Endpoint
- Rate of Good Birth Outcomes
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
A two-arm, multicenter, prospective, randomized clinical trial of a lifestyle modification program with tracked increased physical activity and weight loss (intensive) compared to recommendations to tracking of increased physical activity alone with weight maintenance (standard) in women with obesity and unexplained infertility. This 16 week period of lifestyle modification will be followed by an open label empiric infertility treatment regimen consisting of three cycles of ovarian stimulation with oral medication (clomiphene citrate (CC)), triggering of ovulation with human chorionic gonadotropin (hCG) and intrauterine insemination (IUI).
Detailed Description
Study Objective An intensive lifestyle modification intervention (which includes caloric restriction, use of an over-the-counter weight loss medication, and moderate physical activity with tracking) designed to promote a weight loss of approximately 7% of initial body weight is more likely to achieve a good perinatal outcome (i.e. a healthy term normal weight infant) than a recommendation to standard lifestyle modification with moderate physical activity with tracking (based on publically available activity recommendations) in obese women with unexplained infertility. Patient Population The population will consist of 380 obese women with unexplained infertility, age 18-40 years old. Subjects must have normal ovulatory function and normal ovarian reserve. Additionally, the couple will have no other major infertility factor: the subject will have at least one patent fallopian tube and a normal uterine cavity, and a partner total motile sperm count of at least 5 million in at least one ejaculate. Study Design This will be a two-arm, multicenter, prospective, randomized clinical trial of a lifestyle modification program with tracked increased physical activity and weight loss (intensive) compared to recommendations to tracking of increased physical activity alone with weight maintenance (standard) in women with obesity and unexplained infertility. This 16 week period of lifestyle modification will be followed by an open label empiric infertility treatment regimen consisting of three cycles of ovarian stimulation with oral medication (clomiphene citrate (CC)), triggering of ovulation with human chorionic gonadotropin (hCG) and intrauterine insemination (IUI). Treatment The intensive lifestyle modification intervention will consist of caloric restriction (consumption of approximately 1200-1500 kcal/d), use of an over-the-counter weight loss medication (Alli, which is brand name Orlistat, a gastric lipase inhibitor that limits gut fat absorption), and moderate physical activity (goal of reaching 10,000 steps a day). The pretreatment intervention will last 16 weeks and is designed to promote a weight loss of approximately 7% of total body weight. Women in the standard lifestyle intervention (standard) will receive publicly available written materials that promote engagement in moderate physical activity with target of 10,000 steps a day. Detailed instruction of physical activity will not be provided. Participants in both groups will receive activity tracking devices (Fitbit Wireless Activity Tracker) and wireless scales (Fitbit Aria Wireless Activity Scale) to promote adherence to the inventions and to allow monitoring for compliance by study personnel. The pretreatment intervention will last 16 weeks. Both groups will aim for activity levels of 10,000 steps/day, with a recommendation to increase steps from baseline by 500 steps/per week. The investigators will monitor subjects monthly during this preconception intervention. After 16 weeks of lifestyle modification, all subjects randomized will receive a standardized empiric infertility treatment, regardless of adherence or success in achieving treatment goals. This treatment will consist of ovarian stimulation with CC followed by ultrasound follicular monitoring, hCG trigger of ovulation, and a single partner intrauterine insemination (IUI) per treatment cycle for up to three treatment cycles. The goal for both treatment groups will be to maintain levels of physical activity and weight achieved during the pretreatment phase during the empiric infertility treatment phase. Subjects who conceive will be followed throughout pregnancy with the wireless activity monitor and wireless scale. Additionally there will be three brief onsite visits during pregnancy (per trimester at 16, 24, and 32 weeks) for onsite determination of weight, glycemic, and blood pressure changes and collection of biospecimens. All pregnancy outcomes will be tracked. Subjects who deliver will be encouraged to donate placenta and cord blood to the study repository and then to enroll in our Pregnancy Registry for continued infant follow-up. The investigators will also expand the number and variety of specimens that are collected for the repository from both partners including urine and serum, semen, saliva, placenta and cord blood.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Women ≥18 to ≤ 40 years of age, with one or more years infertility history, desirous of conceiving, regularly ovulating (defined as 9 or more menses per year), at initiation of participation.
- •BMI ≥ 30 kg/m
- •Normal uterine cavity and at least one open fallopian tube confirmed by hysterosalpingography (HSG), sonohysterography (SHG), or laparoscopy/hysteroscopy in the last three years preceding enrollment into the study. An uncomplicated intrauterine non-IVF pregnancy and uncomplicated delivery and postpartum course resulting in live birth within the last three years will also serve as sufficient evidence of a patent tube and normal uterine cavity as long as the subject did not have, during the pregnancy or subsequently, risk factors for Asherman's syndrome or serious pelvic infection or other disorder leading to an increased suspicion for intrauterine abnormality or tubal occlusion.
- •Evidence of ovarian function/reserve as assessed by menstrual cycle day 3 (+/-2 days) FSH ≤10 IU/L with estradiol ≤ 70 pg/mL OR AMH ≥ 1 ng/mL within one year prior to study initiation.
- •Normal or corrected thyroid function within one year of study initiation.
- •Normal or corrected prolactin level within one year of study initiation.
- •In general good health, not taking any medications which could interfere with the study (e.g., FSH, insulin sensitizers).
- •Ability to have inseminations following hCG administration.
- •Male partner with total motile sperm in the ejaculate of at least 5 million sperm, within one year of study initiation.
- •Able to comply with intercourse instructions and collection of semen for insemination.
Exclusion Criteria
- •Currently pregnant or successful pregnancies within 12 months of initiating participation. Clinical intrauterine miscarriages prior to initiating participation, within ASRM guidelines: subjects over 35 must wait six months, while subjects under 35 must wait 12 months. No exclusion for biochemical pregnancies.
- •Undiagnosed abnormal uterine bleeding.
- •Suspicious ovarian mass.
- •Subjects on oral contraceptives, depo-progestins, or hormonal implants (including Implanon). A two month washout period will be required prior to screening for patients on these agents. Longer washouts may be necessary for certain depot contraceptive methods or implants, especially when the implants are still in place. A one-month washout will be required for patients taking oral cyclic progestins.
- •Known 21-hydroxylase deficiency or other enzyme defect causing congenital adrenal hyperplasia.
- •Type I or Type II diabetes mellitus, or if receiving antidiabetic medications.
- •Known significant anemia (Hemoglobin \<10 g/dL).
- •History of deep venous thrombosis, pulmonary embolus, or cerebrovascular event.
- •Known heart disease (New York Heart Association Class II or higher).
- •Known Liver disease (defined as AST or ALT\>2 times normal, or total bilirubin \>2.5 mg/dL).
Arms & Interventions
Intensive Lifestyle Mod. Intervention
The intensive lifestyle modification intervention will consist of caloric restriction (consumption of approximately 1200-1500 kcal/d), use of an over-the-counter weight loss medication (Alli, which is brand name Orlistat, a gastric lipase inhibitor that limits gut fat absorption), and moderate physical activity (goal of reaching 10,000 steps a day). The pretreatment intervention will last 16 weeks and is designed to promote a weight loss of approximately 7% of total body weight.
Intervention: Moderate physical activity
Intensive Lifestyle Mod. Intervention
The intensive lifestyle modification intervention will consist of caloric restriction (consumption of approximately 1200-1500 kcal/d), use of an over-the-counter weight loss medication (Alli, which is brand name Orlistat, a gastric lipase inhibitor that limits gut fat absorption), and moderate physical activity (goal of reaching 10,000 steps a day). The pretreatment intervention will last 16 weeks and is designed to promote a weight loss of approximately 7% of total body weight.
Intervention: Caloric Restriction
Intensive Lifestyle Mod. Intervention
The intensive lifestyle modification intervention will consist of caloric restriction (consumption of approximately 1200-1500 kcal/d), use of an over-the-counter weight loss medication (Alli, which is brand name Orlistat, a gastric lipase inhibitor that limits gut fat absorption), and moderate physical activity (goal of reaching 10,000 steps a day). The pretreatment intervention will last 16 weeks and is designed to promote a weight loss of approximately 7% of total body weight.
Intervention: Orlistat
Standard Lifestyle Intervention
Women in the standard lifestyle intervention (standard) will receive publicly available written materials that promote engagement in moderate physical activity with target of 10,000 steps a day. Detailed instruction of physical activity will not be provided.
Intervention: Moderate physical activity
Outcomes
Primary Outcomes
Rate of Good Birth Outcomes
Time Frame: At time of birth, approximately 17 months into the study
Defined as a live birth of an infant born at ≥ 37 weeks, with a birth weight between 2500 and 4000g and without a major congenital anomaly
Secondary Outcomes
- Live Birth Rate(At time of birth, approximately 17 months into the study)
- Time to Pregnancy in Days(0-8 months)
- Pregnancy Loss Rate(After conception, 0-13 months into the study)
- Multiple Pregnancy Rate(After conception, 1-13 months into the study)
- Birth Weight in Grams(at time of birth, approximately 17 months into the study)
- Mode of Delivery-Cesarean Section(At time of birth, approximately 17 months into the study)