Fit-for-Fertility Multicenter Randomized Controlled Trial
Fit-for-Fertility Multicenter Randomized Controlled Trial
Infertility affects approximately 10-15% of couples and one of its important modifiable risk
 factor is obesity, which affects 19% of Canadian women of reproductive age. Accordingly, many
 organizations have recommended that women should be assisted to adopt a healthy lifestyle
 prior to conception and maintain it during pregnancy. We therefore propose to conduct a
 multicenter randomized controlled trial (RCT) assessing the lifestyle intervention
 Fit-For-Fertility in women with infertility and obesity. Our hypothesis is that the
 Fit-For-Fertility program is an efficient and low cost solution to improve access to
 motherhood for women suffering from obesity and infertility.

 To test our hypothesis, seven fertility clinics having a good ethnic diversity will
 participate in this RCT and recruit a total of 616 women with obesity (BMI according to
 ethnicity) who consult at the fertility clinic. Participants will be randomly allocated to
 one of these two groups: the intervention group will be invited to participate in the Fit-for
 Fertility Program alone for 6 months and then in combination with usual fertility treatments;
 while the control group will receive standard fertility treatments from randomisation. The
 aim of the Fit-for Fertility Program will be to implement progressive and sustainable
 lifestyle changes, using 1) individual sessions with a dietitian and a kinesiologist every
 6-12 weeks, for a total of 18 months or until the end of pregnancy; and 2) eight educational
 group sessions. Evaluation visits will take place prior to randomisation and then every 6
 months for 18 months. Women who become pregnant will be evaluated early during pregnancy and
 at 26 weeks of gestation. Clinical outcomes will be assessed after a total follow up of 24
 months.

 Anticipated contributions: The results of our multicenter RCT will provide important data on
 the importance of a lifestyle program supporting women with obesity consulting in fertility
 clinics, in order to improve their fertility and response to ART, as well as helping them to
 have a healthy baby. This study will also provide valuable information on potential cost
 savings for individuals and the healthcare system.
1. BACKGROUND

 Infertility affects approximately 10-15% of couples and costs associated with medically
 assisted reproduction (MAR) are growing, such that equitable access to high quality
 reproductive care is a challenge for the Canadian health care system. This is especially
 true for women with obesity. A modifiable risk factor for infertility is obesity (body
 mass index (BMI) >= 30 kg/m2), which accounts for as many as 19% of Canadian women of
 reproductive age. Moreover, obesity increases the costs of fertility treatments, reduces
 their effectiveness and predisposes to several pregnancy and neonatal complications. As
 important, maternal pre-pregnancy BMI and excessive gestational weight gain were
 consistently associated with early development of obesity and diabetes in the offspring.
 Childhood obesity is closely linked to adult obesity, which perpetuates the
 intergenerational cycle of obesity. Accordingly, we strongly believe that targeting
 women with obesity prior to conception may be essential to reduce the burden of
 infertility and MAR costs in Canada, as well as obesity and cardiometabolic diseases.

 To prevent these adverse effects, many organizations have recommended that obese women
 should be assisted to adopt a healthy lifestyle prior to conception and maintain it
 during pregnancy. In a recent survey, all women who were obese or overweight and
 considering pregnancy were interested in adopting a healthy lifestyle pre-conception and
 91% reported their willingness to participate in a lifestyle program. However, most
 Canadian women with obesity do not have access to such targeted lifestyle programs
 integrated with their fertility care. Our solution is therefore to give these women
 access to the Fit-for-Fertility Program, an interdisciplinary lifestyle intervention,
 integrated into the fertility clinic care pathway. This program supports participants in
 their adoption of sustainable healthy behaviours, prior conception and during pregnancy.

 To fill these gaps, in 2010 Dr. Baillargeon set up the Canadian network on reproductive
 and maternal health of women with obesity and infertility. Through this network, our
 team has conducted a CIHR-funded RCT evaluating the impact of the Fit-for-Fertility
 Program, which was implemented at the fertility clinic of the Centre hospitalier
 universitaire de Sherbrooke (CHUS), on 130 obese women randomized to 1) Control group:
 standard fertility treatments right away; or 2) Intervention group: follow the
 Fit-for-Fertility program alone for 6 months, then in combination with fertility
 treatments if not pregnant. The analysis of the 108 women who completed at least 6
 months in the study (83%) shows that after a maximum follow-up of 18 months and in
 comparison with the standard fertility treatments (n = 57), the Fit-for-Fertility
 program (n = 51) significantly increased the rates of total pregnancy (61% vs. 39%, p =
 0.02) and spontaneous pregnancy (31% vs. 12%, p = 0.01), as well as a tendency to
 increase live birth (51% vs. 37%, p = 0.14). Such results from the pilot study are
 highly clinically significant. The total cost of this intervention was only $870 per
 participant, as compared to standard fertility care costs averaging $4,400 per woman
 with obesity in the above-mentioned trial. As such, these preliminary results thus
 suggest that our low-cost lifestyle intervention for women who are obese and infertile
 may significantly improve their fertility and reduce the need for expensive MAR. These
 promising findings provide strong justification for further validation in diverse
 Canadian populations using a multicenter trial.

 The general goals of our research program are therefore to i) improve the fertility of
 women with obesity, ii) reduce costs associated with their fertility treatments, and
 iii) promote the health of mothers and their offspring. To achieve this goal, we ask the
 question: Does the Fit-for-Fertility Program improve in a cost-effective manner the live
 birth rate and other fertility outcomes, as well as pregnancy and neonatal outcomes, in
 women with obesity and infertility who consult a fertility clinic, as compared to usual
 care?

 2. OBJECTIVES

 Accordingly, the main objectives of our national multicenter RCT are to:

 1. Evaluate the effectiveness of the Fit-for-Fertility Program on fertility and lifestyle
 outcomes in a diverse Canadian population;

 2. Assess costs per live birth and other measures of cost-effectiveness of the program; and

 3. Determine the impact of the program on maternal and neonatal health.

 3. CENTERS INVOLVED IN THE TRIAL

 Seven fertility clinics covering Canada from coast to coast and having a good ethnic
 diversity will participate in this RCT: Olive Fertility Centre in Vancouver, with its Asian
 population; Pacific Centre for Reproductive Medicine in Edmonton, Mount Sinai Hospital in
 Toronto and Centre hospitalier universitaire (CHU) of Montréal, with large multiethnic
 communities; CHU of Sherbrooke and CHU of Québec, smaller centers with mainly Caucasian
 clientele; and Atlantic Assisted Reproductive Therapies Clinic in Halifax that has a
 Caucasian and Afro-American population. All clinics have provided strong support and
 partnership.

 4. RANDOMIZATION

 Randomization will occur following the baseline visit (V0), when all eligibility criteria
 will be available for the candidate. Group allocation will be concealed using on-line
 computerized randomization with permuted blocks of variable block sizes (2 to 6), stratified
 by center and PCOS status (yes/no), which decreases fertility and may affect response to the
 lifestyle intervention. Randomization list will be generated by an independent statistician.
 Participants will be randomized in two arms using 1:1 ratio. Central randomization will be
 conducted using a customized web-based program designed for the study. The randomization
 process will be initiated by the site investigator or delegate who will access the web-based
 system and enter the patient's confirmation of eligibility and informed consent. The
 patient's unique study identifier and open-label study treatment allocation will then be
 electronically delivered to the local site investigator or delegate.

 Following randomization, the research staff will inform the fertility care team of their
 patient's allocation group. If the participant is randomized to the control group, the
 fertility care team will be informed that their patient can undergo fertility treatments
 immediately, according to their usual care. On the other hand, if the participant is
 randomized to the intervention group, the fertility clinic will be notified that the patient
 will have to postpone any medically assisted reproduction (MAR) procedures for the following
 6 months, during which she will be enrolled in the Fit-for-Fertility Program. At the end of
 this first 6-month period, if the participant is not pregnant, the research staff will
 contact the fertility clinic team to inform them that the participant can now undergo usual
 fertility care, in combination with the Fit-for-Fertility Program.

 5. FOLLOW-UP

 As illustrated in the Study Flow Chart, page ix, research evaluation visits will take place
 in both groups at baseline and every 6 months for a total of 18 months if no pregnancy
 occurs. Women who will become pregnant within the first 18 months of follow-up will be
 evaluated at the beginning of pregnancy and at 24-28 weeks of pregnancy, or up to a total
 follow-up of 24 months. In our pilot trial, only one participant who became pregnant within
 18 months of follow-up delivered after a total follow-up of 24 months. Women who will become
 pregnant after 18 months of follow-up will not undergo research visits during their
 pregnancy. All measures and evaluations performed during these research visits are detailed
 below, in section 8.1, and are listed in the Schedule Table at page x. Patients will be
 instructed to contact the study team if events occur between visits or phone calls.
 Importantly, all clinical outcomes will be ascertained with participants and their medical
 records 24 months after participants' randomization, regardless of the timing of their last
 research visit and the occurrence of a pregnancy. Pregnancy and neonatal outcomes occurring
 after 24 months from a pregnancy achieved within 24 months will not be included in the
 primary analysis of the primary outcome, but will be recorded for secondary analyses.

 6. ANALYSES OF THE DATA

 6.1 Sample Size

 Experts from the Canadian network on reproductive and maternal health of women with obesity
 and infertility were surveyed, and they concluded that the minimal absolute increase in the
 18-month cumulative incidence of live birth (live birth rate) between groups of participants
 that would change clinical practice must be between 10% and 20%. The only RCT that is similar
 to our study was published in the NEJM26 and used an increase of 15% for their sample size
 calculation. Therefore, our sample size calculation was based on a 15% absolute difference,
 an estimated live birth rate of 35% in the control group (from our ongoing RCT), a power of
 95% and an alpha level of 5%, and resulted in 293 women per group (nQuery avisor 4.0).
 Assuming a withdrawal rate of 5% (eligibility criteria violation and loss to follow up), the
 number of women to recruit is 616. A 95% power will provide enough power for most of our
 secondary outcome analyses.

 In order to recruit a total of 616 participants in 18 months, the two clinics with smaller
 practices (CHUS and CHUQ) will need to recruit 53 participants (i.e. 39 per year), and the
 other 5 clinics will have to recruit 102 participants (i.e. 68 per year). These rates of
 recruitment are feasible since a survey of participating fertility clinics showed that
 smaller practices (CHUS, CHUQ) evaluate 80 to 315 new women with obesity per year, and larger
 practices, between 265 and 810.

 6.2 Quantitative Data Statistical Analyses

 The main variable of interest will be 24-month live birth cumulative incidence and the
 primary analyses of interest will be ITT, including all randomized participants with
 available data and no violation of eligibility criteria. The ITT analyses will be
 supplemented by per-protocol analyses where women will be excluded if they drop out of the
 study during the first 6 months. The 24-month cumulative incidences of live birth will be
 compared between the two arms using the Mantel-Haenszel test with stratification by center
 and PCOS status. This analysis will be supplemented by a survival analysis (log rank test)
 where the time to live birth will be used. To assess balance across arms, baseline
 demographic and clinical data of women will be compared between arms. In the very unlikely
 event that a substantial imbalance is found, additional analyses will be carried to assess
 the potential confounding effects of this imbalance, using multiple logistic regression and
 Cox proportional hazards model.

 Similar analyses will be used for other clinical outcome variables, which will be assessed as
 categories, and continuous variables. Subgroup analyses will be performed based on baseline
 age, level of obesity, ethnic origins, socio-economic status, the cause of infertility and
 polycystic ovary syndrome status. A 5% level of significance will be used for all analyses.

 7. ANTICIPATED CONTRIBUTIONS

 The results of our multicenter RCT will have major scientific impact since they will provide
 important data on the importance of a lifestyle program supporting women with obesity
 consulting in fertility clinics, in order to improve their fertility and response to ART as
 well as helping them to have a healthy baby. This study will also provide valuable
 information on potential cost savings for individuals and the healthcare system.
Inclusion Criteria:

 1. Infertility defined as (a) failure to achieve a clinical pregnancy after ≥12 months of
 regular unprotected sexual intercourse, (b) not conceiving after having tried ≥6
 months in women with irregular menstrual cycles or ≥35 years of age; or (c) women with
 an established cause of infertility;

 2. Aged between 18 and 40 years; and

 3. Obesity (BMI ≥ 30 kg/m² or 27 kg/m² for Asian and Latin American), or overweight for
 women with PCOS (BMI ≥ 27 kg/m²).

 Exclusion Criteria:

 1. Any uncontrolled medical or mental condition that contra-indicates fertility
 treatments, based on clinical judgment of the fertility specialist;

 2. If the only clinically indicated MAR procedure is IVF (e.g. bilateral tubal factor,
 severe male factor, etc.) or in case of insemination with donor, because natural
 conception is impossible or highly unlikely;

 3. Recurrent spontaneous abortions (>2 miscarriages at less than 22 weeks of gestation)
 within the last 12 months (with evidence of conception, such as positive β-hCG),
 because these women do not have difficulty to conceive.

 4. Previously diagnosed uncontrolled eating disorder or major depression that would
 contra-indicate the initiation of a lifestyle intervention;

 5. A high level of depressive state, as determined by a score for depression on the
 Hospital Anxiety and Depression Scale (HADS) ≥ 15, since that would contra-indicate
 the initiation of a lifestyle intervention;

 6. Planning for or past history of bariatric surgery;

 7. Planning for or engaging in another intensive lifestyle intervention (that includes
 face-to-face visits every 8 weeks or less, which would be similar to the intervention
 tested);

 8. Inability to understand the language in which group sessions will be provided in the
 participating center, i.e. French in Quebec province and English in other provinces;
 and

 9. Planning to be unable to attend research visits at the participating center for the
 next 18 months, due to moving in another region, for example.