Multidisciplinary Treatment of Obesity Prior to in Vitro Fertilization: Impact on Global Reproductive Outcomes (PRO-FIV Study)

Brief description of study

   The aim of the present study is to evaluate the impact of a multidisciplinary treatment of obesity prior to IVF on global reproductive outcomes and maternofetal metabolic and cardiovascular risk factors.
     This is a randomized controlled trial in obese infertile women before starting an IVF cycle. The intervention is based on a structured multidisciplinary program in support groups, which includes diet, physical activity and psychological therapy. IVF will be started immediately after this therapy. Patients included in the control group will start an IVF cycle immediately after the randomization. The results of this study may allow the identification of patients who would benefit from obesity treatment, so as to establish appropriate preventive and therapeutic strategies and to reduce the maternal obesity impact in future generations.

 Detailed Study Description

 The aim of the present study is to evaluate the impact of a multidisciplinary treatment of obesity prior to IVF on global reproductive outcomes and maternofetal metabolic and cardiovascular risk factors.
      This is a randomized controlled trial in obese infertile women (body mass index 30 kg/m2) before starting an IVF cycle. In the intervention group, the aim is a weight loss of at least 10% in a 16-week period of treatment based on a multidisciplinary approach and support groups, which includes diet, physical activity and psychological therapy. IVF will be started immediately after this period. Patients included in the control group will start an IVF cycle immediately after the randomization. The results of this study may allow the identification of patients who would benefit from obesity treatment, so as to establish appropriate preventive and therapeutic strategies and to reduce the maternal obesity impact in future generations.

Chronic Endometritis and IVF

Brief description of study
 Background:
Embryo quality is known to be a very important determinant to predict the implantation and pregnancy rate in IVF patients, however, the role of uterine integrity or endometrial receptivity cannot be overlooked. Chronic endometritis (CE) is an inflammation of the endometrium diagnosed by the presence of plasma cells in the endometrial stroma. There is not only no census on the definition of CE, the current literature on the impact of CE on reproductive outcome is controversial and consists only of retrospective studies with small sample sizes. Although there is a presumption that CE is related to poor IVF outcome, this belief has not been proven.

 Design:
 Prospective cohort study

 Setting:
 Infertility clinics of 2 academic medical centers

 Patients:
 Patients between the ages of 21 and 35 years old undergoing their first IVF cycle will be invited to participate.

 Main Outcome Measures:
The primary outcome will be ongoing pregnancy after 12 weeks estimated gestational age (EGA) with previously documented fetal cardiac motion. Secondary outcomes will include pregnancy loss rate as defined by chemical pregnancy, blighted ovum or loss of fetal cardiac motion before 12 weeks EGA.

 Materials and Methods:
The cycle prior to IVF, patients will undergo an in-office endometrial biopsy on cycle days 19-24. Samples will be stained for CD138 and the number of plasma cells will be quantified. The number of plasma cells in a sample that yields the best sensitivity and specificity for pregnancy will be determined by a Receiver-Operator-Curve. This number will then be used as a dichotomous variable to assign categories of "positive for CE" and "negative for CE." Pregnancy and miscarriage rates will then be determined in the positive and negative CE sample with Chi Square Analysis. A secondary sub analysis will be performed to determine pregnancy and miscarriage rates in patients who declined to participate in the study.

 Expected Results:
 The investigators hypothesize that higher rates of CE will be found in women failing to conceive with IVF and with subsequent first-trimester miscarriage.

Conversion of in Vitro Fertilization Cycles to Intrauterine Inseminations in Patients With a Poor Ovarian Response to Stimulation

Brief description of study
The purpose of this study is to compare the efficiency of conversion to IUI and IVF in patients with a poor ovarian response to stimulation

Detailed Study Description
In 5 to 10% of in vitro fertilization (IVF) cycles, a poor response to ovarian stimulation (defined as less than 4 mature follicles) is noted, even though high doses of exogenous gonadotropins are used. To date, there is no consensus on the ideal management strategy in poor responders. There are three therapeutic options available nowadays:

Oocyte retrieval is performed and the IVF cycle continued, despite the low number of mature follicles.
Conversion of the IVF cycle to an intrauterine insemination (IUI), on the condition of having at least one patent fallopian tube and good semen parameters.
Cancelation of the IVF cycle. In everyday practice, it is difficult for the physician to cancel the IVF cycle in the presence of 2, 3 or 4 mature follicles, especially following a lengthy stimulation.
If live birth rates were comparable between IUI and IVF, conversion to IUI would be the better option for poor responders, since it would avoid an invasive procedure (oocyte retrieval) and the associated risk of complications, and is associated with at a lower cost.

To our knowledge, no prospective randomized controlled trial comparing IVF to conversion to IUI in poor responders has been published to date. The studies published so far have been retrospective and observational, and had several methodological flaws.

Therefore, we aimed to analyze whether conversion of IVF cycles to IUI in poor responders would result in the same live birth rates as oocyte retrievals followed by embryo transfers.

In Vitro Fertilization Impact on Metabolic Parameters

Brief description of study

A quantitative prospective cohort study will be conducted, where blood samples will be collected at different timings during the IVF protocol, to assess the impact of fertility medications on metabolic parameters of patients undergoing IVF treatment.

Detailed Study Description

Numerous factors predispose women to develop pregnancy-related complications, these include gestational diabetes (GDM), pre-pregnancy obesity, advanced maternal age (> 35 years) and gestational age, abnormal weight gain during pregnancy, family history of diabetes, PCOS and low parity. Evidenced-based studies reported that women with PCOS have a significantly higher risk of developing GDM compared with women without PCOS, independently of the obesity factor; this risk is higher when both factors coexist.

Given the known effect of reproductive hormones on weight-gain, controversies still exist on whether ART predispose women to more adverse obstetric outcomes compared to normal pregnancy. ART describes different procedures to help women become pregnant, with In Vitro Fertilization (IVF) being the most commonly performed. It has been demonstrated that IVF is associated with glucose intolerance in mice and it will be interesting to determine whether this physiologic phenomenon is also altered by IVF medication (such as estrogen and progesterone) in humans. While some studies reported that singleton pregnancies conceived by ART (IVF or ovulation induction) were strongly associated with GDM compared to spontaneous conceptions, other studies did not find significant differences in the risk of GDM. Increased GDM risk presented with IVF can be associated with prenatal obesity or secondary to maternal PCOS condition. The former studies did not specify the body mass index (BMI) and the medical history of participants undergoing IVF, such as the presence of PCOS. Due to limited available data, we still cannot distinguish whether these adverse pregnancy outcomes are due to the pre-existing conditions such as PCOS, or are secondary to the IVF therapy itself.

USFDA approved Annovera (segesterone acetate andethinylestradiolvaginal system)

General Information

 Annovera contains two active components, a progestin - segesterone acetate, and an estrogen - ethinyl estradiol. Both components work together to suppress ovulation. Annovera is specifically indicated for use by females of reproductive potential to prevent pregnancy. Annovera is supplied as a vaginal ring for intravaginal administration. One Annovera is inserted in the vagina. The vaginal system must remain in place continuously for 3 weeks (21 days) followed by a 1-week (7-day) vaginal system-free interval. One vaginal system provides contraception for thirteen 28-day cycles (1year). Please see drug label for specific insertion directions.

 Clinical Results
 FDA Approval
 The FDA approval of Annovera was based on two 1-year multicenter trials enrolling 2,265 females, age 18–40 years, who were healthy and sexually active with regular menstrual cycles. Based on pooled data from the two trials, 2,111 females ≤35 years of age completed 17,427 evaluable 28-day cycles (cycles in which no back-up contraception was used).The pooled pregnancy rate, evaluated by the Pearl Index (PI),was 2.98 per 100 woman-years of Annovera use. Return to fertility was assessed in 290 of the subjects in the two trials who either desired pregnancy or switched to a non-hormonal method after the trials, and all 290 subjects reported a return to fertility during the 6-month follow-up period (defined as a return of menses or pregnancy).

 Side Effects
Adverse effects associated with the use of Annovera may include, but are not limited to, the following:
 headache/migraine
 nausea/vomiting
 vulvovaginal mycotic infection/candidiasis 
abdominal pain lower/upper dysmenorrhea vaginal discharge
 urinary tract infection
 breast tenderness/pain/discomfort
 bleeding irregularities including metrorrhagia diarrhea
 genital pruritus
 The Annovera label comes with the following Black Box

Warning:
Females over 35 years old who smoke should not use Annovera. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use. Mechanism of Action Annovera (segesterone acetateand ethinyl estradiolvaginal system) is a ring-shaped, nonbiodegradable, flexible, opaque white vaginal system containing two active components: a progestin - segesterone acetate, and an estrogen - ethinyl estradiol. When placed in the vagina, each Annovera releases an approximate average 0.15mg/day of segesterone acetate and 0.013mg/day of ethinyl estradiol over the21 days in-use period of each cycle for up to 13 cycles (total of 273 days). Each cycle is 28 days, with 21 days in and 7 days out. The two components work together to suppress ovulation.

Transvaginal vs Transabdominal Ultrasound Guided Embryo Transfer

Brief description of study

Embryo transfer is the last step in the IVF process. it is now recognized that this step should be done carefully and that it affects success rates. in recent years, sonographic guidance appears to increase success rates.

Detailed Study Description

Embryo transfer is the last step in the IVF process. it involves the insertion of a soft catheter through the uterine cervix. It is now recognized that this step should be done carefully and that it affects success rates. The embyos should be carefully deposited in the cavity. special care should be given to avoid touching the uterine fundus during the procedure. In recent years, sonographic guidance appears to increase success rates.

Comparison of Two Embryo Transfer Catheters in Patients Undergoing in Vitro Fertilization and Embryo Transfer

Brief description of study
In-vitro fertilization (IVF) treatment involves development of multiple follicles following ovarian stimulation, oocyte retrieval and embryo transfer (ET). ET is the final and most crucial step of IVF treatment.

The ET catheter has to pass through the endocervical canal to go into the uterine cavity through the internal os. The endocervical canal may be filled up with mucus or blood. Embryos trapped in the mucus or blood after the passage of the endocervical canal may not be able to implant into the endometrium. Guardia Pro Protective ET catheter is designed to allow the safe passage of embryos through cervical mucus and blood as its outer sheath protects the embryo through entry and then opens in petals to further advance the inner catheter and gently place the embryo.

The hypothesis of this study is that the pregnancy rate is significantly higher after ET using protective ET catheters.

Detailed Study Description
In-vitro fertilization (IVF) treatment involves development of multiple follicles following ovarian stimulation, oocyte retrieval and embryo transfer (ET). Despite recent advances in ovarian stimulation, the method of assisted fertilization and improved culture conditions, the implantation potential of embryos remains around 20-25% for a long time.

ET is the final and most crucial step of IVF treatment and pregnancy rates after ET may be affected by various factors. In a Cochrane meta-analysis (Derks et al., 2009), no evidence of a benefit was found for performing ET with a full bladder, the removal of cervical mucus, and flushing the endocervical canal or the endometrial cavity. No data were found on changing the woman's position, the use of a tenaculum, the performance of a dummy transfer, and embryo afterloading. Other meta-analyses demonstrate that the use of soft ET catheters (Buckett, 2008) and transabdominal ultrasound guidance (Brown et al., 2010) lead to a higher chance of clinical pregnancy when compared with the use of stiff catheters and clinical touch respectively.

The ET catheter has to pass through the endocervical canal to go into the uterine cavity through the internal os. The endocervical canal may be filled up with mucus or blood. Embryos trapped in the mucus or blood after the passage of the endocervical canal may not be able to implant into the endometrium. Guardia Pro Protective ET catheter is designed to allow the safe passage of embryos through cervical mucus and blood as its outer sheath protects the embryo through entry and then opens in petals to further advance the inner catheter and gently place the embryo.

There is still no study comparing conventional and protective ET catheters in terms of the pregnancy rate of IVF treatment. The hypothesis of this study is that the pregnancy rate is significantly higher after ET using protective ET catheters.

Research plan Patients attending the Department for IVF-ET will be recruited if they fulfill the inclusion criteria and do not have the exclusion criteria. The FET treatment will be arranged as indicated.

On the day of ET, patients will be randomized according to a computer-generated randomization list in sealed envelopes into two groups: conventional and protective ET catheter groups. Conventional ET catheters will be used in the conventional ET catheter group while protective ET catheters will be used in the protective ET catheter group. Patients would be blinded to the group assigned although the clinical, nursing and laboratory staff will be aware of the type of catheters used.

A maximum of two good quality embryos are to be replaced. Patients are asked to keep a mildly full bladder so that the uterus can be visualized by abdominal sonogram during the procedure. A bivalve speculum is inserted into the vagina and the cervix is cleaned with warm saline and culture medium. The axis, degree of flexion and the configuration of the uterine cavity are determined by transabdominal ultrasound examination before the transfer. Under transabdominal ultrasound guidance, the outer catheter is inserted into the cervical canal 4 cm from the external os, with the tip just beyond the internal os. A malleable obturator is used if difficulty is encountered. The inner transfer catheter with the loaded embryo(s) is then inserted into the uterine cavity via the outer cannula. The aim is to put the tip of the inner catheter inside the uterine cavity 6 cm from the external os and care was taken not to advance the tip beyond 1 cm from the uterine fundus. The transfer volume is gently expelled by the technician. The catheters will be held in place for 30 seconds. Both the inner and outer catheters will be checked by the technician under the microscope to make sure that the embryos have been replaced.

The luteal phase support will be used if needed and antenatal management is as usual, if pregnant.

Sample size estimation The ongoing pregnancy rate of IVF-ET in 2010 was about 30.0%. Assuming a 10% increase following use of protective ET catheters as significant, 356 patients in each arm was required at a power of 80% and a significance level of 5% (Sigmastat, Jandel Scientific, San Rafael, CA, USA). A total of 720 patients will be recruited into the study.

Interim analysis will be performed after recruitment of every 100 subjects