To compare the Safety and Efficacy of Repeated GnRH agonist injections versus rescue hCG for modified Luteal Phase Support in predicted hyper-responders undergoing IVF cycles: A randomized controlled trial

Aim:To compare the efficacy and safety of repeated GnRH agonist injections versus rescue hCG for modified luteal phase support in predicted hyper-responders undergoing IVF with antagonist cycles and agonist trigger in improving IVF outcomesObjectivesPrimary objective:To compare the efficacy of repeated GnRH agonist injections versus rescue hCG for modified luteal phase support in predicted hyper-responders undergoing IVF with antagonist cycle in improving IVF outcomes in terms of clinical pregnancy rates

Secondary objectives:To compare the safety of repeated GnRH agonist versus rescue hCG for modified luteal phase support in predicted hyper-responders undergoing IVF with antagonist cycle in improving IVF outcomes in terms ofOHSS rates

Implantation rate

Hormonal dynamics during luteal phase

Live birth rate

Number of subjects= 100

50: Study group A: Infertile hyper-responders women undergoing GnRH antagonist protocol getting repeated GnRH agonist as modified LPS

50: Study group B: Infertile hyper-responders women undergoing GnRH antagonist protocol getting rescue hCG as modified LPS

 Inclusion criteria:

·       Predicted hyper-responders[19]: fulfilling either of the three criteria

 a.      AFC >16

b.      >13 follicles of >= 11 mm on day of GnRH agonist trigger

c.     Serum estradiol levels (E2) levels > 3500 pg/ml on day of trigger )

 Â·       GnRH antagonist cycles

 Â·       Women aged 22 to < 40 years

·       Unexplained infertility

·       Anovulatory infertility

·       Tubal factor

·       Mild/moderate male factor infertility

 Exclusion criteria:·      > 25 oocytes retrieved at ovum pick up

·      Signs of OHSS post- ovum pick up

·      Any other contraindication to fresh ET

·      Known reasons for impaired implantation (i.e. hydrosalpinx, fibroid distorting the endometrial cavity, Asherman’s syndrome, thrombophilia or endometrial tuberculosis)

·      Previous 2 or more failed IVF

·      Patients who do not give written informed consent to participate

·      BMI (Body mass Index) < 18 or > 30Kg/m2

·      Cycles with frozen spermatozoa or oocytes

·      Oocyte donation cycles

·      Uterine anomalies

Study design: Randomized Controlled Trial

Number of subjects= 100

1)    50: Study group A: Infertile hyper-responders women undergoing GnRH antagonist protocol getting repeated GnRH agonist as modified LPS

2)    50: Study group B: Infertile hyper-responders women undergoing GnRH antagonist protocol getting rescue hCG as modified LPS

 Inclusion criteria:

·       Predicted hyper-responders[19]: fulfilling either of the three criteria

 a.      AFC >16

b.      >13 follicles of >= 11 mm on day of GnRH agonist trigger

c.     Serum estradiol levels (E2) levels > 3500 pg/ml on day of trigger )

 Â·       GnRH antagonist cycles

 Â·       Women aged 22 to < 40 years

·       Unexplained infertility

·       Anovulatory infertility

·       Tubal factor

·       Mild/moderate male factor infertility

 Exclusion criteria:·      > 25 oocytes retrieved at ovum pick up

·      Signs of OHSS post- ovum pick up

·      Any other contraindication to fresh ET

·      Known reasons for impaired implantation (i.e. hydrosalpinx, fibroid distorting the endometrial cavity, Asherman’s syndrome, thrombophilia or endometrial tuberculosis)

·      Previous 2 or more failed IVF

·      Patients who do not give written informed consent to participate

·      BMI (Body mass Index) < 18 or > 30Kg/m2

·      Cycles with frozen spermatozoa or oocytes

·      Oocyte donation cycles

·      Uterine anomalies

Doses of drug:Ovarian stimulation will be started on Day 2/3 of menses after a baseline scan and serum LH. Patients will receive gonadotropins (recombinant FSH) from day 2 of the menstrual cycle with dose depending on patient’s age, BMI (body mass index), AMH, AFC and/or ovarian response in previous cycles. Fixed start antagonist will be given (injection cetrorelix acetate 0.25 mg subcutaneously) from day 6 of stimulation. First scan will be done on day 6 of start of gonadotrophins, and subsequently according to the follicular response. Serial E2, LH and P4 will be monitored on days of scan to further identify and predict hyper-responders. Hyper-responders will be defined as fulfilling either of the four criteriai.               AFC >16ii.              >13 follicles of >= 11 mm on day of GnRH agonist trigger  iii.   Serum estradiol levels (E2) levels > 3500 pg/ml on day of trigger ) Recruitment: on day of triggerThe criteria for final follicular maturation trigger will be at least 3 follicles with diameter >17 mm. All women fulfilling the criteria for hyper-responders on the day of trigger will be recruited in our study. Ovulation trigger will be done by GnRH agonist (Inj Leuprolide 2mg subcutaneously) to avoid the risk of OHSS in these hyper-responders and oocytes will be retrieved 34-36 hours later. If >25 oocytes are retrieved, patients will be excluded from the trial. Intensive luteal phase support will be started from the day of pick-up with Progesterone (Injection susten 100 mg intramuscular or vaginal micronized progesterone (Tab susten 400 mg BD vaginally) along with 2 mg oral estardiol valerate (Progynova) twice daily.Randomization: on day 3 of Ovum pick-upOn day 3 of ovum pick up, if any woman develops signs and symptoms of OHSS will be excluded from the study and rest women will be randomized to either Group A: Multiple dose agonist; or Group B: Rescue hCG as luteal phase supportIntervention: Luteal phase supportGroup A- will receive a total of five injections of GnRH agonist (Injection leuprolide acetate 0.5 mg on day 3, 5, 7, 9 and 11 of ovum pick up)

Group B: Rescue hCG (subcutaneous 1500 IU) on day 3 of ovum pick upMixed block randomization method will be used. Computer generated random number list will be generated by using nQuery software and details of the series will not be revealed to anyone and the allocation sequence will be concealed by sequentially numbered opaque and sealed envelopes. The participants will be allocated into one of the two groups. The envelopes will be prepared by a person not associated with the conduct of the study. The envelopes will be sequentially opened. Adherence to the allocation will be confirmed by the principal investigator.Routine IVF or ICSI will be performed, as appropriate. Freshly ejaculated sperm samples will be prepared by double density gradient centrifugation and each oocyte will be inseminated with 55,000 sperm or ICSI performed depending on the patient profile.Then both the gametes will be incubated at 37°C, 5% O2 and 6% CO2 in the conventional incubator. Fresh embryo transfer will be performed on day 3 or day 5 under ultrasound guidance as per unit protocol depending on the number and quality of embryos available. The choice to transfer of one or two embryos will be decided at a consultation, mainly depending on the patient’s age and the number of embryos replaced in the previous treatment cycles. All remaining good-quality embryos will be vitrified as described using closed CBS-VIT High Security straws in combination with dimethylsulfoxide, ethylene glycol and sucrose as cryoprotectants.Both the groups in addition will receive oral estrogen 2 mg thrice a day and vaginal progesterone 400 mg twice a day until 12 weeks of gestation or until the day of pregnancy test if negative.Follow up:Beta hCG and urine pregnancy test will be performed on day 16 in our laboratory and progesterone will be continued up to 12 weeks of gestation in a normal intrauterine pregnancy and discontinued in case of a biochemical pregnancy or no pregnancy. Clinical pregnancy rates will be calculated as per transvaginal ultrasound performed at 6-7 weeks showing one or more gestational sacs with fetal cardiac activity. Clinical pregnancy rate includes ectopic pregnancy as well.Duration of treatment: 20 days

Investigations: Patients fulfilling the inclusion criteria will be randomised to Study group A (Repeated GnRH agonist injections) or Study group B (Rescue hCG) for Luteal phase support.  Patients will undergo follicular monitoring followed by trigger and oocyte pickup. Hormonal analysis will be done as per the usual hospital protocol. Oocytes will be fertilised by IVF/ICSI. Fresh transfers will be done. The number of oocytes retrieved, clinical pregnancy rates and other secondary outcomes will be compared between study group A vs study group B.