A new strategy for managing poor ovarian responders

Poor ovarian response (POR) occurs in approximately 9.24% of patients undergoing in vitro fertilization (IVF). This is a group of patients that produces less than 4 eggs with conventional IVF stimulation. Included are patients with diminished ovarian reserve and patients age greater than 40 years. A recent consensus definition of POR (the Bologna Criteria) has been discussed in a previous blog. Several strategies have been proposed for managing this difficult group of patients. There isn’t a single stimulation strategy that has been shown to be superior to all others.

In a recent publication (Gandhi GN et al. IVF Lite – A new strategy for managing poor ovarian responders. ivflite 2014:1:22-8) a group of researchers from Mumbai, India have proposed a unique strategy for managing POR. They used a combination of serial minimal stimulation IVF cycles with cryopreservation and accumulation of the embryos. When these cryo-preserved embryos were subsequently transferred, they achieved pregnancy rates of 28.81% per transfer and 48.45% per patient! Here is a summary of their protocols.

Ovarian stimulation was performed with a combination of clomiphene citrate (50 mg daily orally for 10 days) starting on cycle day 2 or 3. Human menopausal gonadotropin (hMG) 150 units daily was started on day-5 of the cycle. A GnRH-antagonist was added when the lead follicle size was 18 – 19 mm in diameter. hCG trigger shot was given (10,000 units) when the lead follicles size was 21 – 22 mm in diameter. Egg retrieval was performed 32 – 34 hours after retrieval. The eggs were fertilized using either IVF or intracytoplasmic sperm injection (ICSI) and the resultant embryos were cryo-preserved three days later. Patients underwent back-to-back stimulations and retrievals till the patient accumulated about six top-grade embryos. On an average, patients needed 2 – 3 retrievals to accumulate the required number of embryos. Embryo transfer was carried out subsequently in a programmed cycle.

They compared 97 POR that underwent IVF lite (287 cycles) with 125 patients that underwent conventional IVF (277 cycles). Conventional IVF meant the use of aggressive stimulation with high doses of FSH and hMG for stimulation.

Of interest is the fact that there was no significant difference in the mean number of mature eggs retrieved in the two groups (2.42 vs. 2.29). The difference in the amount of gonadotropins required to produce one mature egg between the two groups was significantly different: 680.4 units for the IVF lite group and 4956.2 units for the conventional IVF group. The IVF lite group had a higher percentage of good grade embryos. In the IVF lite group, each patient underwent an average of 2.96 cycles of embryo accumulation before planning a frozen embryo transfer. An average of 6.2 embryos were accumulated for each patient. The conventional IVF group had a lower clinical pregnancy rate (15.5% per cycle) and only 24% of patients achieved pregnancy.

The salient points of this study are the following:

1. Using minimal stimulation protocols they retrieved fewer but better quality eggs.

2. Clomiphene citrate has a negative impact on the uterine lining. Therefore, it is important to avoid fresh embryo transfers and cryo-preserve all the embryos.

3. It is possible to run back-to-back cycles in patients with minimal stimulation protocols. This minimizes the time required for multiple retrievals that are necessary for accumulating the desired numbers of embryos for cryo-preservation.

4. It is imperative to have a top notch cryopreservation (vitrification) program for this strategy to be effective.

5. There were no patients that did not have an embryo transfer in the IVF lite group. Cancellation of embryo transfer is a devastating event for patients and occurred in 10% of the conventional IVF cycles.

6. There was no difference in the number of mature eggs retrieved between the two groups.

7. The pregnancy rate per patient (48.45%; with the accumulation of embryos) is comparable to the success rate in normal responding patients.

Limitations of the study include the following:

1. This is a retrospective, nonrandomized study with a relatively small sample size. It would be interesting to have the two protocols analyzed in a prospective randomized study.

2. Embryos were cryo-preserved on day-3 and transfers were subsequently done on day-4 during the cryo-preserved embryo transfer cycles. It would be interesting if even better results can be obtained if embryos were cultured to the blastocyst stage prior to cryo-preservation.

3. The study was limited to POR patients. It would be interesting to evaluate the results of IVF lite in normal responder patients.

We have no experience with the IVF lite protocol at InVia Fertility Specialists. Based on this publication, it makes sense to try it at least as a pilot study.