Minimal Ovarian Stimulation

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Minimal ovarian stimulation (mini-IVF) for IVF utilizing vitrification and cryopreserved embryo transfer Zhang, J et al Reprod Biomed Online: 2010

Dr Daiter’s summary of this research article:

Target: women undergoing mini-IVF protocols at New Hope Fertility Center from 2006-2009 regardless of serum CD 3 FSH or ovarian reserve

Purpose: to determine the reproductive outcomes, especially in an older population or women with reduced ovarian reserve, of mini-IVF protocols (that use clomiphene citrate as well as vitrification for embryo cryopreservation) that use less medication, less injections, producing few eggs of possibly greater quality

Clomiphene citrate used for long durations than the usual 5 days is believed to effectively inhibit the LH surge due to its anti-estrogen effect on the pituitary gland (by down regulation of the estrogen receptors), thus allowing a longer slower stimulation

Protocol includes:

(1) Clomiphene Citrate 50 mg/day started on CD 3 and continued until follicles were mature enough to trigger ovulation,

(2) HMG (Menopur, Ferring Pharmaceuticals) 150 IU SQ every other day was started on CD 5 or CD 8 depending on the basal serum FSH concentration,

(3) GnRHa (Nafarelin acetate nasal solution, Synarel, Pfizer, USA) 300 mcg used to trigger endogenous LH surge once the follicles reached 18 mm diameter and the E2 >300 mcg/mL, along with Indomethacin 50 mg (Indocin, Merck and CO, USA) on the day of trigger to prevent premature ovulation without preventing LH induced egg maturation,

(4) if serum LH rose prior to retrieval (day of trigger?) then a small dose of the GnRH antagonist Cetrotide (cetrorelix acetate, ASTA Medica AG, Germany) 8 mcg was added in the morning,

(5) oocyte retrieval 32-34 hours after GnRHa nasal spray,

(6) vitrification of embryos (using the Kuwayama method of vitrification described in his 2005 article) using a cryoprotectant (combination of ethylene glycol and DMSO) as described in detail in numerous articles (listed and partially described in M+M of article) if they reached blastocyst stage (quality assessed by criteria of Gardner and Schoolcraft, 1999) by day 5-6,

(7) ET with a single embryo if of high quality (grade 1-2 in fresh cycle, according to Veeck’s criteria; for FET blastocysts greater than 3AA using criteria of Gardner and Schoolcraft 1999) or two embryos if not of good quality using a Teramoto catheter under ultrasound guidance, either (a) in fresh cycles on post retrieval day 2-3 or (b) in FET cycles the transfer was in either a natural cycle (6 days after ovulation, method detecting ovulation or ovulation trigger not described) or in a hormone replacement cycle (Estrace 2 mg/day started on CD 3 and Crinone 8% (90 mg twice a day) progesterone gel added from CD 12

2516 patients underwent the mini-IVF protocol, 1580 patients had CD 3 FSH <16 IU/L and 998 patients had CD 3 FSH >15 IU/L, 2957 IVF cycles initiated, 2741 oocyte retrievals, 577 fresh ET, 926 FET, 496 pregnancies (380 from FET cycles), for women with FSH <16 IU/L average number oocytes retrieved 2.3 +/- 2.2 and women with FSH >15 IU/L average number oocytes retrieved 2.1 +/- 2.1 (very low numbers for both groups compared to conventional IVF), cancellation rate for women with FSH <16 IU/L was 7% and for women with FSH >15 IU/L was 8%, overall clinical pregnancy rate was 33% for all 1503 transfers, clinical pregnancy rate higher for vitrified warmed embryo transfer cycles than with fresh ET (41% vs 20%), FSH did not have a significant effect on pregnancy rates, (1) women under 35 with FSH <16 IU/L with fresh ET clinical pregnancy rate per embryo transferred was 27% and with cryopreserved FET the clinical pregnancy rate per embryo transferred was 48%; (2) women under 35 with FSH >15 IU/L the clinical pregnancy rate was 53%; (3) women over 40 with FSH >15 IU/L the clinical pregnancy rate per cryopreserved embryo was 31%, about 33% of eggs developed to blastocysts with mini-IVF

Conclusion: mini-IVF clinical pregnancy rates compare to conventional IVF clinical pregnancy rates despite much less medication and far fewer eggs retrieved in both the young population of women with good ovarian reserve and the older population of women with reduced ovarian reserve.

Dr. Daiter’s review of this research article

​Dr. John J. Zhang is a pioneer in Reproductive Endocrinology and Infertility, including but not limited to the field of mini IVF and natural cycle IVF.

This important article is published in Reproductive BioMedicine Online (2010); an online journal that covers the formation, growth and differentiation of the human embryo; so it is both peer reviewed and relatively current (major changes occur slowly in medical research so research published within the past several years is generally considered current).  It seeks to determine the reproductive outcomes of mini IVF cycles, especially for older women with decreased ovarian reserve (women aged over 40 years with a basal FSH > 15 IU/L) and for younger women with either normal or decreased ovarian reserve (women aged less than 35 years with a basal FSH < 16 IU/L were compared to women aged less than 35 years with a basal FSH > 15 IU/L).

The findings of this study include that with mini IVF there were 2741 oocyte (egg) retrievals and only 1,503 embryo transfers (only 55% of retrievals resulted in embryo transfers); the average number of eggs retrieved from women with a basal FSH < 16 IU/L (ie., 2.3 +/- 2.2 oocytes) was not significantly different from the average number of eggs retrieved from women with a basal FSH > 15 IU/L (ie., 2.1 +/- 2.1 oocytes), however both of these averages are much lower than the average number of eggs retrieved during conventional IVF; clinical pregnancy rates for mini IVF cycles that cryopreserved the embryos using vitrification and then warmed (thawed) them prior to transfer (41%) were more than double the clinical pregnancy rates for fresh embryo transfer (20%), for an overall clinical pregnancy rate of 33% per transfer; clinical pregnancy rates for younger women (<35) with an encouraging basal FSH (<16 IU/L) were higher when the embryos were cryopreserved and transferred on a subsequent controlled cycle (48%) than when they were transferred fresh (27%); younger women (< 35) with decreased ovarian reserve (basal FSH > 15 IU/L) had a clinical pregnancy rate of 53% per embryo transferred; and older women (over 40) with a decreased ovarian reserve (basal FSH > 15 IU/L) had a clinical pregnancy rate of 31% per cryopreserved embryo.

 

The main “take home messages” of this article appear to be that mini-IVF cycles result in embryo transfers for about half of those undergoing egg retrieval (possibly several egg retrievals are required to accumulate enough good quality eggs for transfer) , however the clinical pregnancy rates per embryo transferred compare well to conventional IVF rates despite using far less medication and including large numbers of women with reduced ovarian reserve.

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