Intramuscular vs. Vaginal Progesterone in Frozen Embryo Transfer
“The show notes add more medical details than the podcast. If you remain curious, please read on! ”
This retrospective study is one of two published studies that compare intramuscular progesterone (IMP) to Crinone 8% progesterone vaginal gel (Crinone).
Study Background
WHAT
Intramuscular progesterone vs. Crinone 8% progesterone vaginal gel used in frozen embryo transfer (FET)—> which is more likely to lead to a live birth?
WHY
Progesterone is needed to initiate and continue the first 7-10 weeks of pregnancy
Women undergoing FET do not usually make enough progesterone to successfully continue the early pregnancy
Although most women need external progesterone support during FET, the best way to give this progesterone has yet to be determined
WHERE
Brigham and Women’s Hospital, one of the main teaching hospitals of Harvard Medical School in Boston, Massachusetts
WHEN
January 2014 - January 2019
WHO
Women (N = 1710), see Table 1
Ages 29 - 38 years
Gestational carrier (N = 19) or carrying own intended embryo
Medications per protocol
Ovarian hyperstimulation - gonadotropin-releasing hormone (GnRH) antagonists, GnRH agonists, estradiol priming, and/or low-dose GnRH agonist flare (dates and doses not specified)
Uterine preparation - oral, vaginal, or transdermal estradiol (dates and doses not specified)
Infertility diagnoses included male factor, tubal factor, anovulation, endometriosis, diminished ovarian reserve, uterine factor, gestational carrier, and “other”(not specified)
Embryos
Biological or donated
Created via in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)
Cryopreserved (frozen) on day 5 or 6 per quality of embryo (blastocyst)
+/ - pre-implantation genetic testing (PGT), see Table 2
Single embryo transfer
HOW
Controlled ovarian hyperstimulation ===> oocyte retrieval
IVF or ICSI ===> culture to Day 5 or Day 6 of blastocyst stage
Pre-Transfer Luteal Support —> transfer of one embryo
IMP as 25 mg injections for 5 days before transfer, then 50 mg once daily
Crinone 8% as 90 mg applications twice every day
Day 11 post-transfer, human chorionic gonadotropin (hCG) level checked
Week 7-8 if pregnant ===> ultrasound
Week 11 if pregnancy ===> progesterone discontinued
Statistics (for the uber curious)
All outcomes used log binomial regression to estimate Relative Risk (RR) and 95% Confidence Interval (CI).
Age of oocytes taken into account before calculations
Tested confounders of mother’s BMI, endometrial thickness, embryo quality, date of freeze vs. date of transfer ===> not included in final models because differences were < 10%
Results
More live births in IMP (47.4%) vs. Crinone (41.4%)
Fewer spontaneous abortions in IMP (10.2%) vs. Crinone (14.7%)
Similar biochemical pregnancies in IMP (10.3%) vs. Crinone (11.2%)
Similar clinical pregnancies in IMP (59.5%) vs. Crinone (58.6%)
None of the results were statistically significant
Authors’ Thoughts
Rates of live birth, pregnancy, and spontaneous abortion were similar between IMP and Crinone
Results similar to 2018 study using Crinone but different from 2018 study using Endometrin vaginal insert (not Crinone)
Endometrin concentrates in uterus faster and at higher levels, but is removed faster too
Unclear what are the best doses to use for either Crinone or Endometrin
This Pharmacist’s Thoughts
Study Strengths
Applicable to many US fertility practices (single embryo transfer in blastocyst stage)
Inclusive of many infertility scenarios (using donor eggs, male and female infertility diagnoses, etc.)
Contributes to small arsenal of published IVF studies using Crinone 8% gel
Weaknesses
Were there enough patients in the Crinone group to detect a statistically meaningful difference?
Medications
Intramuscular progesterone locally compounded - proprietary recipe? Replicability of IMP product unlikely in alternate locations
Did the variations in protocols used for ovarian hyperstimulation or for uterine preparation impact results? Details not provided on which drugs, how many patients, etc.
Were there any statistically significant differences in baseline demographics (Tables 1 and 2) between the IMP and Crinone groups? P values not provided
More previous spontaneous abortions in Crinone (75.9%) vs. IMP (71.3%)
More obese patients in IMP (16.1%) vs. Crinone (10.3%)
Differences in fertility diagnoses
More unexplained infertility in Crinone (39.7%) vs. IMP (28.0%)
More diminished ovarian reserve in IMP (10.5%) vs. Crinone (3.5%)
Differences in embryos
More biopsied embryos in IMP (19.5%) vs. Crinone (15.5%)
More good embryos in Crinone (44.7%) vs. IMP (40.9%)
More donor embryos in IMP (5.4%) vs. Crinone (2.6%)
Conclusions
There are baseline differences between the two groups that might invalidate the study results. Although this study showed more spontaneous abortions in the Crinone group (not statistically significant), this group had more spontaneous abortions at baseline. Unfortunately, this non-randomized study does not strongly contribute to the determination of the optimal dosing and routes of administration for progesterone in frozen embryo transfer.
Resources
Bakkensen JB, Racowsky C, Thomas AM, Lanes A, Hornstein MD. Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support following blastocyst cryopreserved single embryo transfer: a retrospective cohort study. Fertil Res Pract. 2020;6:10. Published 2020 Jul 1. doi:10.1186/s40738-020-00079-y
Labarta E. Relationship between serum progesterone (P) levels and pregnancy outcome: lessons from artificial cycles when using vaginal natural micronized progesterone. J Assist Reprod Genet (2020). https://doi.org/10.1007/s10815-020-01862-y
Labarta E, Rodríguez C. Progesterone use in assisted reproductive technology [published online ahead of print, 2020 Jun 4]. Best Pract Res Clin Obstet Gynaecol. 2020;S1521-6934(20)30082-1. doi:10.1016/j.bpobgyn.2020.05.005
Volovsky M, Pakes C, Rozen G, Polyakov A. Do serum progesterone levels on day of embryo transfer influence pregnancy outcomes in artificial frozen-thaw cycles?. J Assist Reprod Genet. 2020;37(5):1129-1135. doi:10.1007/s10815-020-01713-w
