Impact of low serum progesterone levels on the day of embryo transfer on pregnancy outcome: a prospective cohort study in artificial cycles with vaginal progesterone

Abstract

STUDY QUESTION Is there a serum progesterone (P) threshold on the day of embryo transfer (ET) in artificial endometrium preparation cycles below which the chances of ongoing pregnancy are reduced? SUMMARY ANSWER Serum P levels <8.8 ng/ml on the day of ET lower ongoing pregnancy rate (OPR) in both own or donated oocyte cycles. WHAT IS KNOWN ALREADY We previously found that serum P levels <9.2 ng/ml on the day of ET significantly decrease OPR in a sample of 211 oocyte donation recipients. Here, we assessed whether these results are applicable to all infertile patients under an artificial endometrial preparation cycle, regardless of the oocyte origin. STUDY DESIGN, SIZE, DURATION This prospective cohort study was performed between September 2017 and November 2018 and enrolled 1205 patients scheduled for ET after an artificial endometrial preparation cycle with estradiol valerate and micronized vaginal P (MVP, 400 mg twice daily). PARTICIPANTS/MATERIALS, SETTING, METHODS Patients ≤50 years old with a triple-layer endometrium ≥6.5 mm underwent transfer of one or two blastocysts. A total of 1150 patients treated with own oocytes without preimplantation genetic testing for aneuploidies (PGT-A) (n = 184), own oocytes with PGT-A (n = 308) or donated oocytes (n = 658) were analyzed. The primary endpoint was the OPR beyond pregnancy week 12 based on serum P levels measured immediately before ET. MAIN RESULTS AND THE ROLE OF CHANCE Women with serum P levels <8.8 ng/ml (30th percentile) had a significantly lower OPR (36.6% vs 54.4%) and live birth rate (35.5% vs 52.0%) than the rest of the patients. Multivariate logistic regression showed that serum P < 8.8 ng/ml was an independent factor influencing OPR in the overall population and in the three treatment groups. A significant negative correlation was observed between serum P levels and BMI, weight and time between the last P dose and blood tests and a positive correlation was found with age, height and number of days on HRT. Multivariate logistic regression showed that only body weight was an independent factor for presenting serum P levels <8.8 ng/ml. Obstetrical and perinatal outcomes did not differ in patients with ongoing pregnancy regardless of serum P levels being above/below 8.8 ng/ml. LIMITATIONS, REASONS FOR CAUTION Only women with MVP were included. Extrapolation to other P administration forms needs to be validated. WIDER IMPLICATIONS OF THE FINDINGS This study identified the threshold of serum P as 8.8 ng/ml on the day of ET for artificial endometrial preparation cycles necessary to optimize outcomes, in cycles with own or donated oocytes. One-third of patients receiving MVP show inadequate levels of serum P that, in turn, impact the success of the ART cycle. Monitoring P levels in the mid-luteal phase is recommended when using MVP to adjust the doses according to the needs of the patient. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER NCT03272412.

Serum Progesterone Profile Across the Mid and Late Luteal Phase in Artificial Cycles Is Associated With Pregnancy Outcome

“…Some scientifical evidence could support that higher levels could be the “cause” of the final result. It has been recently demonstrated that low serum P levels on the mid luteal phase are related with lower ongoing pregnancy and live birth rates ( 6 ). Thus, those patients with higher basal serum P levels are more prone to have better results.…”

“…In this analysis we included those patients undergoing a hormonal replacement therapy cycle for embryo transfer (n=127). Eligible patients were aged between 18-42 years, with a normal uterus in 2D ultrasound, and being transferred 1-2 good quality blastocysts in a frozen embryo transfer after an artificial endometrial preparation with estradiol valerate and vaginal micronized progesterone (400 mg/12 hours) as described elsewhere ( 6 ).…”

“…The interest on the impact of serum P levels during window of implantation has emerged in the last years. There seems to be a relationship between low serum P levels and poorer outcome, in terms of ongoing pregnancy or live birth rate (1)(2)(3)(4)(5)(6). Most of the studies have been conducted in hormonal replacement therapy cycles, in which there is no endogenous progesterone -due to the lack of ovulation, and luteal phase depends exclusively on the amount of exogenous P given to the patients.…”

“…When using the vaginal route for progesterone administration, ongoing and live birth rates are significantly decreased when serum P is low on the day of embryo transfer, or even one day before/after (1)(2)(3)(4)(5)(6). Prospective studies found that the critical threshold of serum P on the day of ET is about 9 ng/ml (5,6). This negative impact remains present after adjusting for the most important variables, such as origin of oocytes (own or donated) or embryo quality.…”

“…When using the vaginal route for progesterone administration, ongoing and live birth rates are significantly decreased when serum P is low on the day of embryo transfer, or even one day before/after ( 1 – 6 ). Prospective studies found that the critical threshold of serum P on the day of ET is about 9 ng/ml ( 5 , 6 ).…”