Impact of Low Progesterone on Pregnancy Success Rates

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Impact of low progesterone on pregnancy success rates

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

doi.org/10.1093/humrep/deaa322

Background

To date, the optimal levels of progesterone for pregnancy has not been well established.

For this reason, women currently using ART for treatment of infertility or subfertility are given the same dose of progesterone for luteal phase support.

Previous studies of artificial endometrial preparation cycles suggest the likelihood of a minimum progesterone level, below which clinical pregnancy success rates are significantly reduced.

In a study of women undergoing oocyte donation cycles, 1 in 4 women still had serum progesterone levels below 9.2 ng/ml, after receiving 400mg of micronized vaginal progesterone twice daily, resulting in 20% lower ongoing pregnancy rates.

However, whether this finding remains true for women using their own eggs remains unknown, as does the critical threshold where low serum progesterone significantly decreases ongoing pregnancy rates and live birth rates.

Methodology

A total of 1205 infertile patients enrolled in this study, between September 2017 and November 2018, at the IVI RMA Clinic in Valencia, Spain.

Eligible women were ≤50 years old displaying adequate endometrial pattern and thickness (≥6.5mm), following estrogen treatment during the proliferative phase and luteal phase support via micronized vaginal progesterone (400mg), before embryo transfer. Women with uterine or adnexal anomalies were automatically excluded from the study to minimise potential bias.

In total, 1150 women (658 oocyte donation cycles, 492 own oocyte cycles) satisfied the inclusion exclusion criteria,. Of these 1150, 308 oocytes underwent preimplantation genetic testing for aneuploidies (PGT-A). Mean age was 39.6 ±4.6 yrs, with a mean BMI of 23.7 ±4.2 kg/m2, and endometrial thickness of 8.8 ±1.5mm.

Measurement of estradiol and progesterone was carried out on the day of embryo transfer and results blinded to the Doctor, Embryologist and patient to prevent supplementation. In both groups, fresh and thawed oocytes was transferred, from grades A to C, according to the Spanish ASEBIR classification.

Ongoing pregnancy rate was defined by the presence of a fetus after Week 12, while live birth rate was defined by the number of deliveries in which at least one live neonate was delivered.

Results

Initial analysis of clinical outcomes showed a significant decrease in ongoing clinical pregnancy rate as serum progesterone levels trended low on day of embryo transfer.

Serum Progesterone (ng/ml)Ongoing Pregnancy rate (%)Group Percentile
≥ 1957.490
15.8 – 18.947.880
13.7 – 15.756.570
12.4 – 13.656.660
11.2 – 12.357.450
9.9 – 11.151.340
8.8 – 9.853.430
7.6 – 8.740.420
5.9 – 7.541.910
< 5.927.40
Ongoing pregnancy rate according to the deciles of serum progesterone on day of embryo transfer

A critical cutoff of 8.8 ng/ml was established using the overall ongoing pregnancy rates 95% confidence intervals lower limit (46.2%).

Analysis of women below and above this cut-off value confirmed significantly worse pregnancy rates (36.6 vs. 54.4 %), live birth rates (35.5 vs. 52.0 %) and miscarriage rates (23.0 vs. 13.5 %).

Sub-analysis showed this statistically significant result remained true in 2 of the 3 sub-groups; women using own oocytes with PGT-A (Group 2) and women using donated oocytes (Group 3). Women using their own oocytes without PGT-A (Group 1), showed a similar trend however the size of this group was too small (total of 184) to confirm statistical significance.

Multivariate logistic regression analysis showed that after adjusting for confounding variables, between the three sub-groups, serum progesterone less than 8.8 ng/ml was still an independent factor in ongoing pregnancy rates. Interestingly higher body weight also correlated with decreased serum progesterone levels, although a difference of only 2.5Kg suggests other factors beyond weight itself alters progesterone levels.

Subsequently a total of 555 women remained pregnant beyond Week 20, resulting in 529 live births with progesterone levels, below or above 8.8ng/ml, showing no effect on obstetric and or perinatal outcomes (term deliveries, birth weight, hypertension, gestational diabetes, preterm labor and bleeding). Interestingly there was a trend towards higher risk of hypertension among the Oocyte donation group (15.7 vs. 8.2 %) although this finding needs to be confirmed in a larger study.

The authors concluded that women receiving micronized vaginal progesterone during hormone replacement therapy cycles need to achieve a minimum of 8.8 ng/ml to not adversely impact pregnancy success rates, with the standard dose proven insufficient for 30% of participants.

SUMMARY: PREGNANCY SUCCESS RATE WITH LOW PROGESTERONE

Women with low progesterone levels (<8.8ng/ml) during embryo transfer have significantly decreased ongoing pregnancy success rates (36.6% vs 54.4%), decreased live birth rates (35.5% vs 52.0%) and increased miscarriage rates (23.0% vs 13.5%), with an average of 1 in 3 women successfully getting pregnant.

Limitations

  1. Study was limited to only women using natural micronized vaginal progesterone for luteal phase support.
  2. No cleavage stage embryos were included in sub-analysis.

Funding

No external funding was declared for this study.

Glossary

Adnexal
Lump of tissue near the uterus.

Luteal phase
Second half of the menstrual cycle, from ovulation to the start of menstruation.

Neonate
Newborn child.

Oocyte
Unfertilised immature / mature egg.

Subfertility
Reduced fertility with prolonged time of unwanted non-conception.

Similar studies

Cédrin-Durnerin, et al. (2019). Serum progesterone concentration and live birth rate in frozen-thawed embryo transfers with hormonally prepared endometrium. https://doi.org/10.1016/j.rbmo.2018.11.026

Gaggiotti-Marre, et al. (2019). Low serum progesterone the day prior to frozen embryo transfer of euploid embryos is associated with significant reduction in live birth rates. https://doi.org/10.1080/09513590.2018.1534952

Alsbjerg B, et al. (2018). Progesterone levels on pregnancy test day after hormone replacement therapy-cryopreserved embryo transfer cycles and related reproductive outcomes. https://doi.org/10.1016/j.rbmo.2018.08.022

Labarta E, et al. (2017). Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study. https://doi.org/10.1093/humrep/dex316


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