Pregnancy outcomes and factors linked to low levels of progesterone on day of FET

Researchers in a 2022 study found that low levels of progesterone on the day of frozen embryo transfer had reduced live birth rates, and were associated with high BMI, low parity and being of non-European descent.

In medicated frozen embryo transfers (FETs), progesterone needs to be supplemented as there is no corpus luteum that’s formed. It’s not clear if low levels of progesterone on the day of FET are associated with pregnancy outcomes, and what factors are linked to lower levels.

Maignien et al. (2022), in their retrospective cohort study, compared pregnancy outcomes in 915 women with serum progesterone levels on the day of FET ≤9.8 ng/ml (≤31.1 nmol/l) or higher levels at a single IVF center in France between 2019 and 2020. They also determined what factors were associated with those who had low progesterone levels.

Medicated FETs were performed using 200 mg of micronized vaginal progesterone 3 times a day for 5 days before a single blastocyst was transferred and serum progesterone levels were measured.

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Reduced live birth rates in women with low progesterone on day of FET

Women with progesterone ≤9.8 ng/ml on the day of FET had a statistically significant reduction in live birth rates compared to those with higher levels (26.1% vs 33.2%, p=0.045). They also had a significantly higher level of miscarriage before 10 weeks (35.2% vs 21.5%, p=0.008). There was no difference in the clinical pregnancy rate.

Factors associated with low progesterone on day of FET

They compared characteristics of women who had low progesterone on the day of FET to those with higher levels. After statistical adjustment, women with a low progesterone level:

• had a higher BMI (24.9 vs 23.6, odds ratio [95% CI]: 1.06 [1.02-1.11])
• had a higher parity (0.5 vs 0.3, odds ratio [95% CI]: 1.32 [1.04-1.66])
• were more likely to be born outside of Europe (32.3% vs 22.1%, odds ratio [95% CI]: 1.70 [1.21-2.39])
• were more likely to not smoke (4.9% vs 11.9%, odds ratio [95% CI]: 0.43 [0.22-0.87])

Note that this study included 951 women at an IVF center in France. The majority were European (69%), with some that were Asian (5.0%) and African-Caribbean (19.6%). Some (10.2%) were active smokers, and there were more smokers in the higher progesterone group than in the low progesterone group.

Looking at the actual values for parity and BMI, there were small differences in progesterone levels. Women with a parity of 0 had about a 13 ng/ml progesterone level compared to those with a parity of 3 who had about 10.5 ng/ml. Similarly, those with a BMI <20 had progesterone levels at about 13.5 ng/ml compared to about 12 ng/ml in those with BMI >30.

Conclusion

This study found that low progesterone levels on the day of FET were associated with a reduction in live birth and increase in miscarriage rate. They also found a number of factors that were associated with low levels of progesterone, including high BMI, low parity, being of non-European descent and people who didn’t smoke (active smokers had a higher progesterone level in this study).

This data supports other studies that show a cut-off for progesterone levels on the day of FET.

The authors explain the rationale for the factors that were associated with low progesterone levels:

• Different ethnicities may show genetic differences that affect how progesterone is absorbed and cleared.
• Absorption and clearance may also be associated with BMI.
• Parity may lead to a weakening of pelvic muscles and leakage of vaginal progesterone.
• Smoking itself might alter hormone levels.

A limitation of this study is that the researchers only looked at a single FET cycle. Looking at those with a history of low progesterone on the day of FET may be more informative.

Reference

Maignien C, Bourdon M, Marcellin L, Guibourdenche J, Chargui A, Patrat C, Plu-Bureau G, Chapron C, Santulli P. Clinical factors associated with low serum progesterone levels on the day of frozen blastocyst transfer in hormonal replacement therapy cycles. Hum Reprod. 2022 Oct 31;37(11):2570-2577. doi: 10.1093/humrep/deac199. PMID: 36125015.

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

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