Pregnancy outcomes and complications with medicated, natural and mild stimulated FETs

Researchers in a 2022 study found that medicated FETs have a higher miscarriage rate and lower live birth rate compared to modified/natural and mild stimulated FETs.

There are a number of options for endometrial preparation for a frozen embryo transfer (FET), including a medicated or a natural FET, as well as an FET following mild ovarian stimulation. Check out my post on the different FET protocols to learn more about them.

It’s not clear what impact these FET protocols have on pregnancy complications.

Pape et al. (2022) compared pregnancy outcomes and complications from 7,342 pregnant women registered through the Swiss ART-Registry who performed different FET protocols between 2014 and 2019:

• Modified/natural FET (n=998, natural FETs with or without hCG trigger)
• Mild stimulated FET (n=984, low dose ovarian stimulation using hMG with or without GnRH agonist/antagonist, with or without luteal phase support)
• Medicated FET (n=5,360)

In terms of baseline characteristics, there were a number of differences between the groups (confounders) – shown here as medicated FET vs modified/natural FET vs mild stimulated FET:

• Chronic anovulation/PCOS (17.6% vs 5.7% vs 9.8%)
• Advanced endometriosis (5.7% vs 3.7% vs 3.5%)
• Thyroid disease (6.2% vs 3.4% vs 3.2%)
• Single embryo transfers (55.8% vs 48.8% and 38.6%).

To correct for confounders, the researchers statistically adjusted for many characteristics (PCOS, age, number of embryos transferred, and more), but not for endometriosis or thyroid disease which represent smaller differences.

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Medicated FETs showed worsened pregnancy outcomes compared to natural and mild stimulated FETs

The medicated FET group had a higher rate of early miscarriage (<12 weeks) compared to modified/natural and mild stimulated FETs, which was statistically significant (29.1% vs 19.0% vs 19.7%, p<0.001). This result was significant even after adjustment for confounders for both medicated vs modified/natural FETs (adjusted odds ratio [95% CI]: 1.82 [1.51-2.19]) and medicated vs mild stimulated FETs (adjusted odds ratio [95% CI]: 2.06 [1.67-2.54]). This means that after adjustment, miscarriage rates were about twice as high in medicated FETs.

There were lower live birth rates with medicated FETs compared to modified/natural and mild stimulated FETs, which was statistically significant (68.2% vs 78.0% vs 77.2%, p<0.001). The authors attribute this to the higher miscarriage rate.

There were also increases in bleeding during the 1st trimester with medicated FETs compared to modified/natural and mild stimulated FETs, which was statistically significant (8.4% vs 3.5% vs 4.3%, p<0.001). These results were also statisically significant after adjustment.

There were no differences in late miscarriages (3-6 months), ectopic pregnancies and heterotopic pregnancies. Mild stimulated FETs had a higher rate of induced abortions compared to modified/natural or medicated FETs (1.6% vs 0.5% and 0.9%, p=0.037).

Conclusions

This study found an increase in miscarriage rates and 1st trimester bleeding in patients who performed medicated FETs compared to modified/natural and mild stimulated FETs. They also found a decrease in live birth rates in those doing medicated FETs, which can be attributed to the higher miscarriage rate.

There were no differences in late miscarriages, ectopic pregnancies and heterotopic pregnancies, however mild stimulated FETs had a higher rate of induced abortions.

According to the authors, one of the major strengths of this study was the large sample size. However, it was retrospective and randomized patients weren’t used, and there were some differences in the baseline characteristics. Specifically, thyroid disease might contribute to miscarriage and was not adjusted in their statistical models (but this would likely have a small effect given the size of this group).

The reasons behind the increased rate of miscarriage in medicated FETs isn’t clear, but the authors point to a number of studies that suggest hormonal imbalance may be involved. Additionally, the corpus luteum isn’t formed during medicated cycles and this may be an important source for hormones that promote vascularization that is needed to sustain a pregnancy.

A 2020 Cochrane review found insufficient evidence to recommend any particular FET protocol.

Reference

Pape J, Levy J, von Wolff M. Early pregnancy complications after frozen-thawed embryo transfer in different cycle regimens: A retrospective cohort study. Eur J Obstet Gynecol Reprod Biol. 2022 Dec;279:102-106. doi: 10.1016/j.ejogrb.2022.10.015. Epub 2022 Oct 21. PMID: 36308939.

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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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