Live birth rates higher with natural cycle FETs vs medicated FETs

A 2025 randomized controlled trial found that natural cycle FETs led to higher live birth rates and fewer miscarriages than medicated FETs in ovulatory women with a good prognosis.

For a frozen embryo transfer (FET), the endometrium must be properly prepared to support implantation. This can be done using a natural cycle FET that follows the body’s own hormonal signals, or a medicated FET, where estrogen and progesterone are given to mimic a cycle and time the transfer.

Both natural cycle and medicated FETs are widely used, but it’s unclear which one leads to better outcomes. Some studies suggest medicated FETs may carry higher risks of pregnancy complications, possibly due to the absence of the corpus luteum, which produces key hormones in natural cycles.

To help provide more data, a randomized controlled trial (RCT) by Liu et al. (2025) compared live birth rates after natural and medicated FETs in ovulatory women with a good prognosis. Both true and modified natural cycle FETs (without or with hCG trigger) were grouped together to reflect real world scenarios with patients.

For more background, check out my post Comparing frozen embryo transfer/FET protocols.

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Study details

• This was an open-label RCT (no blinding) that took place between 2020 and 2022 at a single IVF center in China.
• The study was pre-registered as ChiCTR2000040640.
• Exclusions: Women with an irregular menstrual cycle, ovulation disorders, or those with intrauterine adhesions.
• Women were randomized to receive a natural cycle or medicated FET 48 h before the start of treatment (on cycle day 5), during the first menstrual cycle following egg retrieval.
• In natural cycles, ovulation was tracked with ultrasound and LH levels. If no surge was seen, hCG was given to trigger ovulation — this was the case in about 35% of NC-FETs.
• In medicated cycles, estradiol was started on day 5 and adjusted based on lining thickness. Once it reached 7 mm and progesterone was low, vaginal progesterone support was added and the FET scheduled. Oral dydrogesterone was started on the day of embryo transfer, and hormone support continued until 10 weeks if pregnancy was confirmed.
• The primary outcome was live birth rate from the FET.

The two groups were well balanced at baseline, with an average age of 30–31, most patients receiving a single blastocyst transfer (80–85%), and low use of PGT-A (around 3%). Most participants had undergone a prior fresh transfer, with FET performed either due to freeze-all strategy or following an unsuccessful fresh cycle. There were similar cancelation rates between groups. A portion of patients in both groups (~27–30%) went straight to FET after retrieval, without waiting for a full menstrual cycle. Over half of the patients had tubal fertility. Overall, the study population represented good-prognosis patients, and baseline characteristics were similar between groups.

In terms of sample size, a total of 902 women were enrolled — 448 were assigned to the natural cycle FET group and 454 to the medicated FET group. The study was designed to detect a 10% difference in live birth rates with about 900 participants. Some patients switched protocols: in the NC-FET group, 101 women who didn’t ovulate switched to medicated FET group, while in the medicated FET group, 29 women with spontaneous ovulation switched to NC-FET. All participants were included in the main (intention-to-treat) analysis, while the per-protocol analysis excluded those who switched groups.

Live birth rates were higher with natural cycle FET than with medicated FET

Not everyone stuck with the protocol they were originally assigned in this study. Some women in the NC-FET group didn’t ovulate and ended up switching to a medicated cycle, while a few in the medicated group ovulated on their own and switched to NC-FET. The researchers accounted for this in several ways.

Here’s what they found depending on how the data was analyzed:

• Intention-to-treat (ITT) analysis — this includes everyone in the group they were originally assigned to, even if they switched. Here the live birth rate was 54.0% (NC-FET) vs. 43.0% (medicated FET), which was statistically significant (risk ratio [95% CI]: 1.26 [1.10-1.44]).
• Per-protocol analysis — this only includes people who actually followed their assigned treatment (those who switched were excluded). Here the live birth rate was 59.5% (NC-FET) vs. 44.4% (medicated FET), which was statistically significant and even stronger than the ITT result (risk ratio [95% CI]: 1.38 [1.19-1.59]).
• Instrumental variable analysis — this adjusts for people who switched protocols to estimate the real-world effect of actually receiving NC-FET vs. medicated FET. Here the live birth rate was +15.6% higher with NC-FET (95% CI: 6.4%-24.8%).

Even though some patients switched protocols, something that reflects how real FET cycles are managed, the benefit of starting with a natural cycle remained clear across all analyses, at least in this group of patients. Whether analyzed by original assignment (ITT), actual treatment (per-protocol), or by the adjusted real-world effect (instrumental variable analysis), NC-FET consistently led to better live birth outcomes than medicated FET.

The researchers also looked at whether the benefit of NC-FET varied by age, embryo stage, or whether patients had a freeze-all cycle. The live birth advantage was statistically significant in the larger subgroups — such as women under 35, those transferring blastocysts, and those who had a freeze-all — but not in smaller ones like older women or cleavage-stage transfers. This was likely due to limited numbers in those groups. “P for interaction tests” weren’t significant, suggesting there was no strong evidence that any subgroup was different from the overall result. The smaller subgroups may simply have been underpowered.

A look at other pregnancy outcomes following natural cycle or medicated FETs

The researchers also looked at other pregnancy outcomes besides live birth for NC-FET vs medicated FETs (all from the ITT analysis):

• Clinical pregnancy: 63.6% vs 56.6%, statistically significant (1.12 [1.01-1.25]).
• Miscarriage: 13.0% vs 21.4%, statistically significant (0.61 [0.41-0.89]).
• Endometrial thickness: 10.9 mm vs 10.4 mm, statistically significant (0.57 [0.38-0.76]).
• No difference in multiple pregnancy, ectopic pregnancy.

They also looked at a variety of adverse pregnancy outcomes, finding no differences in gestational diabetes, hypertensive disorders of pregnancy (like preeclampsia), preterm birth, PPROM, cesarean section, gestational age, birthweight, NICU admission and more. They did find an increase in antepartum hemorrhage (bleeding after 24 weeks) with medicated FETs (14.5% vs 23.1%).

Conclusions

For women with regular cycles, starting FET with a natural cycle led to higher live birth rates and fewer miscarriages and bleeding complications compared to starting with a medicated cycle.

This may be because of the presence of the corpus luteum, a temporary gland formed after ovulation in a natural cycle. The corpus luteum produces important hormones like progesterone, relaxin, and VEGF, which help the endometrial lining thicken, increase blood flow, and prepare for implantation. In a medicated FET, ovulation doesn’t occur, so the body doesn’t form a corpus luteum. Instead, all hormones are given externally, which may not fully replicate the natural hormonal environment needed for optimal implantation.

Unlike other studies, this study found no difference in pregnancy complications like preterm birth or hypertensive disorders, possibly because the study included mostly younger women with a lower baseline risk.

A recent Cochrane review found no clear evidence that any FET preparation protocol (natural, modified natural, or fully medicated) was superior overall, mainly because high-quality studies have been limited, highlighting the need for more studies like the one presented here. The current study wasn’t included in the Cochrane review.

The study had some limitations: it was done at a single center, not blinded, and included mainly good prognosis patients with tubal infertility who were young (average age ~31), so results might not apply to everyone. Nearly 150 patients didn’t stay with their assigned protocol, with most switching from NC-FET to medicated FET. But the authors argue this reflects real-world decision-making, where cycles are adjusted during monitoring to avoid cancellation and support patient care. Besides, additional analyses all showed similar results.

Here’s some additional posts you might want to check out on Remembryo:

• Meta-analysis compares medicated and natural FET adverse pregnancy and birth outcomes — Researchers in a 2023 study found decreased adverse pregnancy and neonatal outcomes in those who performed a natural vs medicated FET, including abnormal birth weights, preeclampsia, preterm births, and more.
• 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.
• Comparing pregnancy outcomes for letrozole, natural and medicated FETs — Researchers in a 2022 study found improved pregnancy outcomes using letrozole-stimulated FETs compared to medicated FETs, which were comparable to natural FETs.
• Comparing frozen embryo transfer/FET protocols — The post discusses various frozen embryo transfer protocols, which includes a medicated FET, natural cycle FET (true natural/modified natural), and mild ovarian stimulated FET, along with their scheduling. In addition, it examines whether one FET protocol is superior to another, the relevance of the corpus luteum in medicated vs natural cycle FETs, and optimal progesterone levels.
  

Related studies

These additional studies were referenced by the authors of the paper and haven’t been covered on Remembryo. They may be helpful if you’re exploring this topic further. This section is available for paid subscribers.

Reference

Liu X, Li W, Wen W, Wang T, Wang T, Sun T, Zhang N, Pan D, Xie J, Liu X, Cai H, Li X, Shi Z, Wang R, Lu N, Bai H, Pan R, Tian L, Meng B, Mu X, Jia H, Zhou H, Cao X, Liu T, Qu P, Liu D, Mol BW, Shi J. Natural cycle versus hormone replacement therapy as endometrial preparation in ovulatory women undergoing frozen-thawed embryo transfer: The compete open-label randomized controlled trial. PLoS Med. 2025 Jun 25;22(6):e1004630. doi: 10.1371/journal.pmed.1004630. PMID: 40561125; PMCID: PMC12193059.

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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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