Natural vs Programmed Frozen Embryo Transfer for Pregnancy

(NatPro Trial)

Not currently recruiting at 14 trial locations

Overseen By Marcelle Cedars, MD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 3

Sponsor: JHSPH Center for Clinical Trials

Must not be taking: Chronic systemic medications

Disqualifiers: Uncontrolled diabetes, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Varies per participant

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two methods for transferring frozen embryos to assist women in becoming pregnant. One method, the modified natural cycle, uses the body's natural hormone production, while the programmed cycle relies on hormone therapy. Women with regular menstrual cycles who are open to either approach may be suitable candidates. Participants must have at least one good-quality frozen embryo and be willing to follow the treatment plan. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking fertility treatment.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you can continue using thyroid medication if needed. If you have a rheumatologic disease requiring chronic systemic medications, you cannot participate in the trial.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you can continue using thyroid medication if needed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the modified natural cycle for frozen embryo transfer (FET) is generally well-tolerated. Studies have found it leads to fewer pregnancy-related complications compared to the programmed cycle. One study reported a 32.6% increase in live birth rates with the natural cycle, suggesting it is both effective and safe for many patients.

In contrast, the programmed cycle, although widely used, has been linked to a higher risk of complications. Research indicates that the natural cycle results in fewer negative outcomes than the programmed cycle. This suggests some safety concerns with the programmed cycle, even though it remains common in clinical practice.

Overall, both treatments are generally considered safe, but the modified natural cycle might slightly reduce risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about comparing the modified natural cycle and programmed cycle for frozen embryo transfers because they are exploring how the presence or absence of the corpus luteum affects pregnancy outcomes. Unlike traditional protocols that may not differentiate based on the natural hormonal environment, the modified natural cycle takes advantage of the body’s own corpus luteum, potentially offering a more natural hormonal balance. On the other hand, the programmed cycle provides a controlled hormonal environment by omitting the corpus luteum, which might standardize and simplify the process. By comparing these two methods, researchers hope to determine which approach leads to better pregnancy success rates, providing valuable insights for couples undergoing fertility treatments.

What evidence suggests that this trial's treatments could be effective for pregnancy?

This trial will compare the modified natural cycle with the programmed cycle for frozen embryo transfer (FET). Research has shown that a modified natural cycle for FET might increase the chances of pregnancy and live birth compared to hormone replacement therapy (HRT) cycles. In a natural cycle, the body's own hormones are used, potentially increasing the likelihood of pregnancy. The programmed cycle, which uses external hormones, is also effective for FET. However, some studies suggest that natural cycles might reduce the risk of negative outcomes. Both methods are effective for FET, but natural cycles might offer advantages in pregnancy rates and safety. ^{3 4 5 6 7}

Who Is on the Research Team?

Valerie Baker, MD

Principal Investigator

Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine

James Segars, MD

Principal Investigator

Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine

Are You a Good Fit for This Trial?

Women aged 18-41 with at least one high-quality or genetically tested blastocyst for IVF, a normal uterine cavity, regular ovulatory cycles, and a BMI <=40. They must be willing to undergo single embryo transfer and randomization to either modified natural or programmed cycle FET. Exclusions include use of donor oocytes, uncontrolled diabetes or hypertension, certain uterine anomalies, and systemic rheumatologic diseases.

Inclusion Criteria

I have at least one healthy embryo frozen for future use.

You have regular periods that happen every 24-35 days, which means you are likely ovulating.

I am open to any treatment cycle and can take progesterone shots if needed.

Exclusion Criteria

Embryos created using donated eggs.

The couple planning to participate in the study is using a method of IVF where one partner provides the eggs and the other partner carries the pregnancy.

You are a surrogate mother carrying someone else's baby.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo up to 3 frozen embryo transfer cycles in either a modified natural or programmed cycle

Varies per participant

Follow-up

Participants are monitored for preeclampsia and live birth outcomes during pregnancy and up to 6 weeks post-delivery

During pregnancy through 6 weeks post-delivery

What Are the Treatments Tested in This Trial?

Interventions

• Modified natural cycle
• Programmed cycle

Trial Overview The NatPro trial is testing two different methods for frozen embryo transfer in IVF: the 'modified natural cycle' which works with the body's own hormones (corpus luteum present), versus the 'programmed cycle' where specific hormones are administered (corpus luteum absent). Women will be randomly assigned to one of these two approaches.

How Is the Trial Designed?

Group I: Programmed cycle Active Control 1 Intervention

corpus luteum absent

Group II: Modified natural cycle Active Control 1 Intervention

corpus luteum present

Who Is Running the Clinical Trial?

JHSPH Center for Clinical Trials

Lead Sponsor

Trials

14

Recruited

11,200+

Published Research Related to This Trial

In a study of 98 women who conceived via frozen-thawed embryo transfer, modified natural cycle FET (NC-FET) was found to significantly reduce the risk of hypertensive disorders during pregnancy compared to artificial cycle FET (AC-FET).

There was no significant difference in birth weights between the two groups, indicating that NC-FET is as effective as AC-FET in terms of neonatal outcomes, making it the preferred method for women with ovulatory cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers? Zaat, TR., Brink, AJ., de Bruin, JP., et al.[2021]

In a study of 530 patients undergoing frozen embryo transfer (FET), no significant differences were found in implantation or ongoing pregnancy rates between hormone replacement therapy (HRT) and natural cycle (NC) protocols, indicating similar efficacy.

However, the HRT group experienced a higher miscarriage rate (21.2%) compared to the natural cycle groups (12.9% for hCG and 11.1% for LH surge), suggesting that while HRT is convenient, it may carry a greater risk of miscarriage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Endometrial Preparation Protocols for Frozen Embryo Transfer on Live Birth Rates. Cerrillo, M., Herrero, L., Guillén, A., et al.[2020]

A systematic review of 18 randomized controlled trials involving 3815 women found no significant differences in live birth or miscarriage rates between natural cycle frozen-thawed embryo transfer (FET) and hormone therapy (HT) FET, indicating that both methods are similarly effective for subfertile women.

The review highlighted that HT FET with GnRHa suppression resulted in lower live birth rates compared to HT alone, suggesting that the addition of GnRHa may be beneficial in improving outcomes for women undergoing FET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cycle regimens for frozen-thawed embryo transfer. Ghobara, T., Gelbaya, TA., Ayeleke, RO.[2023]

Natural cycle frozen-thawed embryo transfer (NC-FET) resulted in a significantly higher clinical pregnancy rate (46.9%) compared to modified natural cycle frozen-thawed embryo transfer (mNC-FET) with luteal phase support (29.7%), indicating that NC-FET may be a more effective approach for embryo transfer.

Even after adjusting for various confounding factors, NC-FET and NC-FET with luteal phase support showed better pregnancy outcomes than mNC-FET, suggesting that the use of hCG triggering or progesterone supplementation in mNC-FET may negatively impact pregnancy success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frozen-thawed embryo transfers in natural cycles with spontaneous or induced ovulation: the search for the best protocol continues. Montagut, M., Santos-Ribeiro, S., De Vos, M., et al.[2018]

The modified natural cycle (mNC) protocol for frozen embryo transfer (FET) resulted in significantly higher clinical pregnancy rates (CPR) and live birth rates (LBR) compared to both natural cycle (NC) and programmed/artificial cycle (AC) protocols, with LBRs of 36.3% for mNC versus 32.3% for NC and 26.6% for AC.

There were no significant differences in outcomes between the NC and AC protocols, indicating that both methods are equally effective, but mNC is the preferred option for better success rates in women undergoing FET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endometrial preparation methods prior to frozen embryo transfer: A retrospective cohort study comparing true natural cycle, modified natural cycle and artificial cycle. Mensing, L., Dahlberg, ES., Bay, B., et al.[2022]

In a study of 198 women undergoing their first frozen embryo transfer (FET) after a failed fresh IVF cycle, delaying the FET by 22 days or more did not improve live birth rates (LBR) or clinical pregnancy rates (CPR) compared to immediate FET.

The only notable difference was a slight delay in ovulation day for the immediate FET group, suggesting that patients can proceed with FET sooner without negatively impacting reproductive outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified natural-cycle cryopreserved embryo transfer: is a washout period needed after a failed fresh cycle? Horowitz, E., Mizrachi, Y., Farhi, J., et al.[2020]

In a study of 229 singleton live births from frozen embryo transfers (FET), no significant differences in obstetric complications or perinatal outcomes were found between natural cycle (NC-FET) and hormone therapy cycle (HT-FET) groups.

Despite NC-FET showing higher serum levels of progesterone and estradiol around the time of embryo transfer, these hormonal differences did not correlate with improved clinical outcomes, suggesting that the hormonal environment may not be the main factor influencing pregnancy success in FET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of serum estradiol and progesterone levels during implantation on obstetrical complications and perinatal outcomes in frozen embryo transfer. Lin, YL., Ho, CH., Chung, MT., et al.[2023]

The COMPETE trial is a large, open-label, randomized controlled study aiming to compare the live birth rates between natural cycle (NC) and hormone replacement treatment (HT) protocols in 888 women undergoing frozen embryo transfer, with the primary outcome being live birth from the first transfer after randomization.

The study will also assess various secondary outcomes related to pregnancy and maternal health, such as miscarriage rates, gestational diabetes, and preterm birth, to evaluate the overall safety and efficacy of both protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of endometrial preparation protocols (natural cycle versus hormone replacement cycle) for frozen embryo transfer (COMPETE): a study protocol for a randomised controlled trial. Liu, X., Wen, W., Wang, T., et al.[2022]

In a study evaluating three different regimens for preparing the endometrium for frozen embryo transfer, all methods (natural cycle, hormonally manipulated artificial programmed, and stimulated cycles) showed similar effectiveness in achieving pregnancy outcomes.

However, the natural cycle regimen was associated with a higher probability of pregnancy compared to the other methods, suggesting it may be the preferred approach for endometrial preparation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of cycle regimen used for endometrium preparation on the outcome of day 3 frozen embryo transfer cycle. Konc, J., Kanyo, K., Varga, E., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4971564/

Modified natural cycle frozen-thawed embryo transfer in ... However, Xiao et al showed that natural cycle had a higher trend of clinical pregnancy rate using natural cycle for FET in their study.

2. sciencedirect.com sciencedirect.com/science/article/pii/S1472648324009787

Cycle management in frozen embryo transfer: the best of ... The latest Cochrane review indicates that FET cycles are as effective as fresh cycles (OR 1.08, 95% CI 0.95–1.22) (Zaat et al., 2021). A notable multicentre ...

3. academic.oup.com academic.oup.com/hropen/article/2025/3/hoaf047/8203478

Pregnancy and perinatal outcomes after modified natural ... Frozen embryo transfers (FETs) have become indispensable in the field of assisted reproduction. Instead of using artificial hormonally stimulated cycles for ...

4. fertstert.org fertstert.org/article/S0015-0282(25)00541-2/fulltext

Modified versions of natural frozen embryo transfers do not ... Four commonly used modified natural, stimulated, and natural FET protocols were evaluated, including: a true natural cycle with no modifications ...

5. frontiersin.org frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1416841/full

Comparison of clinical outcomes and perinatal ... This study highlighted that NC yielded higher live birth and clinical pregnancy rates in comparison to HRT in women with regular menstruation.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10477943/

Obstetric and neonatal outcomes after natural versus ... Based on current evidence, there is no difference in pregnancy rates when natural cycle FET (NC-FET) is compared to artificial cycle FET (AC-FET) ...

7. fertstert.org fertstert.org/article/S0015-0282(25)00324-3/fulltext

MODIFIED-NATURAL CYCLES (mNC) ARE REIGNING ... This study demonstrates a 32.6% increase in live birth for those that utilized a mNC FET. These results may have important clinical implications.