Natural vs Programmed Frozen Embryo Transfer for Pregnancy

(NatPro Trial)

Recruiting at 14 trial locations

Overseen By Kevin Doody, 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

788 Participants Needed

Trial Summary

What is the purpose of this trial?

NatPro is a two-arm, parallel-group, multi-center, randomized trial in which women undergoing frozen embryo transfer (FET) will be randomized to receive either a modified natural cycle (corpus luteum present) or a programmed cycle (corpus luteum absent).

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.

What data supports the idea that Natural vs Programmed Frozen Embryo Transfer for Pregnancy is an effective treatment?

The available research shows that both natural cycle (NC) and hormone therapy (HT) frozen embryo transfers are effective treatments. Some studies suggest that NC might be as good as or even better than HT for patients with regular cycles. This is because NC uses the body's natural hormones, which might lead to better outcomes. However, the research is still ongoing to determine which method is more effective overall. Both methods are simpler and less costly compared to other treatments like repeated fresh embryo transfers. ^{1 2 3 4 5}

What data supports the effectiveness of this treatment for pregnancy?

Research suggests that natural cycle frozen embryo transfer (FET) may be as effective or even better than hormone replacement therapy (HRT) for patients with regular cycles, potentially leading to similar or improved pregnancy outcomes. ^{1 2 3 4 6}

What safety data exists for natural vs programmed frozen embryo transfer treatments?

The safety data for natural vs programmed frozen embryo transfer treatments includes studies on obstetric and neonatal risks, as well as obstetric complications and perinatal outcomes. One study suggests increased obstetric and neonatal risks in artificial cycles compared to modified natural cycles. Another study evaluates obstetric complications and perinatal outcomes in natural cycle (NC-FET) versus hormone therapy cycle (HT-FET), focusing on serum estradiol and progesterone levels. Additionally, there is concern about increased maternal and perinatal morbidity in hormone therapy protocols due to the lack of corpus luteum. Overall, these studies provide insights into the safety and risks associated with different frozen embryo transfer protocols. ^{1 2 5 7 8}

Is frozen embryo transfer generally safe for humans?

Research suggests that there may be increased risks for mothers and newborns when using hormone therapy cycles (HT-FET) compared to natural cycles (NC-FET) for frozen embryo transfers. However, the safety of these methods can vary, and it's important to discuss individual risks with a healthcare provider. ^{1 2 5 7 8}

Is the treatment Modified natural cycle, Programmed cycle a promising treatment for pregnancy?

The Modified natural cycle and Programmed cycle treatments are promising for pregnancy because they are effective in preparing the body for frozen embryo transfer, with some studies suggesting a higher chance of pregnancy with the natural cycle. ^{1 2 5 6 9}

How does the modified natural cycle treatment for frozen embryo transfer differ from other treatments?

The modified natural cycle (mNC) treatment for frozen embryo transfer is unique because it closely mimics a woman's natural menstrual cycle, potentially leading to a higher probability of pregnancy compared to hormonally manipulated or stimulated cycles. Unlike hormone replacement treatments, mNC involves minimal medication, reducing the risk of complications associated with the absence of the corpus luteum, which is important for hormone production during early pregnancy. ^{1 2 5 6 9}

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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 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]

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]

References

1. England 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Frozen-thawed embryo transfers in natural cycles with spontaneous or induced ovulation: the search for the best protocol continues. [2018]

3. Israel pubmed.ncbi.nlm.nih.gov

Impact of Endometrial Preparation Protocols for Frozen Embryo Transfer on Live Birth Rates. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Cycle regimens for frozen-thawed embryo transfer. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Modified natural-cycle cryopreserved embryo transfer: is a washout period needed after a failed fresh cycle? [2020]

6. Germany 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. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers? [2021]

8. Netherlands 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. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

The effect of cycle regimen used for endometrium preparation on the outcome of day 3 frozen embryo transfer cycle. [2022]