PRogrammed Versus Modified Natural Cycle After Euploid Failed Embryo Transfer

The goal of this randomized clinical trial is to compare frozen embryo transfer protocols in patients undergoing a second frozen embryo transfer (FET) after a unsuccessful first programmed FET cycle as a possible treatment for people undergoing infertility treatment.

The purpose of this research study is to:

* Determine if there is a difference between FET protocols in patients who require a second FET cycle.
* Investigate if switching the FET protocol after a failed programmed cycle is beneficial for patients undergoing a second FET cycle.
* Examine pregnancy outcomes including obstetrical and neonatal outcomes (if applicable)
* Obtain uterine flexibility/stiffness measurements via transvaginal ultrasound prior to the embryo transfer procedure. This is called shear wave elastography.

Participants will be randomized in their second FET transfer attempt to either another programmed protocol or a modified natural protocol.

This research study is studying if there is a difference in frozen embryo transfer protocols used (modified natural versus programmed) after a failed first programmed FET cycle, defined as either a negative pregnancy test or a biochemical loss, as a possible treatment for people undergoing infertility treatment and in vitro fertilization (IVF). Participants will be randomized, in a 1:1 ratio, in their second FET transfer attempt to either another programmed protocol or a modified natural protocol. Once randomized, participants will undergo routine FET monitoring based on their randomization allocation, transfer procedure and pregnancy monitoring as applicable. Additional ultrasound images will be obtained prior to the transfer procedure to assess the stiffness or flexibility of the uterus, called shear wave elastography. A participant blood sample and infant buccal swab will be collected for future research studies.

Eligibility Criteria:
Major Inclusion Criteria: The following are major inclusion criteria:

1. Patients planning to undergo frozen embryo transfer cycle with a single euploid blastocyst.
2. Patients who have previously undergone their first unsuccessful frozen embryo transfer cycle, defined as either failure of implantation with negative pregnancy test or biochemical pregnancy, using a programmed cycle protocol.
3. Preimplantation genetic testing for aneuploidy (PGT-A) of the embryo used in failed programmed embryo transfer cycle must have occurred after January 1, 2017.
4. Patients ages 18 to 53 years old as per practice guidelines.
5. Patients with BMI between 16-45 kg/m2.
6. Patients with at least one embryo remaining in storage, from either the same or a separate cohort.
7. Patients with proven ovulatory function, as defined by the presence of regular menstrual cycles or detection of luteinizing hormone surge on serum or urinary test kits.
8. Patients with ≥ 7 mm endometrial thickness prior to progesterone start in prior transfer cycle.
9. Normal uterine cavity as evidenced by recent (within 1 year) saline sonogram or hysteroscopy.

Major Exclusion Criteria: The following are exclusion criteria:

1. More than 1 prior unsuccessful frozen embryo transfer cycle.
2. The prior FET failure having had resulted in a clinical loss or ectopic pregnancy
3. Previously cancelled frozen embryo transfer cycle for inadequate endometrial response.
4. Patients who required a different route of estrogen administration in the prior programmed cycle (vaginal, transdermal, intramuscular).
5. PGT-A analysis of the available embryo for transfer performed prior to January 1, 2017.
6. Anovulatory or oligo-ovulatory patients unable to undergo modified natural endometrial preparation.
7. Patients with an endometrial thickness \< 7 mm prior to progesterone start in prior cycle.
8. History of hypertensive disorders of pregnancy, including gestational hypertension, preeclampsia, and eclampsia.
9. Mullerian anomalies, excluding arcuate uterus and repaired septum.
10. No euploid embryos available for transfer.
11. Concurrent submucosal fibroids, unrepaired uterine defects or present indication for uterine surgery.
12. Communicating hydrosalpinx without plans for surgical correction prior to study enrollment.
13. Failure of patient to agree to enrollment in study with written consent.
14. Concurrent pregnancy.
15. Concomitant use of adjunctive therapies for endometrial proliferation or receptivity, including anticoagulation and antihistamines. These must be discontinued upon enrollment.
16. Embryo planned to be used for transfer generated from surgically obtained sperm.
17. Recurrent/persistent endometrial fluid in prior cycles visualized on the majority of transvaginal ultrasound monitoring.
18. Third party reproduction patients (donor sperm sources can be included).