Introduction:

Based on recent studies the suggestion is that natural cycle frozen embryo transfers (NC FET) should preferably be used, with evidence suggesting that artificial cycle FET (AC FET) is subject to increased risks of adverse obstetric and perinatal outcomes and possibly lower live birth rates. There, however, is limited evidence on the most efficient and effective timing of NC FET following oocyte retrieval.

Objective: In this non-inferiority randomised controlled trial, the effect on reproductive outcomes of NC FET performed immediately following the oocyte retrieval cycle (i.e., after one menstruation) will be investigated.

Materials and Methods: At a single IVF centre, patients will be recruited from infertile patients presenting for freeze-all-IVF treatments. Patients aged 18 to 30 years will be enrolled, if they had ≤2 previous embryo transfers and had ≥1 blastocyst cryopreserved in their freeze-all cycles. Enrolled patients (N = 800) will be randomised (1:1) to either the immediate group (i.e., FET performed in the menstrual cycle immediately following the oocyte retrieval cycle) or the delayed group (i.e., FET performed in the menstrual cycle following two menstruations). All FET will be performed in NC. The primary outcome measure will be clinical pregnancy, defined as the visual confirmation by transvaginal ultrasound scan of a gestational sac with normal heartbeat at >5 weeks of gestation. The analyses will be performed according to per-procedure principles.

Results: The ovarian, endometrial and time to transfer outcomes of the immediate group will be compared with those of the delayed group. The clinical pregnancy rate of the immediate group will be compared with that of the delayed group.

Introduction The increasing success of frozen embryo transfers (FET) in assisted reproductive technology (ART), and, therefore, the increasing use of FET to overcome standard IVF complications (i.e., adverse ovarian stimulation iatrogenesis and intra-cycle discovery of intrauterine abnormalities) and to facilitate the use of modified IVF treatment (i.e., pre-implantation genetic testing and luteal ovarian stimulation) has highlighted disadvantages inherent to FET. The major concern is the evidence that FET pregnancies are subject to adverse obstetric and perinatal outcomes such as placental and hypertensive complications, large for gestational age infants, increased pregnancy loss, increased preterm delivery. Moreover, the presumed benefits of more physiological endometria in FET demands further research into the origins of the adverse obstetric and perinatal outcomes and the elimination of their causes.

Endometrial preparation methods in FET can be divided into two major groups, artificial (AC) and natural cycle (NC) methods. While the initial studies comparing endometrial preparation methods for FET and confirmed by study reviews and meta-analyses, showed that no one method was superior in terms of reproductive outcomes, recent studies have shown that the NC cycle method results in reduced adverse obstetric and perinatal outcome rates and increased live birth rates. There is increasing evidence and understanding that using the AC method significantly increases the risks of adverse obstetric and perinatal outcomes because of the absence of a functional corpus luteum (CL). In addition to the production of hormones (i.e., estrogen and progesterone), CL also produces vasoactive molecules (i.e., relaxin, vascular endothelial growth factor) essential for optimal vascular developments in early pregnancy (i.e., implantation and placentation). Based on recent studies the suggestion, therefore, is that clinicians should preferably use NC FET. Further research, however, may be required to confirm the most optimal endometrial preparation and timing (i.e., embryo and endometrial synchrony) method for FET, because suggested preference is still being based on poor-quality evidence.

There is limited evidence on the most efficient and effective timing of NC FET following oocyte retrieval (i.e., the cycle subject to ovarian stimulation), as nearly all previous studies included the investigation of mostly AC FET. These studies, at most, confirmed that reproductive outcomes were not disadvantaged if FET were performed immediately following the oocyte retrieval cycle. Therefore, suggesting that ovarian stimulation (i.e., supraphysiological hormone levels) had no spill-over effects on endometrial and ovarian function in subsequent menstrual cycles, even in the cycle immediately following oocyte retrieval. Not having an extended delay to FET is considered by most patients to be less stressful and by clinicians to be more efficient. In this non-inferiority randomised controlled trial, the effect on reproductive outcomes of NC FET performed in menstrual cycles immediately following the oocyte retrieval cycle will be investigated.

Inclusion Criteria:

• Patients with female age 18≤40 years.
• Patients who provide written informed consent to participate in the trial and for the use of their anonymized data in research.
• Patients with <2 previous IVF treatments.
• Patients with ≥1 blastocyst cryopreserved.

Exclusion Criteria:

• Patients with female age >40 years
• Patients with female BMI ≥30 kg/m2.
• Female patients with insulin dependent diabetes or non-insulin dependent diabetes mellitus and female patients with gastrointestinal, cardiovascular, pulmonary, liver or kidney disease.
• Female patients with any contraindications or allergies to the drugs used in routine freeze-all-IVF.
• Patients with untreated intrauterine anomalies and tubal pathology.
• Patients undergoing PGT-A (aneuploidy) or PGT-M (monogenic disorders)
• Patients with no blastocysts cryopreserved.

Study participants will be recruited from (unselected) infertile patients presenting for freeze-all-IVF treatment at the IVF centre from the start date of enrollment.

The

To be published immediately after publication acceptance

Open access at the Mendeley Data registry at the URLs provided