Beyond the uterine first pass: optimizing programmed frozen embryo transfers. A mini-review.

With the greatly increased popularity of segmented in vitro fertilization and frozen embryo transfers, progesterone replacement strategies in programmed cycles are being reexamined. Bidirectionality and the limited capacity of the uterine first pass provide an explanation for disconnects between the endometrial and serum levels when either vaginal or intramuscular progesterone is used alone. Whereas monotherapy departs from the physiology of spontaneous pregnancies, combined therapy provides physiologic replacement while minimizing the number of injections.

Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study.

STUDY QUESTION: Does an individualised luteal phase support (iLPS), according to serum progesterone (P4) level the day prior to euploid frozen embryo transfer (FET), improve pregnancy outcomes when started on the day previous to embryo transfer? SUMMARY ANSWER: Patients with low serum P4 the day prior to euploid FET can benefit from the addition of daily subcutaneous P4 injections (Psc), when started the day prior to FET, and achieve similar reproductive outcomes compared to those with initial adequate P4 levels. WHAT IS KNOWN ALREADY: The ratio between FET/IVF has spectacularly increased in the last years mainly thanks to the pursuit of an ovarian hyperstimulation syndrome free clinic and the development of preimplantation genetic testing (PGT). There is currently a big concern regarding the endometrial preparation for FET, especially in relation to serum P4 levels around the time of embryo transfer. Several studies have described impaired pregnancy outcomes in those patients with low P4 levels around the time of FET, considering 10 ng/ml as one of the most accepted reference values. To date, no prospective study has been designed to compare the reproductive outcomes between patients with adequate P4 the day previous to euploid FET and those with low, but restored P4 levels on the transfer day after iLPS through daily Psc started on the day previous to FET. STUDY DESIGN, SIZE, DURATION: A prospective observational study was conducted at a university-affiliated fertility centre between November 2018 and January 2020 in patients undergoing PGT for aneuploidies (PGT-A) IVF cycles and a subsequent FET under hormone replacement treatment (HRT). A total of 574 cycles (453 patients) were analysed: 348 cycles (leading to 342 euploid FET) with adequate P4 on the day previous to FET, and 226 cycles (leading to 220 euploid FET) under iLPS after low P4 on the previous day to FET, but restored P4 levels on the transfer day. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall we included 574 HRT FET cycles (453 patients). Standard HRT was used for endometrial preparation. P4 levels were measured the day previous to euploid FET. P4 > 10.6 ng/ml was considered as adequate and euploid FET was performed on the following day (FET Group 1). P4 < 10.6 ng/ml was considered as low, iLPS was added in the form of daily Psc injections, and a new P4 analysis was performed on the following day. FET was only performed on the same day when a restored P4 > 10.6 ng/ml was achieved (98.2% of cases) (FET Group 2). MAIN RESULTS AND THE ROLE OF CHANCE: Patient's demographics and cycle parameters were comparable between both euploid FET groups (FET Group 1 and FET Group 2) in terms of age, weight, oestradiol and P4 levels and number of embryos transferred. No statistically significant differences were found in terms of clinical pregnancy rate (56.4% vs 59.1%: rate difference (RD) -2.7%, 95% CI [-11.4; 6.0]), ongoing pregnancy rate (49.4% vs 53.6%: RD -4.2%, 95% CI [-13.1; 4.7]) or live birth rate (49.1% vs 52.3%: RD -3.2%, 95% CI [-12; 5.7]). No significant differences were also found according to miscarriage rate (12.4% vs 9.2%: RD 3.2%, 95% CI [-4.3; 10.7]). LIMITATIONS, REASONS FOR CAUTION: Only iLPS through daily Psc was evaluated. The time for Psc injection was not stated and no serum P4 determinations were performed once the pregnancy was achieved. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides information regarding an 'opportunity window' for improved ongoing pregnancy rates and miscarriage rates through a daily Psc injection in cases of inadequate P4 levels the day previous to FET (P4 < 10.6 ng/ml) and restored values the day of FET (P4 > 10.6 ng/ml). Only euploid FET under HRT were considered, avoiding one of the main reasons of miscarriage and implantation failure and overcoming confounding factors such as female age, embryo quality or ovarian stimulation protocols. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received. B.C. reports personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, IBSA and Gedeon Richter outside the submitted work. N.P. reports grants and personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, Theramex and Besins International and personal fees from IBSA and Gedeon Richter outside the submitted work. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT03740568.

Low progesterone levels on the day before natural cycle frozen embryo transfer are negatively associated with live birth rates.

STUDY QUESTION: Are progesterone (P) levels on the day before natural cycle frozen embryo transfer (NC-FET) associated with live birth rate (LBR)? SUMMARY ANSWER: Regular ovulatory women undergoing NC-FET with serum P levels <10 ng/ml on the day before blastocyst transfer have a significantly lower LBR than those with serum P levels >10 ng/ml. WHAT IS KNOWN ALREADY: The importance of serum P levels around the time of embryo transfer in patients undergoing FET under artificial endometrial preparation has been well established. However, no study has analyzed the importance of serum P levels in patients undergoing FET under a true natural endometrial preparation cycle. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study including 294 frozen blastocyst transfers under natural cycle endometrial preparation at a university-affiliated fertility centre between January 2016 and January 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients had regular menstrual cycles and underwent NC-FET with their own oocytes. Only patients who had undergone serum P measurement between 8 am and 11 am on the day before FET were included. Patients did not receive any external medication for endometrial preparation or luteal phase support. Patients were divided into two groups according to serum P levels below or above 10 ng/ml on the day before FET. Univariate analysis was carried out to describe and compare the cycle characteristics with reproductive outcomes. To evaluate the effect of P, a multivariable logistic model was fitted for each outcome after adjusting for confounding variables. MAIN RESULTS AND THE ROLE OF CHANCE: Mean serum P levels on the day before FET were significantly higher in patients who had a live birth compared to those who did not (14.5 ± 7.0 vs 12.0 ± 6.6 ng/ml, 95% CI [0.83; 4.12]). The overall clinical pregnancy rate (CPR) and LBR were 42.9% and 35.4%, respectively. Patients in the higher P group (>10 ng/ml) had a higher LBR (41.1% vs 25.7%: risk difference (RD) 15.4%, 95% CI [5; 26]) and CPR (48.6% vs 33.0%: RD 15.6%, 95% CI [4; 27]). Patients with higher serum P levels on the day before FET (63% of patients) had an improved LBR (odds ratio: 1.05; 95% CI [1.02; 1.09]). Women with serum P levels <10 ng/ml on the day before FET (37% of patients) had significantly higher weights (62.5 ± 9.9 vs 58.1 ± 7.1 kg, 95% CI [1.92; 6.90]) and BMI (22.9 ± 3.6 vs 21.6 ± 2.7 kg/m2, 95% CI [0.42; 2.25]) compared to patients with P levels >10 ng/ml. LIMITATIONS, REASONS FOR CAUTION: The main limitation of our study is its retrospective design. Other potential limitations are the detection of LH surge through urine testing and the inclusion of patients who did and did not undergo preimplantation genetic testing for aneuploidies. The protocol used in our institution for monitoring NC-FET does not look for the onset of progesterone secretion by the corpus luteum, and a slow luteinisation process or delay of corpus luteum function cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: We provide evidence that a minimum serum P threshold (P >10 ng/ml) might be required for improved reproductive outcomes in NC-FET. This result suggests that there are different mechanisms by which P is produced and/or distributed by each patient. This study also provides an excellent model to evaluate the impact of luteal phase defect through NC-FET. A prospective evaluation to assess whether P supplementation should be individualised according to patient's needs is necessary to support our findings. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used, and there are no competing interests.

Factors associated with serum progesterone concentrations the day before cryopreserved embryo transfer in artificial cycles.

RESEARCH QUESTION: What factors determine serum progesterone concentrations the day before cryopreserved embryo transfer in artificially prepared cycles? DESIGN: Retrospective cohort study at a university-affiliated fertility centre including infertile women under 45 years old using own oocytes who underwent a total of 685 single cryopreserved blastocyst transfers under hormonal therapy. Determinants that affected live birth rate (LBR) were analysed using a multivariate logistic regression. Univariate analysis and multivariate linear regression were used to evaluate independent factors that affect serum progesterone concentrations. RESULTS: Age (odds ratio [OR] 0.93; 95% confidence interval [CI] 0.89-0.96), duration of oestradiol (OR 0.96; 95% CI 0.92-0.99), serum progesterone concentrations (OR 1.04; 95% CI 1.01-1.08) and patients who underwent preimplantation genetic testing for aneuploidies (PGT-A) (OR 2.17; 95% CI 1.55-3.03) were independently associated with LBR. After univariate analysis, determinants of progesterone concentrations were: age, weight, history of a previous cryopreserved embryo transfer with serum progesterone concentrations <10 ng/ml, and time of blood extraction. The multivariate linear regression showed that increasing age presented a positive correlation with progesterone concentrations (ß = 0.11; 95% CI 0.01-0.20). On the contrary, significant negative correlations with progesterone concentrations were shown for a previous history of serum progesterone value <10 ng/ml (ß = -3.13; 95% CI -4.45 to -1.81]), higher weight (ß = -0.05; 95% CI -0.08 to -0.01) and the time of blood sampling during the day (ß = -0.13; 95% CI -0.25 to -0.01). CONCLUSIONS: This study adds more evidence regarding the importance of serum progesterone concentrations before frozen embryo transfer (FET). It also showed that body weight, age, time of blood sampling and a history of low progesterone are determinants associated with progesterone concentrations before blastocyst FET.

Reproductive outcomes in recipients are not associated with oocyte donor body mass index up to 28 kg/m2: a cohort study of 2722 cycles.

The effect of increasing donor body mass index (BMI) on clinical pregnancies was retrospectively analysed in a cohort of consecutive 2722 donor oocyte IVF cycles. The relationship between donor BMI and clinical pregnancies was assessed after adjusting for recipient BMI. Clinical pregnancy rates and live birth rates (LBR) were no different with increasing donor BMI (up to donor BMI ≤28 kg/m2). The odds of pregnancy did not vary with donor BMI. Compared with donor BMI quartile 1, OR 95% CI of clinical pregnancy was 1.01 (0.82 to 1.25), 1.01 (0.82 to 1.25) and 0.90 (0.73 to 1.12) for quartiles 2, 3 and 4 respectively. A statistically significant reduction of cumulative LBR (P = 0.036) and LBR (P = 0.011) was observed in the results of donation cycles according to recipient BMI quartiles. A reduced odds of clinical pregnancy was observed with increasing recipient BMI. Compared with recipient BMI quartile 1, OR 95% CI of clinical pregnancy was 0.84 (0.68 to 1.03), 0.79 (0.63 to 00.97) and 0.78 (0.63 to 0.971) for quartiles 2, 3 and 4, respectively. A negative effect on oocyte donation cycle outcomes with increased donor BMI was not found after adjusting oocyte donor and recipient BMI.