Rectal progesterone administration secures a high ongoing pregnancy rate in a personalized Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) protocol: a prospective interventional study.

STUDY QUESTION: Can supplementation with rectal administration of progesterone secure high ongoing pregnancy rates (OPRs) in patients with low serum progesterone (P4) on the day of blastocyst transfer (ET)? SUMMARY ANSWER: Rectally administered progesterone commencing on the ET day secures high OPRs in patients with serum P4 levels below 35 nmol/l (11 ng/ml). WHAT IS KNOWN ALREADY: Low serum P4 levels at peri-implantation in Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) cycles impact reproductive outcomes negatively. However, studies have shown that patients with low P4 after a standard vaginal progesterone treatment can obtain live birth rates (LBRs) comparable to patients with optimal P4 levels if they receive additionalsubcutaneous progesterone, starting around the day of blastocyst transfer. In contrast, increasing vaginal progesterone supplementation in low serum P4 patients does not increase LBR. Another route of administration rarely used in ART is the rectal route, despite the fact that progesterone is well absorbed and serum P4 levels reach a maximum level after ∼2 h. STUDY DESIGN, SIZE, DURATION: This prospective interventional study included a cohort of 488 HRT-FET cycles, in which a total of 374 patients had serum P4 levels ≥35 nmol/l (11 ng/ml) at ET, and 114 patients had serum P4 levels <35 nmol/l (11 ng/ml). The study was conducted from January 2020 to November 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients underwent HRT-FET in a public Fertility Clinic, and endometrial preparation included oral oestradiol (6 mg/24 h), followed by vaginal micronized progesterone, 400 mg/12 h. Blastocyst transfer and P4 measurements were performed on the sixth day of progesterone administration. In patients with serum P4 <35 nmol/l (11 ng/ml), 'rescue' was performed by rectal administration of progesterone (400 mg/12 h) starting that same day. In pregnant patients, rectal administration continued until Week 8 of gestation, and oestradiol and vaginal progesterone treatment continued until Week 10 of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: Among 488 HRT-FET single blastocyst transfers, the mean age of the patients at oocyte retrieval (OR) was 30.9 ± 4.6 years and the mean BMI at ET 25.1 ± 3.5 kg/m2. The mean serum P4 level after vaginal progesterone administration on the day of ET was 48.9 ± 21.0 nmol/l (15.4 ± 6.6 ng/ml), and a total of 23% (114/488) of the patients had a serum P4 level lower than 35 nmol/l (11 ng/ml). The overall, positive hCG rate, clinical pregnancy rate, OPR week 12, and total pregnancy loss rate were 66% (320/488), 54% (265/488), 45% (221/488), and 31% (99/320), respectively. There was no significant difference in either OPR week 12 or total pregnancy loss rate between patients with P4 ≥35 nmol/l (11 ng/ml) and patients with P4 <35 nmol/l, who received rescue in terms of rectally administered progesterone, 45% versus 46%, P = 0.77 and 30% versus 34%, P = 0.53, respectively. OPR did not differ whether patients had initially low P4 and rectal rescue or were above the P4 cut-off. Logistic regression analysis showed that only age at OR and blastocyst scoring correlated with OPR week 12, independently of other factors like BMI and vitrification day of blastocysts (Day 5 or 6). LIMITATIONS, REASONS FOR CAUTION: In this study, vaginal micronized progesterone pessaries, a solid pessary with progesterone suspended in vegetable hard fat, were used vaginally as well as rectally. It is unknown whether other vaginal progesterone products, such as capsules, gel, or tablet, could be used rectally with the same rescue effect. WIDER IMPLICATIONS OF THE FINDINGS: A substantial part of HRT-FET patients receiving vaginal progesterone treatment has lowserum P4. Adding rectally administered progesterone in these patients increases the reproductive outcome. Importantly, rectal progesterone administration is considered convenient, and progesterone pessaries are easy to administer rectally and of low cost. STUDY FUNDING/COMPETING INTEREST(S): Gedeon Richter Nordic supported the study with an unrestricted grant as well as study medication. B.A. has received unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA and Marckyrl Pharma. P.H. has received honoraria for lectures from Gedeon Richter, Merck, IBSA and U.S.K. has received grant from Gedeon Richter Nordic, IBSA and Merck for studies outside this work and honoraria for teaching from Merck and Thillotts Pharma AB and conference expenses covered by Merck. The other co-authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER (25): EudraCT no.: 2019-001539-29.

Endometriosis patients benefit from high serum progesterone in hormone replacement therapy-frozen embryo transfer cycles: a cohort study.

RESEARCH QUESTION: What is the optimal serum progesterone cut-off level in patients with endometriosis undergoing hormone replacement therapy frozen embryo transfer (HRT-FET) with intensive progesterone luteal phase support? DESIGN: A cohort study, including 262 HRT-FET cycles in 179 patients all diagnosed with endometriosis either by laparoscopy or by ultrasound in patients with visible endometriomas. Pre-treatment consisted of 42 days of oral contraceptive pills and 5 days' wash-out, followed by 6 mg oral oestrogen daily. Exogenous progesterone supplementation with vaginal progesterone gel 90 mg/12h commenced when the endometrium was 7 mm or thicker. From the fourth day of vaginal progesterone supplementation, patients also received intramuscular progesterone 50 mg daily. Blastocyst transfer was scheduled for the sixth day of progesterone supplementation. RESULTS: The overall positive HCG, live birth (LBR) and total pregnancy loss rates were 60%, 39% and 34%, respectively. The optimal progesterone cut-off level was 118 nmol/l (37.1 ng/ml) defined as the maximum of the Youden index. The unadjusted LBR was significantly higher in patients with progesterone measuring 118 nmol/l or above compared with patients with progesterone measuring less than 118 nmol/l (51% [44/86] versus 34% [59/176], P = 0.01), whereas the adjusted odds ratio for a live birth was 2.1 (95% CI 1.2 to 3.7) after adjusting for age, body mass index, blastocyst score, blastocyst age, quality and number of blastocysts transferred. CONCLUSIONS: Serum progesterone levels above 118 nmol/l (37.1ng/ml) resulted in significantly higher LBR compared with lower serum progesterone levels, suggesting that a threshold for optimal serum progesterone exists.

Association with pre-pregnancy BMI on early pregnancy loss in infertility patients in first HRT-FET cycles: A retrospective cohort study.

OBJECTIVE: To investigate the association between pre-pregnancy body mass index (BMI) and the early pregnancy loss rate in patients in first hormone replacement therapy-frozen-thawed embryo transfer (HRT-FET) cycles and find the threshold. METHODS: A retrospective cohort study was conducted using a total of 14030 HRT-FET cycles at the Reproductive Center from January 2017 to December 2021. The association of pre-pregnancy BMI on early pregnancy loss rate in patients in HRT-FET cycles was assessed by performing univariate analysis, multivariable logistic regression, curve fitting and threshold effect analysis. RESULTS: There were 2076 cycles of early pregnancy loss, and the pregnancy loss rate was 14.80%. After adjusting for confounding factors, the early pregnancy loss rate of the obese group was significantly higher than that of the normal weight group (P < 0.05). The threshold effect analysis showed that as the pre-pregnancy BMI ranged from 21.2 to 25.8 kg/m2, the early pregnancy loss rate came to the plateau phase at the low level. In addition, when the BMI was ≥ 25.8 kg/m2, the early pregnancy loss rate increased by 3% (aOR = 1.03, P = 0.01) with each 1 kg/m2 increment of BMI. CONCLUSION: The early pregnancy loss rate might achieve a low level when the pre-pregnancy BMI was within the range of 21.2- 25.8 kg/m2. The early pregnancy loss rate would increase when pre-pregnancy BMI is more than 25.8 kg/m2. For patients in HRT-FET cycles, adjusting their pre-pregnancy BMI to the optimal level by following a healthy diet and daily exercise may help to reduce the early pregnancy loss.

Does serum progesterone level impact the ongoing pregnancy rate in frozen embryo transfer under artificial preparation with vaginal progesterone? Study protocol for a randomized controlled trial.

BACKGROUND: In previous retrospective studies, low serum progesterone level on the embryo transfer day is associated with lower clinical pregnancy and ongoing pregnancy rates. Whether adding progesterone in low serum progesterone patients can rescue the outcome, there is no sufficient evidence from randomized controlled studies. METHODS: This trial is a clinical randomized controlled study (high serum progesterone vs low serum progesterone 1:1, 1:1 randomization ratio of intervention vs the control group with low serum progesterone). The eligible hormone replacement therapy-frozen embryo transfer (HRT-FET) cycles, will be recruited and randomly assigned to two parallel groups when serum progesterone is < 7.24µg/l on the day of embryo transfer for D3. The intervention group will be extrally given intramuscular progesterone 40 mg per day from D3 to 8 weeks of gestation if clinical pregnancy. The primary outcome is the ongoing pregnancy (beyond 12 weeks of gestation) rate. DISCUSSION: The findings of this study will provide strong evidence for whether the progesterone addition from the D3 in low serum progesterone patients can improve the outcome in the HRT-FET cycle. TRIAL REGISTRATION: ClinicalTrials.gov NCT04248309 . Registered on January 28, 2020.

Comparison of vaginal progesterone gel combined with oral dydrogesterone versus intramuscular progesterone for luteal support in hormone replacement therapy-frozen embryo transfer cycle.

BACKGROUND: It remains under subject of debate regarding the optimal route of luteal support for hormone replacement therapy- frozen embryo transfer (HRT-FET) cycles. We compared efficacy of vaginal progesterone gel combined with oral dydrogesterone and intramuscular progesterone for HRT-FET lutein support. METHODS: This is a retrospective observational study. After matching for propensity score of getting vaginal + oral treatment, a total of 208 FET cycles in the vaginal progesterone combined with oral dydrogesterone and 624 cycles in the intramuscular progesterone group were enrolled. Pregnancy outcomes and neonatal outcomes including chemical pregnancy rate, clinical pregnancy rate, implantation rate, spontaneous abortion rate, live birth rate, gestational weeks, pre-term delivery, birth weight, and congenital anomalies rate were compared. RESULTS: No significant differences were observed in patient characteristics such as age, duration of infertility, type of infertility, or hormone level after matching. Chemical pregnancy rate (68.3 % versus 70.5 %), clinical pregnancy rate (64.9 % versus 64.4 %), implantation rate (52.3 % versus 50.2 %), spontaneous abortion rate (21.5 % versus 18.4 %), and live birth rate (49.0 % versus 51.3 %) were similar in both group without statistically significant difference. No significant differences in neonatal outcomes were observed between the two groups. CONCLUSION: We observed similar pregnancy outcomes in both vaginal progesterone gel combined with oral dydrogesterone and intramuscular progesterone protocol. Vaginal progesterone gel combined with oral dydrogesterone can be substituted for intramuscular progesterone given that vaginal plus oral use has good safety and is more convenient and may be associated with less side effect caused by intramuscular injection.

Perinatal outcomes after fresh versus vitrified-warmed blastocyst transfer: retrospective analysis.

OBJECTIVE: To investigate the possible effect of controlled ovarian stimulation on the perinatal outcomes of assisted reproductive technology pregnancies, by comparing the outcomes from fresh ET with frozen ET (FET) with blastocysts of similar quality. DESIGN: Retrospective observational study. SETTING: Private fertility center. PATIENT(S): Seven hundred eighty-four fresh transfers and 382 vitrified-warmed double blastocyst transfers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Miscarriage, perinatal mortality, preterm delivery, live birth, live-birth weights, and gestational age of live births. RESULT(S): FET resulted in higher implantation rates (51.5% vs. 40.6%), higher live-birth rates per transfer (56.8% vs. 44.3%), and lower ectopic pregnancy rates (0.32% vs. 1.80%). FET pregnancies also had higher day 14 ßhCG levels per implantation (148.2 vs. 176.2 IU/L) and higher infant birth weights (singletons Δ109.4 g, twins Δ124 g). Female infants benefitted the most in terms of birth weight. Miscarriage, premature delivery, perinatal morbidity, and live birth per pregnancy were all nonsignificantly different between fresh ET and FET. CONCLUSION(S): Clinically significant differences between the peri-implantation and perinatal outcomes of fresh ET and FET suggest better endometrial receptivity and placentation in FET cycles.