Perinatal outcomes of pregnancies following autologous cryopreserved ovarian tissue transplantation: a systematic review with pooled analysis.

OBJECTIVE: This study aimed to synthesize the existing evidence on perinatal outcomes after autologous cryopreserved ovarian tissue transplantation, concurrently identifying key factors influencing these outcomes. DATA SOURCES: A comprehensive search was performed on MEDLINE, Embase, and Cochrane Library databases to identify relevant studies on the effect of autologous cryopreserved ovarian tissue transplantation on perinatal outcomes from inception to October 22, 2023. Where there was missing information, the authors were contacted for updated data. STUDY ELIGIBILITY CRITERIA: Observational studies, such as cohort studies, case series, and case reports that reported a live birth after autologous cryopreserved ovarian tissue transplantation, were considered eligible. Studies lacking data on women's demographic characteristics, autologous cryopreserved ovarian tissue transplantation procedure details, or perinatal outcomes were excluded. In addition, cases involving fresh or nonautologous transplantations and those addressing primary ovarian insufficiency were excluded. METHODS: Two reviewers (M.E. and E.U.) independently performed the study selection, data extraction, and risk of bias assessment, and the results were then reviewed together. The PRISMA guidelines were followed, and the protocol was registered on PROSPERO (CRD42023469296). RESULTS: This review included 58 studies composed of 122 women with 162 deliveries (154 singletons and 8 twins) after autologous cryopreserved ovarian tissue transplantation, resulting in 170 newborns. Of note, 83.6% of the women had a malignant disease. Moreover, most of these women (51.0%) were exposed to some form of chemotherapy before ovarian tissue cryopreservation. Of the 162 childbirths, 108 (66.7%) were conceived naturally, and 54 (33.3%) were conceived through assisted reproductive techniques. The birthweight of 88.5% of newborns was appropriate for gestational age, whereas 8.3% and 3.1% were small for gestational age and large for gestational age, respectively. The preterm birth rate was 9.4%, with the remaining being term deliveries. Hypertensive disorders of pregnancy were noted in 18.9% of women, including pregnancy-induced hypertension in 7.6%, preeclampsia in 9.4%, and hemolysis, elevated liver enzymes, and low platelet count in 1.9%. The incidences of gestational diabetes mellitus and preterm premature rupture of membranes were 3.8% for each condition. Neonatal anomalies were reported in 3 transplant recipients with 4 newborns: arthrogryposis, congenital cataract, and diaphragmatic hernia in a twin. Finally, among the recipients' characteristics, not receiving chemotherapy before ovarian tissue cryopreservation (odds ratio, 0.23; 95% confidence interval, 0.07-0.72; P=.012) and natural conception (odds ratio, 0.29; 95% confidence interval, 0.09-0.92; P=.035) were associated with a lower perinatal complication rate. CONCLUSION: On the basis of low certainty evidence from observational studies, perinatal complication rates did not increase after autologous cryopreserved ovarian tissue transplantation compared with the general pregnant population, except for preeclampsia. This could be due to chemotherapy exposure, underlying medical conditions, and the common use of assisted reproductive techniques. Further larger studies are needed to explore the causes of increased preeclampsia incidence in autologous cryopreserved ovarian tissue transplantation pregnancies.

The effect of ≤6 cm sized noncavity-distorting intramural fibroids on in vitro fertilization outcomes: a systematic review and meta-analysis.

IMPORTANCE: The potential detrimental effects of fibroids on natural fecundity and in vitro fertilization (IVF) outcomes may be influenced by their size, location, and number. The impact of small noncavity-distorting intramural fibroids on reproductive outcomes in IVF is still controversial, with conflicting results. OBJECTIVE(S): To determine whether women with noncavity-distorting intramural fibroids of ≤6 cm size have lower live birth rates (LBRs) in IVF than female age-matched controls with no fibroids. DATA SOURCES: MEDLINE, Embase, Global Health, and Cochrane Library databases were searched from inception until July 1, 2022. STUDY SELECTION AND SYNTHESIS: Women undergoing IVF with noncavity-distorting intramural fibroids ≤6 cm constituted the study group (n = 520), whereas women with no fibroid formed the controls (n = 1392). Female age-matched subgroup analyses were performed to evaluate the impact of different cut-offs for size (≤6, ≤4, and ≤2 cm), location (the International Federation of Gynecology and Obstetrics [FIGO] type-3), and the number of fibroids on reproductive outcomes. Mantel-Haenszel odds ratios (ORs) with 95% confidence intervals (CIs) were used for outcome measures. All statistical analyses were performed using RevMan 5.4.1 MAIN OUTCOME MEASURE(S): The primary outcome measure was LBR. Secondary outcome measures were clinical pregnancy, implantation, and miscarriage rates. RESULT(S): After adopting the eligibility criteria, 5 studies were included in the final analysis. Women with ≤6 cm noncavity-distorting intramural fibroids had significantly lower LBRs (OR: 0.48, 95% CI: 0.36-0.65, 3 studies, I2=0; low-certainty evidence) compared with women with no fibroids. A significant reduction in LBRs was noted in ≤4 cm but not in the ≤2 cm subgroups. The FIGO type-3 fibroids of 2-6 cm size were associated with significantly lower LBRs. Owing to a lack of studies, the impact of the number of noncavity-distorting intramural fibroids (single vs. multiple) on IVF outcomes could not be assessed. CONCLUSION(S): We conclude that 2-6 cm sized noncavity-distorting intramural fibroids have a deleterious effect on LBRs in IVF. The presence of FIGO type-3 fibroids of 2-6 cm size is associated with significantly lower LBRs. Conclusive evidence from high-quality randomized controlled trials, the reference standard study design for studies of health care interventions, is needed before myomectomy might be offered in daily clinical practice to women with such small fibroids before undergoing IVF treatment.

A drop in serum progesterone from oocyte pick-up +3 days to +5 days in fresh blastocyst transfer, using hCG-trigger and standard luteal support, is associated with lower ongoing pregnancy rates.

STUDY QUESTION: Do early- and mid-luteal serum progesterone (P4) levels impact ongoing pregnancy rates (OPRs) in fresh blastocyst transfer cycles using standard luteal phase support (LPS)? SUMMARY ANSWER: A drop in serum P4 level from oocyte pick-up (OPU) + 3 days to OPU + 5 days (negative ΔP4) is associated with a ∼2-fold decrease in OPRs. WHAT IS KNOWN ALREADY: In fresh embryo transfer cycles, significant inter-individual variation occurs in serum P4 levels during the luteal phase, possibly due to differences in endogenous P4 production after hCG trigger and/or differences in bioavailability of exogenously administered progesterone (P) via different routes. Although exogenous P may alleviate this drop in serum P4 in fresh transfer cycles, there is a paucity of data exploring the possible impact on reproductive outcomes of a reduction in serum P4 levels. STUDY DESIGN, SIZE, DURATION: Using a prospective cohort study design, following the initial enrollment of 558 consecutive patients, 340 fulfilled the inclusion and exclusion criteria and were included in the final analysis. The inclusion criteria were: (i) female age ≤40 years, (ii) BMI ≤35 kg/m2, (iii) retrieval of ≥3 oocytes irrespective of ovarian reserve, (iv) the use of a GnRH-agonist or GnRH-antagonist protocol with recombinant hCG triggering (6500 IU), (v) standard LPS and (vi) fresh blastocyst transfer. The exclusion criteria were: (i) triggering with GnRH-agonist or GnRH-agonist plus recombinant hCG (dual trigger), (ii) circulating P4 >1.5 ng/ml on the day of trigger and (iii) cleavage stage embryo transfer. Each patient was included only once. The primary outcome was ongoing pregnancy (OP), as defined by pregnancy ≥12 weeks of gestational age. PARTICIPANTS/MATERIALS, SETTING, METHODS: A GnRH-agonist (n = 53) or GnRH-antagonist (n = 287) protocol was used for ovarian stimulation. Vaginal progesterone gel (Crinone, 90 mg, 8%, Merck) once daily was used for LPS. Serum P4 levels were measured in all patients on five occasions: on the day of ovulation trigger, the day of OPU, OPU + 3 days, OPU + 5 days and OPU + 14 days; timing of blood sampling was standardized to be 3-5 h after the morning administration of vaginal progesterone gel. The delta P4 (ΔP4) level was calculated by subtracting the P4 level on the OPU + 3 days from the P4 level on the OPU + 5 days, resulting in either a positive or negative ΔP4. MAIN RESULTS AND THE ROLE OF CHANCE: The median P4 (min-max) on the day of triggering, day of OPU, OPU + 3 days, OPU + 5 days and OPU + 14 days were 0.83 ng/ml (0.18-1.42), 5.81 ng/ml (0.80-22.72), 80.00 ng/ml (22.91-161.05), 85.91 ng/ml (15.66-171.78) and 13.46 ng/ml (0.18-185.00), respectively. Serum P4 levels uniformly increased from the day of OPU to OPU + 3 days in all patients; however, from OPU + 3 days to OPU + 5 days, some patients had a decrease (negative ΔP4; n = 116; 34.1%), whereas others had an increase (positive ΔP4; n = 220; 64.7%), in circulating P4 levels. Although the median (min-max) P4 levels on the day of triggering, the day of OPU, and OPU + 3 days were comparable between the negative ΔP4 and positive ΔP4 groups, patients in the former group had significantly lower P4 levels on OPU + 5 days [69.67 ng/ml (15.66-150.02) versus 100.51 ng/ml (26.41-171.78); P < 0.001] and OPU + 14 days [8.28 ng/ml (0.28-157.00) versus 19.01 ng/ml (0.18-185.00), respectively; P < 0.001]. A drop in P4 level from OPU + 3 days to OPU + 5 days (negative ΔP4) was seen in approximately one-third of patients and was associated with a significantly lower OPR when compared with positive ΔP4 counterparts [33.6% versus 49.1%, odds ratio (OR); 0.53, 95% CI; 0.33-0.84; P = 0.008]; this decrease in OPR was due to lower initial pregnancy rates rather than increased overall pregnancy loss rates. For negative ΔP4 patients, the magnitude of ΔP4 was a significant predictor of OP (adjusted AUC = 0.65; 95% CI; 0.59-0.71), with an optimum threshold of -8.73 ng/ml, sensitivity and specificity were 48.7% and 79.2%, respectively. BMI (OR; 1.128, 95% CI; 1.064-1.197) was the only significant predictor of having a negative ΔP4; the higher the BMI, the higher the risk of having a negative ΔP4. Among positive ΔP4 patients, the magnitude of ΔP4 was a weak predictor of OP (AUC = 0.56, 95% CI; 0.48-0.64). Logistic regression analysis showed that blastocyst morphology (OR; 5.686, 95% CI; 1.433-22.565; P = 0.013) and ΔP4 (OR; 1.013, 95% CI; 0.1001-1.024; P = 0.031), but not the serum P4 level on OPU + 5 days, were the independent predictors of OP. LIMITATIONS, REASONS FOR CAUTION: The physiological circadian pulsatile secretion of P4 during the mid-luteal phase is a limitation; however, blood sampling was standardized to reduce the impact of timing. WIDER IMPLICATIONS OF THE FINDINGS: Two measurements (OPU + 3 days and OPU + 5 days) of serum P4 may identify those patients with a drop in P4 (approximately one-third of patients) associated with ∼2-fold lower OPRs. Rescuing these IVF cycles with additional P supplementation or adopting a blastocyst freeze-all policy should be tested in future randomized controlled trials. STUDY FUNDING/COMPETING INTEREST(S): None. S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. P.H. has received unrestricted research grants from MSD and Merck, as well as honoraria for lectures from MSD, Merck, Gedeon-Richter, Theramex, and IBSA. H.Y. declares receipt of honorarium for lectures from Merck, IBSA and research grants from Merck and Ferring. The remaining authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: The study was registered at clinical trials.gov (NCT04128436).

Adnexal masses in patients with colorectal cancer.

OBJECTIVE: To evaluate the clinicopathological features and outcomes of patients undergone surgery for benign and metastatic adnexal masses during the surveillance of colorectal cancer (CRC). METHODS: A single institute retrospective study involving 90 patients diagnosed with CRC that undergone surgery at Hacettepe University Hospital between 2000-2018. Clinicopathological and survival data was obtained from hospital records. RESULTS: Elevated blood levels of CEA (HR, 1.23; 95 % CI: 1.03-1.24; p = 0.01), adnexal masses larger than 5 cm (HR, 3.296; 95 % CI: 1.527-7.076; p = 0.002), bilaterality of adnexal mass (HR, 2.200; 95 % CI: 2.464-11.969; p = 0.001) and high PCI score (HR, 0.150; 95 % CI: 0.044-0.479; p = 0.01) were found to be significantly associated with ovarian metastasis. There was a significant difference in overall survival (OS), with respect to complete and incomplete resection in adnexal surgery of ovarian metastasis (46.6 vs. 29.6 months; p = 0.004). The median survival time was 32.8 months for patients with ≤ 24 months interval time to adnexal metastasis surgery, and 48.5 months for patients with >24 months interval time to adnexal metastasis surgery (p = 0.001). CONCLUSION: This study showed that numerous clinicopathological variables such as bilaterality and size of adnexal mass, serum blood levels of CEA and PCI score may have a significant impact on the prediction and management of ovarian masses diagnosed during CRC surveillance. Complete resection and interval time to adnexal surgery is significantly associated with OS.

A cut-off value for systemic immune-inflammation index in the prediction of adverse neonatal outcomes in preterm premature rupture of the membranes.

AIM: To determine a cut-off value for systemic immune-inflammation index (SII)(neutrophil × platelet /lymphocyte) in the prediction of adverse neonatal outcomes in preterm premature rupture of the membranes (PPROM). METHODS: This retrospective cohort study was conducted among singleton pregnancies with PPROM. Cases were divided into two main groups: Group 1) PPROM diagnosed at 24th-28th weeks of gestation and Group 2) PPROM diagnosed at >28th-34th weeks of gestation. Thereafter, main study groups were divided into two subgroups: Subgroup A: pregnancies with favorable neonatal outcomes and Subgroup B: pregnancies with composite adverse neonatal outcomes. Subgroups were compared in terms of demographic features, clinical characteristics, laboratory test results and SII values. Furthermore, cut-off values of SII for the prediction of composite adverse neonatal outcomes were determined for two main groups. A Mann-Whitney U test was conducted to compare the median values and the chi-square test was used to compare categorical variables among the groups. Receiver operating characteristic (ROC) curves were used to assess the performance of SII value in predicting composite adverse neonatal outcomes. RESULTS: Significant differences were observed for median platelet and SII values between the subgroups (P < 0.001 for both in group 1 and P = 0.002 and P = 0.005, respectively, in group 2). Cut-off values of 1695.14 109 /L (83.3% sensitivity, 85.7% specificity) and 1430.90 × 109 /L (71.4% sensitivity, 75.7% specificity) for composite adverse neonatal outcomes were determined, respectively in group 1 and 2 according to the ROC curve analysis. CONCLUSION: SII may be used as an additional indicator for the prediction of adverse neonatal outcomes in PPROM.

Circulating gut microbiota metabolite trimethylamine N-oxide and oral contraceptive use in polycystic ovary syndrome.

OBJECTIVES: Polycystic ovary syndrome (PCOS) is associated with an increased cardiometabolic risk that might not necessarily translate into adverse cardiovascular outcome later in life. Recently, alterations in gut microbial composition have been reported in the syndrome. Microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and its precursors are closely linked with development of atherosclerotic cardiovascular disease, independently of traditional risk factors. We aimed to assess whether TMAO and its precursors are altered in PCOS and to determine potential impact of treatment on these metabolites. DESIGN: Prospective study. PATIENTS: Twenty-seven overweight/obese patients with PCOS and 25 age- and BMI-matched healthy control women. MEASUREMENTS: At baseline, fasting serum TMAO and its precursors were measured after a 3-day standardized diet. Patients received 3-month OC therapy along with general dietary advice after which all measurements were repeated. RESULTS: Patients had higher total testosterone (T) and free androgen index (FAI) whereas whole-body fat mass, fasting plasma glucose, insulin and lipids were similar between the groups. PCOS group showed significantly higher serum levels of TMAO and its precursors; choline, betaine and carnitine. TMAO and choline showed correlations with T. After 3 months of OC use, TMAO and its precursors significantly decreased along with reductions in BMI, T and FAI. CONCLUSIONS: This study reports for the first time that TMAO and its precursors are elevated in PCOS which might contribute to increased cardiometabolic risk of the syndrome and that short-term OC use along with lifestyle intervention is associated with reduction of these microbiome-dependent metabolites.