Prevalence, causes, and impact of non-visualized pregnancy losses in a recurrent pregnancy loss population.

STUDY QUESTION: Does the occurrence of non-visualized pregnancy loss (NVPL) affect future reproductive outcomes in patients with recurrent pregnancy loss (RPL)? SUMMARY ANSWER: The number of previous NVPLs is a significant predictor of subsequent live birth in patients with RPL. WHAT IS KNOWN ALREADY: The number of preceding miscarriages is a strong indicator for future reproductive outcomes. However, NVPL particularly has been sparsely addressed in previous literature. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study of 1981 patients attending a specialized recurrent pregnancy loss clinic (RPL) from January 2012 to March 2021. A total of 1859 patients met the inclusion criteria of the study and were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with a history of RPL, defined as ≥2 pregnancy losses before 20 weeks gestation, who attended a specialized RPL clinic in a tertiary care center were included. Patients' evaluation included parental karyotyping, antiphospholipid antibodies screening, uterine cavity assessment with hysterosalpingography (HSG) or hysteroscopy, maternal thyroid stimulating hormone (TSH) testing, and serum hemoglobin A1C testing. Other investigations were performed only when indicated such as testing for inherited thrombophilias, serum prolactin, oral glucose tolerance test, and endometrial biopsy. Patients were divided into three groups; patients who experienced NVPLs only (pure NVPLs group), patients with only visualized pregnancy losses (pure VPLs group), and patients with history of both NVPLs and VPLs (mixed group). Statistical analysis was performed using Wilcoxon rank-sum tests for continuous variables and Fisher's exact tests for categorical variables. Significance was detected when P values <0.05. A logistic regression model was used to determine the impact of NVPLs and VPLs numbers on any live birth subsequent to the initial RPL clinic visit. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of patients with pure NVPLs, pure VPLs, and mixed losses was 14.7% (274/1859), 31.8% (591/1859), and 53.5% (994/1859), respectively. The prevalence of acquired and congenital uterine anomalies diagnosed by HSG or hysteroscopy was significantly different between pure NVPLs, pure VPLs, and mixed groups (16.8% versus 23.7% versus. 20.7%, respectively P = 0.05). There were no significant differences in the results of other RPL investigations or baseline demographics between the three groups. A logistic regression model controlling for maternal age at the initial RPL clinic visit and the follow-up duration showed that the numbers of NVPLs (odds ratio (OR): 0.77, CI: 0.68-0.88) and VPLs (OR: 0.75, CI: 0.64-0.86) are strong predictors for subsequent live births after the initial RPL clinic visit (P < 0.001). The odds of having a live birth decreased by 23% and 25% with each additional NVPL and VPL, respectively. LIMITATIONS, REASONS FOR CAUTION: This study may be limited by its retrospective design. Some of our data, including home pregnancy tests and obstetric history, are based on patient self-reporting, which could have overstated the true prevalence of NVPLs. Another limitation is the lack of available live birth data for all patients at the time of the analysis. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study to examine and analyze the reproductive outcomes of patients with pure NVPLs in a substantial cohort of patients with RPL. NVPLs seem to affect future live births the same way as clinical miscarriages, which supports their inclusion in RPL definitions. STUDY FUNDING/COMPETING INTEREST(S): This study was supported in part by Canadian Institute Heath Grant (CIHR): Reference Number/W11-179912 and Women's Health Research Institute (WHRI), Vancouver, BC, Canada. M.A.B: Research grants from Canadian Institute for Health Research (CIHR) and Ferring Pharmaceutical. M.A.B. is on the advisory board for AbbVie and Baxter. TRIAL REGISTRATION NUMBER: N/A.

Impact of 3.5% O2 culture on embryo development and clinical outcomes: a comparative study.

OBJECTIVE: To evaluate the effect of culturing human embryos in vitro in 3.5% oxygen (O2) concentration. DESIGN: Comparative study. SETTING: Private IVF center. PATIENT(S): The study included 558 women in two groups. INTERVENTION(S): After intracytoplasmic sperm injection (ICSI), women's oocytes were assigned to undergo cultivation in either 3.5% O2 concentration (intervention) or 5% O2 level (control group), continuously, from day 0 through day 5 or 6. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (PR) after ET. RESULT(S): There were significantly higher fertilization and cleavage rates in the 3.5% O2 group (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.53-1.93) and (OR 3.74, 95% CI 2.30-6.07) than in the 5% O2 group. The compaction rate on day 3, and the number of formed, high-quality and cryopreserved blastocysts on day 5 were significantly lower in 3.5% O2 than in 5% O2 concentration ([OR 0.81, 95% CI 0.69-0.91], [OR 0.40, 95% CI 0.36-0.46], [OR 0.32, 95% CI 0.28-0.37] and [OR 0.47, 95% CI 0.40-0.54]), respectively. Culturing embryos in 3.5% O2 concentration led to significantly lower rates of biochemical pregnancy, clinical PR, and implantation ([OR 0.66, 95% CI 0.47-0.92], [OR 0.60, 95% CI 0.43-0.84] and [OR 0.61, 95% CI 0.46-0.81]), respectively. CONCLUSION(S): Culturing human embryos, continuously from day 0 to 5 or 6, in 3.5% O2 concentration is associated with significantly lower blastocyst formation rate and clinical outcomes parameters, but rather with significantly higher rates of fertilization and cleavage. Whether these findings hold true for other patient populations and culture media brands remain unknown.

Humid versus dry incubator: a prospective, randomized, controlled trial.

OBJECTIVE: To evaluate the efficacy of a dry versus humidified incubator on human embryo development ex vivo. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Private fertility centers. PATIENT(S): A total of 297 women undergoing in vitro fertilization randomized into two groups. INTERVENTION(S): From days 0 to day 5 or 6 of culture, intervention group embryos exposed to dry culture and control group embryos exposed to humidified culture. MAIN OUTCOME MEASURE(S): Subsequent ongoing pregnancy rate. RESULT(S): After transfer of embryos, there were statistically significantly lower rates of clinical and ongoing pregnancy in the dry culture arm than in the humidified culture arm (odds ratio [OR] 0.57; 95% confidence interval [CI], 0.36-0.91; versus OR 0.54; 95% CI, 0.34-0.85). On day 3 of culture, embryo quality and compaction were lower in the dry culture group (OR 0.38; 95% CI, 0.32-0.45) than in the group exposed to humidified culture (OR 0.23; 95% CI, 0.19-0.27). On day 5 of culture, embryos in dry culture had a lower rate of blastocyst formation (OR 0.39; 95% CI, 0.33-0.46), quality (OR 0.34; 95% CI, 0.29-0.40), and cryopreservation (OR 0.41; 95% CI, 0.35-0.48). CONCLUSION(S): In this study, human embryos cultivated ex vivo in a dry incubator had statistically significantly decreased implantation and clinical and ongoing pregnancy rates. Our findings indicate the need for larger multicenter, randomized, controlled trials. CLINICAL TRIAL REGISTRATION NUMBER: NCT01695096.