Endometrial microbiota composition is associated with reproductive outcome in infertile patients.

BACKGROUND: Previous evidence indicates associations between the female reproductive tract microbiome composition and reproductive outcome in infertile patients undergoing assisted reproduction. We aimed to determine whether the endometrial microbiota composition is associated with reproductive outcomes of live birth, biochemical pregnancy, clinical miscarriage or no pregnancy. METHODS: Here, we present a multicentre prospective observational study using 16S rRNA gene sequencing to analyse endometrial fluid and biopsy samples before embryo transfer in a cohort of 342 infertile patients asymptomatic for infection undergoing assisted reproductive treatments. RESULTS: A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus and Streptococcus was associated with unsuccessful outcomes. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes. CONCLUSIONS: Our findings indicate that endometrial microbiota composition before embryo transfer is a useful biomarker to predict reproductive outcome, offering an opportunity to further improve diagnosis and treatment strategies. Video Abstract.

Natural cycle IVF reduces the risk of low birthweight infants compared with conventional stimulated IVF.

STUDY QUESTION: Are perinatal outcomes improved in singleton pregnancies resulting from fresh embryo transfers performed following unstimulated/natural cycle IVF (NCIVF) compared with stimulated IVF? SUMMARY ANSWER: Infants conceived by unstimulated/NCIVF have a lower risk of being low birthweight than infants conceived by stimulated IVF; however, this risk did not remain significant after adjusting for gestation age. WHAT IS ALREADY KNOWN: Previous studies have shown that infants born after modified NCIVF have a higher average birthweight and are less likely to be low birthweight than those infants conceived with conventional stimulated IVF. STUDY DESIGN, SIZE AND DURATION: Retrospective cohort study of singleton live births in non-smoking women undergoing fresh IVF-embryo transfer cycles from 2007 to 2013 in a single IVF center. The women were stratified by stimulated (n = 174) or unstimulated (n = 190) IVF exposure status. Unstimulated/NCIVF is defined as IVF without the use of exogenous gonadotrophins, and only includes the use of HCG to time oocyte retrieval. PARTICIPANTS/MATERIALS, SETTING, METHODS: Demographic data including maternal age, BMI, infertility diagnosis and IVF cycle characteristics were collected. The perinatal outcomes used for comparison between the two study groups were length of gestation, birthweight, preterm delivery, very preterm delivery, low birthweight, small for gestational age and large for gestational age. MAIN RESULTS AND ROLE OF CHANCE: Although women in the NCIVF group were older than those in the stimulated group (35.0 versus 34.2 years, P < 0.05), parity and history of prior ART cycles were comparable between the groups. The mean birthweight was significantly higher in the NCIVF group by 163 g than in the stimulated group (3436 ± 420 g versus 3273 ± 574 g, P < 0.05). Consistent with this finding, there were also less low birthweight (<2500 g) infants in the NCIVF group versus stimulated group (1 versus 8.6%, P < 0.005). The reduction in risk for low birthweight in the NCIVF group remained significant after adjustment for maternal age, infertility diagnosis, ICSI, number of embryos transferred and blastocyst transfer (odds ratio (OR) 0.07; 95% CI 0.014-0.35). As NCIVF group had less preterm infants, additional adjustment for gestational age was performed and this showed a tendency towards lower risk of low birthweight in NCIVF (OR 0.11; 95% CI 0.01-1.0). While gestational age at delivery was comparable between the groups, both preterm births (<37 weeks gestation) (31 versus 42%, P < 0.05) and very preterm births (<32 weeks gestation) (0.52 versus 6.3%, P < 0.005) were significantly reduced in the NCIVF group. However, after adjustment for potential confounders, the reduction in risk of preterm and very preterm delivery associated with the NCIVF group was no longer significant (OR 1.1; 95% CI 0.48-2.5). LIMITATIONS, REASONS FOR CAUTION: Limitations of this study are the retrospective nature of the data collection and the lack of information about parental characteristics associated with birthweight. WIDER IMPLICATIONS OF THE FINDINGS: The improved perinatal outcomes following successful unstimulated/NCIVF suggest that this treatment should be considered as a viable option for infertile couples. NCIVF could reduce potential adverse perinatal outcomes such as low birthweight related to fresh embryo transfers performed following ovarian stimulation. The etiology of the improved perinatal outcomes following NCIVF needs to be explored further to determine if the improvement is derived from endometrial factors versus follicular/oocyte factors. STUDY FUNDING/COMPETING INTERESTS: The study was supported by the following grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD K12HD047018 (W.M.), NICHD K12HD001271 (L.A.K.). The authors have no competing interests.

Follicular and estradiol parameters that improve success with natural cycle in vitro fertilization.

OBJECTIVE: To describe clinical thresholds for follicle size and estradiol levels to optimize success with natural cycle in vitro fertilization (NCIVF). STUDY DESIGN: Descriptive cohort of candidates for stimulated IVF, < 43 years old, with regular menstrual cycles, regardless of ovarian reserve or fertility treatment history. Patients underwent NCIVF, defined as oocyte retrieval, fertilization and embryo transfer after human chorionic gonadotropin (hCG) trigger without luteinizing hormone (LH) suppression or ovarian stimulation medications. RESULTS: A total of 422 patients underwent 821 NCIVF cycles. Clinical pregnancy rates per cycle start, retrieval, and transfer were 13%, 17%, and 32%, respectively, for all patients and 19%, 25%, and 49% for patients < 30 years old. The threshold estradiol level on day of hCG was 101 pg/mL; below that level no clinical pregnancies occurred. Likewise, a mean follicular diameter > 15 mm was the optimal threshold for hCG trigger. Anti-Müllerian hormone and follicle-stimulating hormone levels did not predict success in NCIVF, and no statistical difference in clinical pregnancy rates between day 3 or day 5 embryo transfer was observed. CONCLUSION: NCIVF is an effective therapy for infertile patients regardless of their ovarian reserve. Cycle cancellation due to a premature LH surge can be reduced, without sacrificing success, by triggering smaller follicles above a threshold level of estradiol.

Utilization and success rates of unstimulated in vitro fertilization in the United States: an analysis of the Society for Assisted Reproductive Technology database.

OBJECTIVE: To examine the utilization and outcomes of natural cycle (unstimulated) IVF as reported to the Society of Assisted Reproductive Technology (SART) in 2006 and 2007. DESIGN: Retrospective analysis. SETTING: Dataset analysis from the SART Clinical Outcome Reporting System national database. PATIENT(S): All patients undergoing IVF as reported to SART in 2006 and 2007. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Utilization of unstimulated IVF; description of patient demographics; and comparison of implantation and pregnancy rates between unstimulated and stimulated IVF cycles. RESULT(S): During 2006 and 2007 a total of 795 unstimulated IVF cycles were initiated. Success rates were age dependent, with patients <35 years of age demonstrating clinical pregnancy rates per cycle start, retrieval, and transfer of 19.2%, 26.8%, and 35.9%, respectively. Implantation rates were statistically higher for unstimulated compared with stimulated IVF in patients who were 35 to 42 years old. CONCLUSION(S): Unstimulated IVF represents <1% of the total IVF cycles initiated in the United States. The pregnancy and live birth rates per initiated cycle were 19.2% and 15.2%, respectively, in patients <35 years old. The implantation rates in unstimulated IVF cycles compared favorably to stimulated IVF. Natural cycle IVF may be considered in a wide range of patients as an alternative therapy for the infertile couple.