Obstetric and Neonatal Outcomes After Transferring More Than One Embryo in Patients With Preimplantation Genetic Testing.

OBJECTIVE: To compare obstetric and neonatal outcomes after single embryo transfer (SET) compared with multiple embryo transfer (MET) from frozen-thawed transfer cycles of embryos that underwent preimplantation genetic testing for aneuploidies (PGT-A). METHODS: We conducted a retrospective cohort study from the SART CORS (Society for Assisted Reproductive Technology Clinic Outcome Reporting System) national database. Clinical and demographic data were obtained from the SART CORS database for all autologous and donor egg frozen-thawed transfer cycles of embryos that underwent PGT-A between 2014 and 2016, after excluding cycles that used frozen oocytes, fresh embryo transfer, and transfers of embryos from more than one stimulation cycle. Multivariable linear and log-binomial regression models were used to estimate the relative and absolute difference in live-birth rate, multiple pregnancy rate, gestational age at delivery, and birth weight between SET compared with MET. RESULTS: In total, 15,638 autologous egg transfer cycles and 944 donor egg transfer cycles were analyzed. Although the live-birth rate was higher with MET compared with SET in the autologous oocyte cycles (64.7% vs 53.2%, relative risk [RR] 1.24, 95% CI, 1.20-1.28), the multiple pregnancy rate was markedly greater (46.2% vs 1.4%, RR 32.56, 95% CI, 26.55-39.92). Donor oocyte cycles showed similar trends with an increased live-birth rate (62.0% vs 49.7%, RR 1.26, 95% CI, 1.11-1.46) and multiple pregnancy rate (54.0% vs 0.8%) seen with MET compared with SET. Preterm delivery rates and rates of low birth weight were significantly higher in MET compared with SET in both autologous and donor oocyte cycles and were also higher in the subanalysis of singleton deliveries that resulted from MET compared with SET. CONCLUSION: Despite some improvement in live-birth rate, nearly half of the pregnancies that resulted from MET of embryos that underwent PGT-A were multiples. Compared with SET, MET is associated with significantly higher rates of neonatal morbidity, including preterm delivery and low birth weight. The transfer of more than one embryo that underwent PGT-A should continue to be strongly discouraged, and patients should be counseled on the significant potential for adverse outcomes.

Presence of endometrial nucleolar channel systems at the time of frozen embryo transfer in hormone replacement cycles with successful implantation.

OBJECTIVE: To detect nucleolar channel systems (NCSs) in cells in endometrial aspirations obtained immediately before embryo transfer during blastocyst hormone replacement therapy-frozen embryo transfer (HRT-FET) cycles without affecting implantation. DESIGN: Prospective case series. SETTING: University-affiliated fertility clinic. PATIENTS: Five patients who underwent an HRT-FET cycle consented to lower uterine segment aspiration using an open-tip embryo transfer catheter during a routine mock transfer performed immediately before embryo transfer. INTERVENTIONS: Exfoliated cells in the aspirated endometrial secretions were analyzed for the presence of NCSs using indirect immunofluorescence and, in one case, electron microscopy for unambiguous identification. MAIN OUTCOME MEASURES: On the basis of a previous study, positive NCS status was defined as the presence of NCSs in at least 3 endometrial epithelial cells (EECs). The effect of endometrial aspiration on implantation and pregnancy outcomes was assessed. RESULTS: Biochemical pregnancy, as evidenced by positive ß-human chorionic gonadotropin, was seen in 5 of 5 patients, and clinical pregnancy was seen in 2 of 5 patients. NCSs were detected in exfoliated EECs of uterine secretions in 4 of 5 patient samples and could not be unequivocally identified in 1 of 5 patient samples, which was designated as indeterminate. CONCLUSIONS: This is the first report of NCS detection in HRT-FET cycles in the absence of follicular development and ovulation. NCS status can be determined in exfoliated EECs of uterine secretions obtained at the time of embryo transfer while maintaining implantation. Our study furthers the goal of establishing whether individualized point of care testing of NCS status in HRT-FET cycles can determine optimal endometrial receptivity and improve pregnancy outcomes.

Differential impact of controlled ovarian hyperstimulation on live birth rate in fresh versus frozen embryo transfer cycles: a Society for Assisted Reproductive Technology Clinic Outcome System study.

OBJECTIVE: To study the impact of both controlled ovarian hyperstimulation (COH) length and total gonadotropin (GN) dose individually and in concert on live birth rates (LBR) in both fresh and freeze-all in vitro fertilization embryo transfer (IVF-ET) cycles. DESIGN: Historical cohort study. SETTING: Not applicable. PATIENT(S): The U.S. national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System from 2014 to 2015 was used to identify patients undergoing autologous GN stimulation IVF cycles with the use of GnRH antagonist-based suppression protocols where a single embryo transfer was performed as part of a fresh IVF-ET cycle (fresh, n = 14,866) or the first frozen embryo transfer after a freeze-all cycle (frozen, n = 2,964), and not including preimplantation genetic testing cycles. The patients' demographic and cycle characteristics, duration of COH, total GN dose, and pregnancy outcomes were extracted. Binomial regression models estimated trend and relative risk of live birth with respect to days of stimulation and total GN dose singularly, and after adjustment for a priori confounders including age, parity, body mass index, diagnosis, and maximum follicle-stimulating hormone in both fresh and frozen embryo transfer cycles. Both days of stimulation and total GN dose were then added to the multivariate model to show whether they were independently associated with LBR. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Live birth rate. RESULTS: In both fresh and frozen cycles, length of COH was significantly associated with total GN dose. On univariate analysis, LBR decreased significantly with increasing length of stimulation and increasing total GN dose in both fresh and frozen cycles. On multivariable analysis including both days of stimulation and total GN dose, days of stimulation was no longer significantly correlated with LBR, whereas total GN dose remained significantly correlated with LBR in fresh cycles only. When total GN doses ranging from <2,000 IU through 5,000 IU to >5,000 IU were compared, a significant improvement in live birth rate was noted with lower total GN doses. Specifically, GN doses <2,000 IU had a 27% higher rate of live birth compared with GN dose >5,000 IU. For GN dose groups up to 4,000 IU, the estimated effect on LBR was similar. There was a marginal improvement (13%) in LBR with GN doses of 4,000 IU to 5,000 IU compared with >5,000 IU. When the multivariate model was applied to the frozen cycles, neither total GN dose nor days of stimulation was significantly associated with LBR. CONCLUSIONS: High total GN dose but not prolonged COH is associated with decreasing LBRs in fresh cycles, whereas neither factor significantly affects LBR in frozen cycles. Consideration should be given to minimizing the total GN dose when possible in fresh autologous cycles, either by decreasing the daily dose or by limiting the length of stimulation to improve LBRs. In freeze-all cycles, the use of higher GN doses does not seem to adversely affect the LBR of the first frozen embryo transfer. High total GN dose likely exerts a negative impact on the endometrium and/or oocyte/embryo unrelated to the length of stimulation. The differential effect of total GN dose on LBR in fresh and frozen cycles may imply a greater impact exerted on the endometrium rather than the oocyte.

Length of ovarian stimulation does not impact live birth rate in fresh donor oocyte cycles: a SART CORS study.

PURPOSE: To evaluate the effect of controlled ovarian hyperstimulation length and total gonadotropin (GN) dose on recipient live birth rate (LBR) in fresh donor oocyte cycles. METHODS: Data was obtained from SART CORS on all fresh donor oocyte GnRH antagonist cycles (n = 1049) between 2014 and 2015 which resulted in a single embryo transferred. Donor and recipient demographic information and cycle characteristics were extracted. Binomial regression was used to estimate LBR with respect to days of stimulation (DOS) and total GN dose. Multivariate analysis was performed to evaluate these relationships after controlling for confounders. RESULTS: Overall LBR in fresh donor oocyte cycles was 57%. Average stimulation length was 14.3 ± 4.9 days, and total GN dose was 2464 ± 1062 IU. On univariate analysis, neither days of stimulation (p = 0.5) nor total GN dose (p = 0.57) was independently correlated with LBR. However, in prolonged stimulations (> 15 days) with high total GN dose (> 3000 IU), as both the cycle length and total GN dose increased, LBR significantly decreased from 63.81 to 48.15% (p = 0.02) and from 67.61 to 48.15% (p = 0.01), respectively. Multivariate analysis showed no significant effect of either DOS or total GN dose on LBR. CONCLUSIONS: LBR is significantly decreased in fresh donor oocyte cycles when cycles are prolonged with high total GN dose. However, after controlling for confounders neither DOS nor total GN dose significantly affects LBR.

The association between obstetrical history and preterm birth in women with uterine anomalies.

OBJECTIVE: To estimate the association between obstetric history and preterm birth in women with uterine anomalies. METHODS: This was a retrospective cohort study of women with uterine anomalies managed by one maternal-fetal medicine practice from 2005 to 2016. Women were separated into three groups based on their most recent pregnancy outcome: preterm birth <37 weeks, nulliparous, and term birth. Delivery outcomes were compared across the three groups, with the primary outcome being preterm birth <37 weeks. A subgroup analysis was performed in women with major uterine anomalies (unicornuate, bicornuate, and didelphys). RESULTS: A total of 283 women with uterine anomalies were included. Preterm birth <37 weeks was 60.4% in women with prior preterm birth versus 18.2% in nulliparous women, versus 15.8% in women with a prior term birth (p < .001). The difference between nulliparous women and women with a prior term birth was not significant (p = .635). Among the 118 women with major uterine anomalies, the likelihood of preterm birth was also highest in the prior preterm birth group (71.4 versus 26.1 versus 25.0%, p < .001), and the difference between nulliparous women and women with a prior term birth was not significant (p = .906). CONCLUSIONS: In women with uterine abnormalities, a prior preterm birth is significantly associated with recurrent preterm birth. However, a prior term birth does not lower the risk of preterm birth as compared to nulliparous women.

Outcomes of Twin Pregnancies in Women 45 Years of Age or Older.

OBJECTIVE: To investigate outcomes of twin gestations in women 45 years or older at the time of delivery. METHODS: This was a retrospective cohort study of 139 women with twin gestations who were at least 45 years old when they delivered. They were cared for at two referral centers between 2005 and 2016. Analysis included baseline characteristics and pregnancy outcomes including mode of delivery, gestational age at delivery, hypertensive disease in pregnancy, gestational diabetes, and fetal growth restriction. Univariate analysis of the association between patient characteristics and outcomes was performed. RESULTS: The mean maternal age at delivery was 47.3±1.9 years with 99.3% undergoing in vitro fertilization and 95% using donor eggs. Patients had low baseline rates of hypertension (7.2%), obesity (9.5%), and pregestational diabetes (1.4%). The average gestational age of delivery was 35.4 weeks; 22.3% delivered before 34 weeks of gestation. There were high rates of cesarean delivery (93.5%, 95% confidence interval [CI] 87.7-96.8%), preeclampsia (44.6%, 95% CI 36.3-53.3%), and gestational diabetes (19%, 95% CI 13.0-26.8%). Preeclampsia developed in 50.5% of nulliparous women compared with 30.5% of women with a prior birth (P=.028). Preterm birth at less than 34 weeks of gestation occurred in 18.1% of women of white race compared with 30.3% of women of nonwhite race (P=.036). CONCLUSION: Twin pregnancy in a predominantly healthy cohort of women who were at least 45 years old when they delivered was associated with high rates of cesarean delivery, preeclampsia, and gestational diabetes, but overall favorable outcomes.

Adjuvant gonadotrophin-releasing hormone agonist trigger with human chorionic gonadotrophin to enhance ooplasmic maturity.

This study investigates whether an adjuvant gonadotrophin-releasing hormone agonist (GnRHa) trigger with human chorionic gonadotrophin (HCG) improves fresh intracytoplasmic sperm injection (ICSI) cycle outcomes in patients with poor fertilization history after standard HCG trigger alone. This study compared 156 patients with <40% fertilization rate in a prior ICSI cycle with standard HCG trigger who underwent another ICSI cycle with a combined 2 mg GnRHa and 1500 IU HCG ovulatory trigger. There was no difference in the baseline demographics, ovarian stimulation outcomes or sperm parameters of the groups. More mature oocytes were retrieved in the combined trigger group compared with the HCG trigger group: 12 (9-14) versus 10 (7-12); P = 0.01. The fertilization rate in the combined trigger group (59.2%) was higher than the HCG group (35.3%); P = 0.01. The odds of clinical pregnancy and live birth were 1.8 and 1.7 times higher, respectively, when comparing the former group to the latter; P = 0.03. The results suggest that combined GnRHa and HCG trigger in ICSI cycles is a reasonable approach to increase oocyte maturity, specifically ooplasmic maturity, thereby increasing fertilization and improving ICSI cycle outcomes in patients with a history of poor fertilization after standard HCG trigger alone.

Glycemic control in twin pregnancies with gestational diabetes: are we improving or worsening outcomes?

OBJECTIVE: To estimate the association between glycemic control and adverse outcomes in twin pregnancies with gestational diabetes (GDM). STUDY DESIGN: A cohort of patients with twin pregnancies and GDM were identified from one maternal-fetal medicine practice from 2005 to 2014. Patients with prepregnancy diabetes were excluded. First, outcomes were compared between patients with GDMA1 and GDMA2 (gestational age at delivery, birthweight, small for gestational age (SGA, birthweight <10th percentile), preeclampsia, and cesarean delivery). Then, finger stick glucose logs were reviewed and correlated with the risk of SGA and preeclampsia. Abnormal finger stick values were defined as: fasting ≥ 90 mg/dL, 1-h postprandial ≥ 140 mg/dL, 2-h postprandial ≥ 120 mg/dL. RESULTS: Sixty-six patients with twin pregnancies and GDM were identified (incidence 9.1%). Comparing the 43 patients with GDMA1 to the 23 patients with GDMA2, outcomes were similar, aside from patients with GDMA1 having lower birthweight of the smaller twin (2184 ± 519 g versus 2438 ± 428 g, p = 0.040). The risk of preeclampsia was not associated with glycemic control. Patients with SGA had lower mean fasting values (83.3 ± 5.5 versus 87.2 ± 7.7 mg/dL, p = 0.033), and a lower percentage of abnormal fasting values (24.0% versus 36.9%, p = 0.040), abnormal post-breakfast values (9.9% versus 27.1%, p = 0.003), and total abnormal values (20.1% versus 27.7%, p = 0.055). CONCLUSION: In twin pregnancies with GDM, improved glycemic control is not associated with improved outcomes, and is associated with a higher risk of SGA. Prospective trials in twin pregnancies should be performed to establish goals for glycemic control in twin pregnancies.

Human Papillomavirus Infection, Infertility, and Assisted Reproductive Outcomes.

The human papillomavirus (HPV) is a sexually transmitted infection common among men and women across all geographic and socioeconomic subgroups worldwide. Recent evidence suggests that HPV infection may affect fertility and alter the efficacy of assisted reproductive technologies. In men, HPV infection can affect sperm parameters, specifically motility. HPV-infected sperm can transmit viral DNA to oocytes, which may be expressed in the developing blastocyst. HPV can increase trophoblastic apoptosis and reduce the endometrial implantation of trophoblastic cells, thus increasing the theoretical risk of miscarriage. Vertical transmission of HPV during pregnancy may be involved in the pathophysiology of preterm rupture of membranes and spontaneous preterm birth. In patients undergoing intrauterine insemination for idiopathic infertility, HPV infection confers a lower pregnancy rate. In contrast, the evidence regarding any detrimental impact of HPV infection on IVF outcomes is inconclusive. It has been suggested that vaccination could potentially counter HPV-related sperm impairment, trophoblastic apoptosis, and spontaneous miscarriages; however, these conclusions are based on in vitro studies rather than large-scale epidemiological studies. Improvement in the understanding of HPV sperm infection mechanisms and HPV transmission into the oocyte and developing blastocyst may help explain idiopathic causes of infertility and miscarriage.

Effect of Methotrexate or Salpingectomy for Ectopic Pregnancy on Subsequent In Vitro Fertilization-Embryo Transfer Outcomes.

OBJECTIVE: To investigate the effect of methotrexate (MTX) or salpingectomy for ectopic pregnancy on the outcomes of subsequent in vitro fertilization (IVF)-embryo transfer (ET) cycles. DESIGN: Retrospective cohort study (Canadian Task Force Classification II-3). SETTING: Academic center. PATIENTS: All patients undergoing fresh IVF-ET between January 2004 and July 2013 after treatment of an ectopic pregnancy with MTX or salpingectomy in the preceding IVF-ET cycle were analyzed for potential inclusion. INTERVENTION: MTX or laparoscopic salpingectomy for an ectopic pregnancy followed by a subsequent IVF-ET cycle. MEASUREMENTS AND MAIN RESULTS: A total of 144 patients with sonographically confirmed ectopic pregnancies were identified during the study period. Of these, 107 (74.3%) patients were treated with MTX and 37 (25.7%) were treated with laparoscopic salpingectomy. Eighty-eight patients (82.2%) in the MTX group and 22 patients (59.4%) patients in the salpingectomy group underwent a subsequent IVF-ET cycle. There were no significant differences in demographic data or baseline cycle characteristics between the 2 groups. No difference was observed in basal follicle-stimulating hormone (FSH) level before and after MTX or salpingectomy treatment. Indicators of ovarian responsiveness, including total days of stimulation, total dosage of gonadotropins, and number of mature oocytes before and after either treatment, were comparable in the 2 groups. The number of doses of MTX (1 vs > 1) did not correlate with changes in ovarian response. The pregnancy outcomes, specifically live birth, were equivalent in the 2 groups. Comparing post-MTX cycles and post-salpingectomy cycles, patients in the latter group required higher doses of gonadotropins (+705 IU vs +221.5 IU; p < .01), although the number of mature oocytes remained similar in the 2 groups. CONCLUSION: Treatment of ectopic pregnancies with MTX or salpingectomy might not adversely affect ovarian reserve, ovarian responsiveness, or subsequent IVF cycle outcomes. However, in our study cohort, patients treated with MTX, those s treated with laparoscopic salpingectomy required higher gonadotropin doses in a subsequent cycle to attain the same number of mature oocytes.

Pregnancy outcomes in patients with prior uterine rupture or dehiscence.

OBJECTIVE: To report obstetric outcomes in a series of women with prior uterine rupture or prior uterine dehiscence managed with a standardized protocol. METHODS: Series of patients delivered by a single maternal-fetal medicine practice from 2005 to 2013 with a history of uterine rupture or uterine dehiscence. Uterine rupture was defined as a clinically apparent, complete scar separation in labor or before labor. Uterine dehiscence was defined as an incomplete and clinically occult uterine scar separation with intact serosa. Patients with prior uterine rupture were delivered at approximately 36-37 weeks of gestation or earlier in the setting of preterm labor. Patients with prior uterine dehiscence were delivered at 37-39 weeks of gestation based on obstetric history, clinical findings, and ultrasonographic findings. Patients with prior uterine rupture or uterine dehiscence were followed with serial ultrasound scans to assess fetal growth and lower uterine segment integrity. Outcomes measured were severe morbidities (uterine rupture, hysterectomy, transfusion, cystotomy, bowel injury, mechanical ventilation, intensive care unit admission, thrombosis, reoperation, maternal death, perinatal death). RESULTS: Fourteen women (20 pregnancies) had prior uterine rupture and 30 women (40 pregnancies) had prior uterine dehiscence. In these 60 pregnancies, there was 0% severe morbidity noted (95% confidence interval [CI] 0.0-6.0%). Overall, 6.7% of patients had a uterine dehiscence seen at the time of delivery (95% CI 2.6-15.9%). Among women with prior uterine rupture, the rate was 5.0% (95% CI 0.9-23.6%), whereas among women with prior uterine dehiscence, the rate was 7.5% (95% CI 2.6-19.9%). CONCLUSION: Patients with prior uterine rupture or uterine dehiscence can have excellent outcomes in subsequent pregnancies if managed in a standardized manner, including cesarean delivery before the onset of labor or immediately at the onset of spontaneous preterm labor.

Effect of oocyte donation on pregnancy outcomes in in vitro fertilization twin gestations.

OBJECTIVE: To estimate the effect of oocyte donation on pregnancy outcomes in patients with twin pregnancies conceived via IVF. DESIGN: Retrospective cohort study. SETTING: Patients with IVF twin pregnancies delivered by one maternal-fetal medicine practice from 2005 to 2013. PATIENT(S): Fifty-six patients with IVF twin pregnancies who had oocyte donation and 56 age-matched controls with IVF twin pregnancies who used autologous oocytes. We excluded women aged >50 years because there were no age-matched controls aged >50 years using autologous oocytes. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Gestational hypertension, pre-eclampsia. RESULT(S): The baseline characteristics were similar between the groups, including maternal age, race, parity, chorionicity, and comorbidities. The mean (±SD) age was 43.0 ± 6.0 vs. 41.9 ± 1.7 years. There were no differences in outcomes between the groups in regard to preterm birth, birth weight, or gestational diabetes. There was a greater incidence of gestational hypertension (32.1% vs. 13.0%) and pre-eclampsia (28.3% vs. 13.0%) in the group that underwent IVF with donor oocytes. CONCLUSION(S): In patients who conceive twin pregnancies using IVF, oocyte donation increases the risk of gestational hypertension and pre-eclampsia. However, this did not translate into increased rates of preterm birth or low birth weight. Patients who require oocyte donation should be carefully counseled regarding the increased risk for pre-eclampsia and gestational hypertension but should be reassured that oocyte donation does not seem to lead to other adverse outcomes.

Type of congenital uterine anomaly and adverse pregnancy outcomes.

OBJECTIVE: To estimate whether the severity of uterine anomaly is associated with the risk of adverse pregnancy outcomes. METHODS: Retrospective cohort study of patients delivered by one maternal fetal medicine group from 2005 to 2012. We included 158 patients with a singleton pregnancy and a uterine anomaly, as well as an equal number of randomly selected unexposed singleton pregnancies delivered by the same group. Patients with uterine anomalies were subdivided into those with major fusion defects (unicornuate, bicornuate and didelphys) and minor fusion defects (arcuate, septate and t-shaped). RESULTS: The incidence of adverse pregnancy outcomes increased across unexposed patients, patients with minor fusion defects and patients with major fusion defects. These included preterm birth < 37 weeks, preterm birth < 35 weeks, birth weight < 10th percentile, birth weight < 5th percentile, preeclampsia, malpresentation and cesarean delivery. CONCLUSION: The incidence of adverse pregnancy outcomes and cesarean delivery is increased in patients with minor fusion defects and is further increased in patients with major fusion defects.