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Although the exact etiology of endometriosis is unknown, several hypotheses about its origin exist. Of these, Sampson's theory of retrograde menstruation is the most widely accepted. Multiple in-vitro and in vivo models have been developed to study endometriosis. Several key steps are required to establish an endometriotic implant: presence of ectopic endometrial glands and stroma, attachment of endometrial cells to the peritoneum, invasion into the mesothelium, and survival and growth of the ectopic tissue. Many of these steps are similar to those associated with neoplasia, and numerous biologic pathways are involved. It is likely that both intrinsic factors within the ectopic endometrium and permissive alterations within the host are important to the development of endometriosis. [ABSTRACT FROM AUTHOR]

Of the estimated 1.5 million men and women who were diagnosed as having cancer in 2010, approximately 10% are younger than 45 years. For these individuals, cancer treatment can be lifesaving but can permanently affect reproductive capacity. The American Society of Clinical Oncology has recommended that oncologists discuss the possibility of infertility with reproductive-age cancer patients and offer referral for fertility preservation consultation and therapy. Fertility preservation is an emerging field that offers treatment aimed at protecting future reproductive ability for individuals with cancer or other serious illnesses. Although fertility preservation strategies vary by patient age and sex, many allow patients to store gametes or reproductive tissues for potential future use to create offspring. As an emerging discipline, many questions remain about the role of fertility preservation. We performed a MEDLINE search from 1950 to June 2010 using the following MeSH terms: amenorrhea; antineoplastic agents; ovarian failure; premature; infertility, female; fertility preservation; infertility, male; adolescent and cancer; child and cancer; cryopreservation; and reproductive technologies, assisted. Studies considered for inclusion included those written in English and published before June 2010. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether the use of vaginal Endometrin plus intramuscular progesterone on every third day (VIM) in programmed frozen embryo transfer (FET) is associated with lower pregnancy and live birth rates compared to daily intramuscular progesterone (IM). FET data from a single program were collected between November 2018 and December 2021. A total of 903 FETs were analyzed, including 504 FETs in the IM group, and 399 FETs in the VIM group. Inclusion criteria were women undergoing FETs with either 50 mg daily IM progesterone only (control) or 200 mg Endometrin twice daily plus 50 mg IM progesterone on every third day, with the transfer of a single day 5 or 6 frozen embryo. There were no significant differences in patient age at time of FETs, BMI, endometrial thickness, blastocyst quality, or infertility diagnosis between the groups. The VIM had significantly lower positive hCG and clinical pregnancy rates compared to the IM (60.2% vs 72.0% and 40.6% vs 56.7%, respectively, P = 0.0002 and P < 0.0001). The live birth rate was 36.1% in the VIM, compared to 49.4% in the IM (P < 0.0001). These findings also remained significant when excluding FETs with donor egg (35.9% vs 50.1%, P < 0.0001). This study demonstrated that VIM in FET cycles yields significantly lower pregnancy and live birth rates compared to IM along. IM progesterone alone may be preferable to combined Endometrin and IM progesterone in patients undergoing programmed frozen embryo transfers., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Background: The purpose of the current study was to determine the utility of early follicular phase follicle-stimulating hormone (FSH) testing in patients undergoing in vitro fertilization (IVF)., Methods: This was a retrospective review of patients from 2012 to 2015 at Mayo Clinic in Rochester, Minnesota, USA. Included subjects had a normal anti-Müllerian hormone (AMH) of 1 to 9 ng/ml and antral follicle count (AFC) of 10 to 29. Patients were stratified by FSH level when associated estradiol was less than 50 ng/ml . In total, 225 patients were categorized into three groups: high FSH (FSH ≥10 IU/L ; n= 36), normal FSH (>5 IU/L and <10 IU/L ; n=170), and low FSH (FSH ≤5 IU/L ; n= 19). ANOVA and multiple logistic regression were used for statistical comparisons and for evaluation of the relationships between variables; significance level was set at <0.05., Results: There were no significant differences in demographics, IVF cycle type, or peak estradiol level between the groups. Patients with a high basal FSH level had a similar clinical pregnancy rate and live birth rate compared to controls and patients with low FSH. High FSH level was associated with decreased follicular development (17 versus 22; p<0.01), oocyte yield (15 versus 18; p=0.02), and embryo yield (8 versus 10; p=0.04) despite higher total doses of gonadotropins., Conclusion: Patients with normal AMH and AFC levels could be further stratified into lower responders and starting doses of medications can be adjusted based on high basal FSH levels. Therefore, it is suggested to counsel patients on pregnancy outcomes which seem to be quite similar regardless of the FSH level., Competing Interests: Conflict of Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright© 2023, Avicenna Research Institute.)

Study Question: Do women with polycystic ovary syndrome (PCOS) have a greater risk of adverse pregnancy complications (gestational diabetes, preeclampsia, cesarean section, placental abnormalities) and neonatal outcomes (preterm birth, small for gestational age, prolonged delivery hospitalization) compared to women without a PCOS diagnosis and does this risk vary by BMI, subfertility and fertility treatment utilization?, Summary Answer: Deliveries to women with a history of PCOS were at greater risk of complications associated with cardiometabolic function, including gestational diabetes and preeclampsia, as well as preterm birth and prolonged length of delivery hospitalization., What Is Known Already: Prior research has suggested that women with PCOS may be at increased risk of adverse pregnancy outcomes. However, findings have been inconsistent possibly due to lack of consistent adjustment for confounding factors, small samples size and other sources of bias., Study Design, Size, Duration: Massachusetts deliveries among women ≥18 years old during 2013-2017 from state vital records linked to hospital discharges, observational stays and emergency department visits were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) and the Massachusetts All-Payers Claims Database (APCD)., Participants/materials, Setting, Methods: PCOS was identified by ICD9 and ICD10 codes in APCD prior to index delivery. Relative risks (RRs) and 95% CI for pregnancy and delivery complications were modeled using generalized estimating equations with a log link and a Poisson distribution to take multiple cycles into account and were adjusted a priori for maternal age, BMI, race/ethnicity, education, plurality, birth year, chronic hypertension and chronic diabetes. Tests for homogeneity investigated differences between maternal pre-pregnancy BMI categories (<30, ≥30, <25 and ≥25 kg/m2) and between non-infertile deliveries and deliveries that used ART or had a history of subfertility (defined by birth certificates, SART CORS records, APCD or hospital records)., Main Results and the Role of Chance: Among 91 825 deliveries, 3.9% had a history of PCOS. Women with a history of PCOS had a 51% greater risk of gestational diabetes (CI: 1.38-1.65) and a 25% greater risk of preeclampsia (CI: 1.15-1.35) compared to women without a diagnosis of PCOS. Neonates born to women with a history of PCOS were more likely to be born preterm (RR: 1.17, CI: 1.06-1.29) and more likely to have a prolonged delivery hospitalization after additionally adjusting for gestational age (RR: 1.23, CI: 1.09-1.40) compared to those of women without a diagnosis of PCOS. The risk for gestational diabetes for women with PCOS was greater among women with a pre-pregnancy BMI <30 kg/m2., Limitations, Reasons for Caution: PCOS was defined by ICD documentation prior to delivery so there may be women with undiagnosed PCOS or PCOS diagnosed after delivery included in the unexposed group. The study population is limited to deliveries within Massachusetts among most private insurance payers and inpatient or observational hospitalization in Massachusetts during the follow-up window, therefore there may be diagnoses and or deliveries outside of the state or outside of our sample that were not captured., Wider Implications of the Findings: In this population-based study, women with a history of PCOS were at greater risk of pregnancy complications associated with cardiometabolic function and preterm birth. Obstetricians should be aware of patients' PCOS status and closely monitor for potential pregnancy complications to improve maternal and infant perinatal health outcomes., Study Funding/competing Interest(s): This work was supported by the NIH (R01HD067270). S.A.M. receives grant funding from NIH, AbbVie and the Marriot Family Foundation; payment/honoraria from the University of British Columbia, World Endometriosis Research Foundation and Huilun Shanghai; travel support for attending meetings for ESHRE 2019, IASP 2019, National Endometriosis Network UK meeting 2019; SRI 2022, ESHRE 2022; participates on the data safety monitoring board/advisory board for AbbVie, Roche, Frontiers in Reproductive Health; and has a leadership role in the Society for Women's Health Research, World Endometriosis Research Foundation, World Endometriosis Society, American Society for Reproductive Medicine and ESHRE. The other authors have no conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Numerous studies have demonstrated that assisted reproductive technology (ART: defined here as including only in vitro fertilization and related technologies) is associated with increased adverse pregnancy, neonatal, and childhood developmental outcomes, even in singletons. The comparison group for many had often been a fertile population that conceived without assistance. The Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART) was initiated to define a subfertile population with which to compare ART outcomes. Over more than 10 years, we have used the MOSART database to study pregnancy abnormalities and delivery complications but also to evaluate ongoing health of women, infants, and children. This article will review studies from MOSART in the context of how they compare with those of other investigations. We will present MOSART studies that identified the influence of ART and subfertility/infertility on adverse pregnancy (pregnancy hypertensive disorder, gestational diabetes, placental abnormality) and delivery (preterm birth, low birthweight) outcomes as well as on maternal and child hospitalizations. We will provide evidence that although subfertility/infertility increases the risk of adverse outcomes, there is additional risk associated with the use of ART. Studies exploring the contribution of placental abnormalities as one factor adding to this increased ART-associated risk will be described., Competing Interests: Conflicts of interest: All authors’ institutions received support and travel funds from one or both grants. There are no other conflicts of interest.

Background: Endometriosis and uterine fibroids are common gynecologic conditions associated with a greater risk for infertility. Previous research has suggested that these conditions are associated with adverse pregnancy outcomes, potentially because of increased utilization of fertility treatments., Objective: Our objective was to investigate whether women with a history of endometriosis or fibroids had a greater risk for adverse pregnancy outcomes and whether this risk varied by infertility history and fertility treatment utilization., Study Design: Deliveries (2013-2017) recorded in Massachusetts' vital records were linked to assisted reproductive technology data, hospital stays, and all-payer claims database. We identified endometriosis and fibroids diagnoses via the all-payer claims database before index delivery. Adjusted relative risks for pregnancy complications were modeled using generalized estimating equations with a log link and Poisson distribution. The influence of subfertility or infertility and assisted reproductive technology was also investigated., Results: Among 91,825 deliveries, 1560 women had endometriosis and 4212 had fibroids. Approximately 30% of women with endometriosis and 26% of women with fibroids experienced subfertility or infertility without utilizing assisted reproductive technology, and 34% of women with endometriosis and 21% of women with fibroids utilized assisted reproductive technology for the index delivery. Women with a history of endometriosis or fibroids were at a greater risk for pregnancy-induced hypertension, preeclampsia, or eclampsia (endometriosis relative risk, 1.17; fibroids relative risk, 1.08), placental abnormalities (endometriosis relative risk, 1.65; fibroids relative risk, 1.38), and cesarean delivery (endometriosis relative risk, 1.22; fibroids relative risk, 1.17) than women with no history of those conditions. Neonates born to women with a history of endometriosis or fibroids were also at a greater risk for preterm birth (endometriosis relative risk, 1.24; fibroids relative risk, 1.17). Associations between fibroids and low birthweight varied by fertility status or assisted reproductive technology (P homogeneity=.01) and were stronger among noninfertile women., Conclusion: Endometriosis or fibroids increased the risk for adverse pregnancy outcomes, possibly warranting differential screening or treatment., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To investigate hospitalizations up to 8 years after live birth among women who used assisted reproductive technology (ART) or who were subfertile compared with women who conceived naturally., Design: Retrospective cohort., Setting: Deliveries among privately insured women aged ≥18 years between 2004 and 2017 from Massachusetts state vital records were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System and hospital observational/inpatient stays., Patient(s): We compared patients with ART, medically assisted reproduction (MAR), and unassisted subfertile (USF) delivery with those with fertile delivery., Intervention(s): NA., Main Outcome Measure(s): Postdelivery hospitalization information was derived from the International Classification of Diseases codes for discharges and combined by type. The relative risks and 95% confidence intervals (CIs) of hospitalization for up to the first 8 years postdelivery were modeled., Result(s): Among 492,515 deliveries, 5.6% used ART, 1.6% used MAR, and 1.8% were USF. Compared with fertile deliveries, deliveries that used ART or MAR or were USF were more likely to have hospital utilization (inpatient or observational stay) for any reason for up to 8 years of follow-up (USF, adjusted relative risk [aRR], 1.18 [95% CI, 1.12-1.25]; MAR, aRR, 1.20 [1.13-1.27]; and ART, aRR, 1.29 [1.25-1.34]). Assisted reproductive technology deliveries had an increased risk of hospitalization for conditions of the cardiovascular system (aRR, 1.31 [95% CI, 1.20-1.41]), overweight/obesity (aRR, 1.30 [1.17-1.44]), diabetes (aRR, 1.25 [1.05-1.49]), reproductive tract (aRR, 1.62 [1.47-1.79]), digestive tract (aRR, 1.39 [1.30-1.49]), thyroid (aRR, 2.02 [1.80-2.26]), respiratory system (aRR, 1.13 [1.03-1.24]), and cancer (aRR, 1.40 [1.18-1.65]) up to 8 years after delivery. Deliveries with MAR and subfertility had similar patterns of hospitalization as ART deliveries., Conclusion(s): Women who conceived through fertility treatment or experienced subfertility were at increased risk of subsequent hospitalization resulting from a variety of chronic and acute conditions., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate assisted reproductive technology (ART) outcomes among adolescent and young-adult female cancer survivors., Methods: The Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) data were linked to the Massachusetts Cancer Registry for 90,928 ART cycles in Massachusetts to women ≥ 18 years old from 2004 to 2013. To estimate relative risks (RR) and 95% confidence intervals (CI), we used generalized estimating equations with a log link that accounted for multiple cycles per woman and a priori adjusted for maternal age and cycle year. The main outcomes of interest were ART treatment patterns; number of autologous oocytes retrieved, fertilized, and transferred; and rates of implantation, clinical intrauterine gestation (CIG), live birth, and pregnancy loss., Results: We saw no difference in number of oocytes retrieved (aRR: 0.95 (0.89-1.02)) or proportion of autologous oocytes fertilized (aRR: 0.99 (0.95-1.03)) between autologous cycles with and without a history of cancer; however, cancer survivors required a higher total FSH administered (aRR: 1.12 (1.06-1.19)). Among autologous cycle starts, cycles in women with a history of cancer were less likely to result in CIG compared to no history of cancer (aRR: 0.73 (0.65-0.83)); this relationship was absent from donor cycles (aRR: 1.01 (0.85-1.20)). Once achieving CIG, donor cycles for women with a history of cancer were two times more likely to result in pregnancy loss (aRR: 1.99 (1.26-3.16))., Conclusions: Our analysis suggests that cancer may influence ovarian stimulation response, requiring more FSH and resulting in lower CIG among cycle starts., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The purpose of this study was to determine if morphometric parameters that can be measured quantitatively using a time-lapse embryo incubator are associated with aneuploidy. Embryos cultured in a time-lapse incubator and assessed with preimplantation genetic testing for aneuploidy (PGT-A) were analyzed retrospectively. Morphokinetic analysis included timing of cell divisions. Quantitative morphometric measurements included the distance between the second and first polar body, zona pellucida thickness at the pronuclear stage and at the 2-cell stage, and blastomere area at the 2- and 4-cell stages. Symmetry at the 2-cell stage was determined by percent difference between blastomeres; symmetry at the 4-cell stage was the percent difference between the smallest and largest blastomeres. Maternal age, blastocyst grade and day of biopsy were recorded. Euploid embryo characteristics were compared to aneuploid embryos. A receiver operating characteristic (ROC) curve was used to evaluate cell symmetry as a predictor of aneuploidy. Embryos (n = 182) from 21 patients (age 22-43; median = 34) were analyzed. Of the 182 embryos, 45% were euploid. Euploid and aneuploid embryos had similar morphokinetics and morphometry across many measures. As expected, age and blastocyst grade were associated with embryo ploidy. It was notable that, additionally, symmetry at the 4-cell stage (27% vs 31%, p = 0.01) was also associated with embryo ploidy. The optimized cutoff from the ROC curve to predict aneuploidy was determined to be 21%. Embryos with > 21% asymmetry at the 4-cell stage had high rates of aneuploidy while morphokinetic parameters were similar. In conclusion, this suggests that embryo selection models using time-lapse parameters would improve if they incorporate cleavage-stage morphometrics., (© 2021. Society for Reproductive Investigation.)

Background: Hysteroscopy requires accurate collection of unabsorbed distension media to measure patient fluid absorption. We assessed the effectiveness and usability of a novel total capture drape compared with a standard drape during hysteroscopy., Method: Simulation trials were followed by an early-phase study to compare fluid-capture efficiency and measures of drape usability during hysteroscopy randomizing the total capture drape compared with a standard drape., Experience: Simulation trials indicated complete collection of unabsorbed fluid with the total capture drape and progressive loss of unabsorbed fluid with the standard drape. An early-phase study with 68 women found no statistical difference between groups for the hysteroscopic fluid deficit, but saw fewer cases with lost fluid in the total capture drape compared with the standard drape. Direct observation and focus group data indicated a trend for better capture of unabsorbed fluid with the total capture drape, along with increased usability once surgeons became familiar with correct placement., Conclusion: Simulation and early-phase study results are favorable for the total capture drape, demonstrating comparable fluid collection with the standard drape. With repeated use and in-service training, surgeons expressed greater confidence in the accuracy of the hysteroscopic fluid deficit with the total capture drape compared with the standard drape. Design modifications should improve overall usability and fluid-capture efficiency., Competing Interests: Financial Disclosure Paul B. Marshburn, M.D. disclosed being the inventor of U.S. patent No. 10,182,877 granted on January 22, 2019, covering the Total Capture Drape design and use. He reported no funding or financial gain from the patented drape. Paul B. Marshburn disclosed a payment for consulting from Cardinal Health. Brittany L. Anderson-Montoya disclosed receiving funding from the Society for Simulation in Healthcare for Associate Editor duties for the Journal and Mission Health for a guest speaker lecture. Leslie Hansen-Lindner reports receiving funding for expert testimony. The other authors did not report any potential conflicts of interest., (Copyright © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Contemporary embryo biopsy in the United States involves the removal of several cells from a blastocyst that would become the placenta for preimplantation genetic testing. Embryos are then cryopreserved while patients await biopsy results, with transfers occurring in a subsequent cycle as a single frozen-thawed embryo transfer, if euploid., Objective: We sought to determine if removal of these cells for preimplantation genetic testing was associated with adverse obstetrical or neonatal outcomes after frozen-thawed single embryo transfer., Study Design: We linked assisted reproductive technology surveillance data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System to birth certificates and maternal and neonatal hospitalization discharge diagnoses in Massachusetts from 2014 to 2017, considering only singleton births after frozen-thawed single embryo transfers. We compared outcomes of cycles having embryo biopsy (n=585) to those having no biopsy (n=2191) using chi-square for categorical and binary variables and logistic regression for adjusted odds ratios and 95% confidence intervals, adjusting for mother's age, race, education, parity, body mass index, birth year, insurance, and all infertility diagnoses., Results: Considering no biopsy as the reference, there was no difference between groups with respect to preeclampsia (adjusted odds ratio, 0.82; 95% confidence interval, 0.42-1.61; P=.5685); pregnancy-induced hypertension (adjusted odds ratio, 0.85; 95% confidence interval, 0.46-1.59; P=.6146); placental disorders, including placental abruption, placenta previa, placenta accreta, placenta increta, and placenta percreta (adjusted odds ratio, 1.16; 95% confidence interval, 0.60-2.24; P=.6675); preterm birth (adjusted odds ratio, 1.22; 95% confidence interval 0.73-2.03; P=.4418); low birthweight (adjusted odds ratio, 1.12; 95% confidence interval, 0.58-2.15; P=.7355); cesarean delivery (adjusted odds ratio, 1.04; 95% confidence interval, 0.79-1.38; P=.7762); or gestational diabetes mellitus (adjusted odds ratio, 0.83; 95% confidence interval, 0.50-1.38; P=.4734). In addition, there was no difference between the groups for prolonged hospital stay for mothers (adjusted odds ratio, 1.23; 95% confidence interval, 0.83-1.80; P=.3014) or for infants (95% confidence interval, 1.29; 95% confidence interval, 0.72-2.29; P=.3923)., Conclusion: Embryo biopsy for preimplantation genetic testing does not increase the odds for diagnoses related to placentation (preeclampsia, pregnancy-related hypertension, placental disorders, preterm delivery, or low birthweight), maternal conditions (gestational diabetes mellitus), or maternal or infant length of stay after delivery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate the diagnostic performance of the antimüllerian hormone (AMH) level determined using the Access AMH assay for predicting poor ovarian response (POR) defined as ≤4 oocytes retrieved, including the validation of the predefined AMH cutoff of 0.93 ng/mL in both serum and plasma., Design: Prospective cohort study., Setting: Fifteen private and academic fertility centers (14 in the United States and 1 in Canada)., Patient(s): Women aged 21-45 years planning controlled ovarian stimulation for in vitro fertilization., Intervention(s): None., Main Outcome Measure(s): Number of oocytes retrieved, categorized as POR and normal-to-high ovarian response (non-POR). The correlation of AMH level and antral follicle count., Result(s): Data were available for 472 participants who completed the study (74 with POR and 398 non-POR). The mean AMH serum level among those with POR was 0.99 ng/mL (median 0.76 ng/mL) compared with 2.83 ng/mL (median 2.36 ng/mL) among the normal-to-high responders. For confirmation of the 0.93 ng/mL AMH level cutoff as a predictor of POR, a receiver operating characteristic analysis gave an area under the curve of 0.852, with corresponding sensitivity and specificity of 63.5% and 89.2%, respectively. The associated positive predictive value was 52.2% and the negative predictive value was 92.9%. The AMH plasma values demonstrated a strong correlation with AMH serum values with an r value = 0.9980. The previously established AMH cutoff of 1.77 ng/mL for antral follicle count >15 resulted in a sensitivity of 83.8% (95% confidence interval [CI] 77.7-88.5) and a specificity of 59.9% (95% CI 54.2-65.4)., Conclusion(s): This study validated the previously established AMH cut-point for the prediction of POR. Because this cut-point may vary depending on the assay used, the specific AMH assay should be reported in the literature whenever possible., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To determine whether pregnancy outcomes are poor or futile when an intended day 5 transfer is converted to a cleavage-stage transfer because of poor embryo development or a lower number of embryos., Design: Retrospective cohort study., Setting: Academic medical center., Patients: Women with a limited number of embryos, defined as ≤6 two pronuclear embryos, after in vitro fertilization., Interventions: Patients who had a cleavage-stage transfer were age matched with patients who had a day 5 transfer., Main Outcome Measures: Live birth rate., Results: A total of 146 women were included in the study with 73 women in each group. Cleavage-stage transfer was associated with significantly lower implantation and clinical pregnancy rates compared with those of day 5 transfer. Although the live birth rate of the cleavage-stage transfer group was lower than that of the day 5 transfer group (25% vs. 40%, respectively), the cleavage-stage transfer still resulted in a live birth rate of 25%. A subanalysis comparing women who did and did not achieve live birth after cleavage-stage transfer demonstrated a live birth rate of 27% when at least one grade A embryo was transferred vs. 17% when a lesser quality embryo (grade B or C) was transferred., Conclusions: As expected, the live birth rate after cleavage-stage transfer was lower than that after day 5 transfer. However, the live birth rate of cleavage-stage transfer still fell into acceptable practice, >5%, for patients who were otherwise at very high risk of having no day 5 embryo transfer. Extended culture may not be necessary for all patients.

Purpose: We previously developed a subfertile comparison group with which to compare outcomes of assisted reproductive technology (ART) treatment. In this study, we evaluated whether insurance claims data in the Massachusetts All Payers Claims Database (APCD) defined a more appropriate comparison group., Methods: We used Massachusetts vital records of women who delivered between 2013 and 2017 on whom APCD data were available. ART deliveries were those linked to a national ART database. Deliveries were subfertile if fertility treatment was marked on the birth certificate, had prior hospitalization with ICD code for infertility, or prior fertility treatment. An infertile group included women with an APCD outpatient or inpatient ICD 9/10 infertility code prior to delivery. Fertile deliveries were none of the above. Demographics, health risks, and obstetric outcomes were compared among groups. Multivariable generalized estimating equations were used to calculate adjusted relative risk (aRR) and 95% confidence intervals (CI)., Results: There were 70,726 fertile, 4,763 subfertile, 11,970 infertile, and 7,689 ART-treated deliveries. Only 3,297 deliveries were identified as both subfertile and infertile. Both subfertile and infertile were older, and had more education, chronic hypertension, and diabetes than the fertile group and less than the ART-treated group. Prematurity (aRR = 1.15-1.17) and birthweight (aRR = 1.10-1.21) were increased in all groups compared with the fertile group., Conclusion: Although the APCD allowed identification of more women than the previously defined subfertile categorization and allowed us to remove previously unidentified infertile women from the fertile group, it is not clear that it offered a clinically significantly improved comparison group.

Objective: Assisted reproductive technology (ART)-treated women exhibit increased risk of premature delivery compared to fertile women. We evaluated whether ART treatment modalities increase prematurity and whether placental abnormalities and pregnancy-induced hypertensive (PIH) disorders mediate these risks., Method(s): This retrospective study of ART-treated and fertile deliveries (2004-2017) used an ART-cycle database linked to Massachusetts birth certificates and hospital discharges. Outcomes of late preterm birth (LPTB: 34-36 weeks gestation) and early preterm birth (EPTB: <34 weeks gestation) were compared with term deliveries (≥37 weeks gestation) in ART-treated (linked to the ART database) and fertile (no indicators of infertility or ART) deliveries. ART treatments with autologous oocyte, donor oocyte, fresh or frozen embryo transfer (FET), intracytoplasmic sperm injection (ICSI) and no-ICSI were separately compared to the fertile group. Adjusted odds ratios (AOR) were calculated with multivariable logistic regression: placental abnormalities or PIH were quantified in the pathway as mediators., Results: There were 218,320 deliveries: 204,438 fertile and 13,882 ART-treated. All treatment types increased prematurity (AOR 1.31-1.58, LPTB; AOR 1.34-1.48, EPTB). Placental abnormalities mediated in approximately 22% and 38% of the association with LPTB and EPTB, respectively. PIH mediated 25% and 33% of the association with LPTB and EPTB in FET and donor oocyte cycles, more than other treatments (<10% LPTB and <13% EPTB)., Conclusions: ART-treatment and all ART modalities increased LPTB and EPTB when compared with fertile deliveries. Placental abnormalities modestly mediated associations approximately equally, while PIH was a stronger mediator in FET and donor oocyte cycles. Reasons for differences require exploration.

Purpose: Investigate the relationship between history of cancer and adverse pregnancy outcomes according to subfertility/fertility treatment., Methods: Deliveries (2004-2013) from Massachusetts (MA) Registry of Vital Records and Statistics were linked to MA assisted reproductive technology data, hospital discharge records, and Cancer Registry. The relative risks (RR) and 95% confidence intervals of adverse outcomes (gestational diabetes (GDM), gestational hypertension (GHTN), cesarean section (CS), low birth weight (LBW), small for gestational age (SGA), preterm birth (PTB), neonatal mortality, and prolonged neonatal hospital stay) were modeled with log-link and Poisson distribution generalized estimating equations. Differences by history of subfertility/fertility treatment were investigated with likelihood ratio tests., Results: Among 662,630 deliveries, 2,983 had a history of cancer. Women with cancer history were not at greater risk of GDM, GHTN, or CS. However, infants born to women with prior cancer had higher risk of LBW (RR: 1.19 [1.07-1.32]), prolonged neonatal hospital stay (RR: 1.16 [1.01-1.34]), and PTB (RR: 1.19 [1.07-1.32]). We found clinically and statistically significant differences in the relationship between cancer history and SGA by subfertility/fertility treatment (p value, test for heterogeneity = 0.02); among deliveries with subfertility or fertility treatment, those with a history of cancer experienced a greater risk of SGA (RRsubfertile: 1.36 [1.02-1.83])., Conclusions: Women with a history of cancer had greater risk of some adverse pregnancy outcomes; this relationship varied by subfertility and fertility treatment.

Objective: To compare incidence, risk factors, and etiology of women's deaths in fertile, subfertile, and undergoing assisted reproductive technology (ART) in the years after delivery., Design: Retrospective cohort., Setting: University hospital., Patient(s): Women who had delivered in Massachusetts., Intervention(s): This study used data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System linked to vital records, hospital stays, and the Massachusetts death file. Mortality of patients delivered from 2004-2013 was evaluated through 2015. The exposure groups, determined on the basis of the last delivery, were ART-treated (linked to Society for Assisted Reproductive Technology Clinic Outcome Reporting System), subfertile (no ART but with indicators of subfertility including birth certificate checkbox for fertility treatment, prior hospitalization for infertility [International Classification of Disease codes 9 628 or V23], and/or prior delivery with checkbox or ART), or fertile (neither ART nor subfertile). Numbers (per 100,000 women-years) and causes of death were obtained from the Massachusetts death file., Main Outcome Measure(s): Mortality of women after delivery in each of the three fertility groups and the most common etiology of death in each., Result(s): We included 483,547 women: 16,429 ART, 11,696 subfertile, and 455,422 fertile among whom there were 1,280 deaths with 21.1, 25.5, and 44.7 deaths, respectively, per 100,000 women-years. External causes (violence, accidents, and poisonings) were the most common reasons for death in the fertile group. Deaths occurred on average 46 months after delivery. When external causes of death were removed, there were 19.1, 17.0, and 25.6 deaths per 100,000 women-years and leading causes of death in all groups were cancer and circulatory problems., Conclusion(s): The study presents reassuring data that death rates within 5 years of delivery in ART-treated and subfertile women do not differ from those in fertile women., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To compare neonatal health outcomes after fresh versus frozen ET (FET)., Design: Retrospective analysis of a population-based database of linked clinically assisted reproductive technology (ART) data with state vital records. Multivariable logistic regression was used to model the association between deliveries from fresh versus FET and adverse health outcomes, controlling for maternal characteristics., Setting: Not applicable., Patient(s): Live-born singleton infants born to Massachusetts women who conceived by fresh or FET after ART using autologous oocytes between July 1, 2004, and December 31, 2013., Intervention(s): None., Main Outcome Measure(s): Preterm birth, low birth weight, neonatal mortality, birth defects, organ system conditions., Result(s): Compared with infants conceived from fresh embryos, those born to mothers who underwent FET were less likely to be small for gestational age (adjusted odds ratio [AOR] = 0.56; 95% confidence interval [CI], 0.44-0.70) and low birth weight (AOR = 0.72; 95% CI, 0.59-0.88) but more likely to be large for gestational age (AOR = 1.47; 95% CI, 1.26-1.70) and to experience greater odds of infectious disease (AOR = 1.46; 95% CI, 1.03-2.06), respiratory (AOR = 1.23; 95% CI, 1.07-1.41), and neurologic (AOR = 1.32; 95% CI, 1.04-1.68) conditions. There were no statistically significant differences in preterm birth, neonatal mortality, birth defects, cardiovascular, hematologic, and gastrointestinal/feeding conditions, and for infants ≥ 35 weeks, no statistically significant differences in prolonged hospital stay (>3 days for vaginal delivery, >5 days for cesarean)., Conclusion(s): Compared with infants conceived from fresh ET, those born by FET have higher birth weight but increased odds of infectious disease, hematologic, respiratory, and neurologic abnormalities. These risks should be considered when making decisions on fresh versus FET., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of frozen, compared with fresh, embryo transfer on neonatal and pediatric weight and weight gain trajectory., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): Women who underwent fresh or frozen embryo transfer at the Mayo Clinic from 2010 to 2014. All included embryo transfers resulted in a singleton live birth. Children were followed from birth to at least 18 months. When possible, growth was evaluated to 5 years of age., Interventions(s): Fresh versus frozen embryo transfer., Main Outcome Measure(s): Propensity score methodology was used to balance the two groups by maternal characteristics and gestational age before evaluating outcomes. Each infant and childhood growth measurement was compared between the two groups., Result(s): Of the 136 women, 87 underwent a fresh embryo transfer and 49 underwent a frozen embryo transfer. Birth length and head circumference were significantly different in infants delivered after fresh versus frozen embryo transfer. There was a statistically significant difference in birth weight between infants born after fresh versus frozen embryo transfer. However, this difference did not persist when adjusted for gestational age, sex, and maternal factors. Childhood growth measurements including age- and sex-specific weight, and body mass index percentiles were not significantly different between groups., Conclusion(s): This study confirmed an association of frozen embryo transfer and increased birth weight, but the association did not persist when controlling for confounding maternal factors. We found no effect of fresh versus frozen embryo transfer on neonatal weight and childhood weight gain trajectory., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Pre-pregnancy and post-delivery hospitalizations were compared as markers for health among women who conceived using assisted reproductive technology (ART), non-ART medically assisted reproduction (MAR), no treatment (unassisted subfertile), and who were fertile., Methods: We analyzed hospital discharge data linked to Massachusetts birth certificates from 2004 to 2013 within 5 years prior to pregnancy and 8-365 days post-delivery. ART deliveries were linked from a national ART database; MAR deliveries had fertility treatment but not ART; unassisted subfertile women had subfertility but no ART or MAR; and fertile women had none of these. Prevalence of diagnoses during hospitalization was quantified. Multivariable logistic regression models with fertile deliveries as reference were adjusted for maternal age, race, education, year, and plurality (post-delivery only) with results reported as adjusted odds ratios (AORs) and 95% confidence intervals (CI)., Results: Of 170,605 privately insured, primiparous deliveries, 10,458 were ART, 3005 MAR, 1365 unassisted subfertile, and 155,777 fertile. Pre-pregnancy hospitalization occurred in 6.8% and post-delivery in 2.8% of fertile women. Subfertile groups had more pre-pregnancy hospitalizations (AOR, 95% CI: 1.84, 1.72-1.96 ART; 1.41, 1.24-1.60 MAR; 3.02, 2.62-3.47 unassisted subfertile) with endometriosis, reproductive organ disease, ectopic pregnancy/miscarriage, and disorders of menstruation, ovulation, and genital tract being common. Post-delivery hospitalizations were significantly more frequent in the ART (AOR 1.19, 95% CI 1.05-1.34) and unassisted subfertile (1.59, 1.23-2.07) groups with more digestive tract disorders, thyroid problems, and other grouped chronic disease conditions., Conclusions: Greater likelihood of hospitalization in the ART, MAR, and unassisted subfertile groups is largely explained by admissions for conditions associated with subfertility.

Iatrogenic menopause with consequent infertility is a major complication in reproductive-age women undergoing hematopoietic cell transplantation (HCT). Recent guidelines recommend a discussion of the possibility of infertility and the options for fertility preservation as part of informed consent before initiation of any cancer-directed therapy, including HCT. Women age 15 to 49 years at the time of allogeneic HCT, between the years 2001 and 2017, were identified from the Mayo Clinic Rochester institutional HCT database. One hundred seventy-seven women were eligible, of whom 49 (28%) were excluded due to documented postmenopausal state or prior hysterectomy. The median age of the cohort was 31 years (range, 15 to 49 years) with median gravidity and parity being G1P1 (range, G0 to G8, P0 to P6). Fifty-four (42%) women were nulligravid at the time of HCT. Eighty-two percent underwent myeloablative conditioning (MAC), whereas 18% underwent reduced-intensity conditioning (RIC). Only 34 women (27%) had documented fertility counseling within 72 hours of diagnosis, and a total of 61 (48%) received fertility counseling prior to HCT. Thirty-eight women (30%) were referred to a reproductive endocrinologist, of whom 13 (10%) underwent assisted reproductive technologies (ART; nine oocyte cryopreservation, four embryo cryopreservation). Of these, nine procedures yielded successful cryopreserved tissue (two completed at outside institutions). The median time to completion of the seven successful ART procedures at Mayo Clinic was 13 days (range, 9 to 15 days). The remainder of women referred to reproductive endocrinology did not undergo ART due to disease severity (68%), financial barriers (20%), and/or low antral follicle count (12%). Ninety-three women (73%) received leuprolide for ovarian suppression prior to conditioning. Three (4%) of 75 women who underwent MAC and were alive >365 days after HCT had spontaneous menstrual recovery after HCT (median time, 14 months; range, 6 to 21 months), in comparison to 10 (50%) of 20 women who underwent RIC and were alive >365 days after HCT (P < .01) (median, 21.5 months; range, 5 to 83 months). In the latter cohort, there were two spontaneous pregnancies, occurring at 71 and 72 months after HCT, respectively. Oncofertility is an emerging field due to an increasing number of young cancer survivors. Herein, we document that even at a large tertiary HCT center, the rate of documented fertility counseling and reproductive endocrinology referrals was low and the rate of ART was even lower. Spontaneous menstrual recovery was rare but more likely in the setting of nonmalignant disease and RIC HCT. A concerted multidisciplinary effort is needed to understand parenthood goals and to explore the impact of HCT on decision making about fertility preservation and parenthood. These efforts could improve oncofertility referral, ART utilization, and reproductive outcomes., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: Diagnostic delay is common in endometriosis. There is an unmet need for a symptom-based, patient-completed screening tool to facilitate discussions between patients and physicians about potential endometriosis symptoms. The objective of this study was to develop and assess the patient-completed Painful Periods Screening Tool (PPST) to assess the presence of potential endometriosis symptoms., Methods: To develop and refine the PPST, a cross-sectional qualitative study was conducted with women with endometriosis and healthy controls. Following identification of potentially relevant concepts in the literature and input from clinical experts, a draft version of the PPST was tested during in-depth individual interviews with 16 women: 11 with endometriosis and 5 healthy controls., Results: The six draft items of the PPST were refined iteratively in two rounds of interviews, and one item was deleted following the second set of interviews. All concepts included in the final five-item PPST were found to be relevant to women with endometriosis, and all 11 participants with endometriosis endorsed at least one of the items. No core symptoms of endometriosis were noted as missing from the PPST., Conclusion: The PPST assesses the most important endometriosis-related symptoms and may help facilitate discussions between patients and physicians, promoting earlier diagnosis and treatment of endometriosis.

Purpose: To determine whether differences in birth outcomes among assisted reproductive technology (ART)-treated, subfertile, and fertile women exist in primiparous women with, singleton, vaginal deliveries., Methods: Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) data were linked to Massachusetts vital records and hospital discharges for deliveries between July 2004 and December 2010. Primiparous women with in-state vaginal deliveries, adequate prenatal care, and singleton birth at ≥ 20 weeks (n = 117,779) were classified as ART-treated (linked to ART data from SART CORS, n = 3138); subfertile (not ART-treated but with indicators of subfertility, n = 1507); or fertile (neither ART-treated nor subfertile, n = 113,134). Outcomes of prematurity (< 37 weeks), low birthweight (< 2500 g), perinatal death (death at ≥ 20 weeks to ≤ 7 days), and maternal prolonged length of hospital stay (LOS > 3 days) were compared using multivariable logistic regression., Results: Compared to fertile, higher odds were found for prematurity among ART-treated (adjusted odds ratio [AOR] 1.40, 95% confidence interval [CI] 1.25-1.50) and subfertile (AOR 1.25, 95% CI 1.03-1.50) women, low birthweight among ART-treated (AOR 1.41, 95% CI 1.23-1.62) and subfertile (AOR 1.40, 95% CI 1.15-1.71) women, perinatal death among subfertile (AOR 2.64, 95% CI 1.72-4.05), and prolonged LOS among ART-treated (AOR 1.33, 95% CI 1.19-1.48) women. Differences remained despite stratification by young age and absence of pregnancy/delivery complications., Conclusions: Greater odds of prematurity and low birthweight in ART-treated and subfertile, and perinatal death in subfertile deliveries are evident among singleton vaginal deliveries. The data suggest that even low-risk pregnancies to ART-treated and subfertile women be managed for adverse outcomes.

Objective: To quantify the effect of medical and obstetrical factors on the odds of cesarean delivery, comparing assisted reproductive technology (ART)-treated women and women with subfertility not treated with ART versus fertile women., Design: Retrospective cohort., Setting: Not applicable., Patient(s): Singleton deliveries to primiparous women; with the source of this data being the Massachusetts vital and hospital records linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System data (2004-2010)., Intervention(s): None., Main Outcome Measure(s): Mode of delivery., Result(s): The 173,130 deliveries included 5,768 ART-treated, 2,657 subfertile (1,627 non-ART medically assisted reproduction [MAR] and 1,030 unassisted infertile), and 164,705 fertile pregnancies and 117,743 vaginal and 55,387 cesarean deliveries. ART-treated women were older, more often white and non-Hispanic, and with more private insurance, previous uterine surgery, gestational diabetes, pregnancy hypertension, bleeding, and placental complications than fertile women. Overall rates of cesarean delivery were 45.7%, 43.3%, and 31.1% for ART-treated, subfertile, and fertile women and 41.7% and 45.9% for MAR and unassisted infertile deliveries. When adjusted for demographics, underlying medical factors, previous uterine surgery, and placental and delivery complications, adjusted odds ratios (ORs) compared with fertile women were 1.27 for ART-treated and 1.15 for subfertile women, with greater odds among unassisted infertile (OR 1.26) but not MAR (OR 1.09) women. The strongest confounders of odds of cesarean delivery were age and previous uterine surgery., Conclusion(s): ART and unassisted infertility were associated with greater odds of cesarean compared with fertile women. Underlying medical and obstetrical risks had strong confounding effects strongly attenuating the odds for cesarean delivery., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate a new fully automated antimüllerian hormone (AMH) assay for prediction of poor ovarian response (POR) to ovarian stimulation defined as four or fewer oocytes retrieved., Design: Prospective cohort study., Setting: Thirteen private and academic fertility centers in the United States., Patients(s): A total of 178 women undergoing their first in vitro fertilization (IVF) cycle eligible for the study were consented and enrolled, with data available from 160 women for prediction of POR and 164 women for AMH correlation with antral follicle count (AFC)., Intervention(s): None., Main Outcome Measure(s): Cutoff point for AMH that predicts POR. Correlation of AMH with AFC, and cutoff point for AMH that correlates with antral follicle count >15., Result(s): The mean AMH among the poor responders was 0.74 ng/mL, compared with 3.20 ng/mL for normal to high responders. The AMH cutoff at 90% specificity for predicting POR with the use of the receiver operating characteristic (ROC) curve was 0.93 ng/mL, with an associated sensitivity of 74.1%. For prediction of POR, ROC analysis showed that AMH (area under the ROC curve [AUC] = 0.929) was significantly better than FSH (AUC = 0.615; P<.0001). AMH was positively correlated with AFC (Spearman rho = 0.756). The AMH at 90% sensitivity for AFC >15 was 1.75, with specificity of 59.1%., Conclusion(s): A fully automated AMH assay can be a useful biomarker for predicting POR in IVF cycles. Because AMH cutoff points vary depending on the assay used, future studies should continue to calibrate test results to clinically important outcomes., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study is to evaluate frequency of hospitalization before, during, and after assisted reproductive technology (ART) treatment by cycle outcome., Methods: Six thousand and one hundred thirty women residing in Massachusetts undergoing 17,135 cycles of ART reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SARTCORS) from 2004 to 2011 were linked to hospital discharges and vital records. Women were grouped according to ART treatment cycle outcome as: no pregnancy (n = 1840), one or more pregnancies but no live birth (n = 968), or one or more singleton live births (n = 3322). Hospital delivery discharges during 1998-2011 were categorized as occurring before, during, or after the ART treatment. The most prevalent ICD-9 codes for non-delivery hospital discharges were compared. Groups were compared using chi square test using SAS 9.3 software., Results: The proportion of any hospitalization was 57.0, 58.3, and 91.3% for women with no pregnancy, no live birth, and ART singleton live birth, respectively; the proportion of non-delivery hospitalizations was 30.4, 31.0, and 28.3%, respectively. The non-ART delivery proportion after ART treatment did not differ by group (33.4, 36.2, and 36.9%, respectively, p = 0.17). Most frequent non-delivery diagnoses (including fibroids, obesity, ectopic pregnancy, depression, and endometriosis) also did not differ by group. A secondary analysis limited to only women with no delivery discharges before the first ART cycle showed similar results., Conclusions: All groups had live birth deliveries during the study period, suggesting an important contribution of non-ART treatment or treatment-independent conception to overall delivery and live births. Hospitalizations not associated with delivery suggested similarity in morbidity for all ART patients regardless of success with ART treatment.

Background: Children born from fresh in vitro fertilization (IVF) cycles are at greater risk of being born smaller and earlier, even when limited to singletons; those born from frozen cycles have an increased risk of large-for-gestational age (LGA) birthweight (z-score ≥1.28). This analysis sought to overcome limitations in other studies by using pairs of siblings, and accounting for prior cycle outcomes, maternal characteristics, and embryo state and stage., Methods: Pairs of singleton births conceived with IVF and born between 2004 and 2013 were identified from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database, matched for embryo stage (blastocyst versus non-blastocyst) and infant gender, categorized by embryo state (fresh versus frozen) in 1st and 2nd births (four groups)., Results: The data included 7795 singleton pairs. Birthweight z-scores were 0.00-0.04 and 0.24-0.26 in 1st and 2nd births in fresh cycles, and 0.25-0.34 and 0.50-0.55 in frozen cycles, respectively. LGA was 9.2-9.8 and 14.2-15.4% in 1st and 2nd births in fresh cycles, and 13.1-15.8 and 20.8-21.0% in 1st and 2nd births in frozen cycles. The risk of LGA was increased in frozen cycles (1st births, adjusted odds ratios (AOR) 1.74, 95% CI 1.45, 2.08; and in 2nd births when the 1st birth was not LGA, AOR 1.70, 95% CI 1.46, 1.98 for fresh/frozen and 1.40, 1.11, 1.78 for frozen/frozen)., Conclusions: Our results with siblings indicate that frozen embryo state is associated with an increased risk for LGA. The implications of these findings for childhood health and risk of obesity are unclear, and warrant further investigation., Competing Interests: Compliance with ethical standards This study was approved by the Committees for the Protection of Human Subjects at the Dartmouth College, Michigan State University, and University of Michigan. Conflict of interest BL is a research consultant to the Society for Assisted Reproductive Technology (SART). EW is under contract with SART to maintain the SART CORS database. MBB, JES, JPT, and CCC have no conflicts to declare.

Objective: Uncontrolled hypothyroidism has been associated with an increased risk of adverse pregnancy outcomes. We aimed to assess the effectiveness of increasing levothyroxine (LT4) dose on reducing the risk of adverse outcomes for pregnant women with TSH level greater than the recommended 1st trimester limit., Design, Patients, Measurements: We reviewed the electronic medical records of pregnant women evaluated from January 2011 to December 2013, who had history of LT4-treated hypothyroidism and were found to have TSH > 2·5 mIU/l in 1st trimester. Women were divided into two groups: group A - LT4 dose was increased within two weeks from the TSH test, group B - LT4 dose remained stable. We compared the frequency of pregnancy loss (primary outcome) and other prespecified pregnancy-related adverse outcomes between groups., Results: There were 85 women in group A (median TSH: 5·0, interquartile range 3·8-6·8 mIU/l) and 11 women in group B (median TSH: 4·5, interquartile range 3·2-4·9 mIU/l). The groups were not different in baseline clinical and socioeconomic characteristics. The mean interval between TSH test and LT4 dose increase was 4·5 (SD 4·6) days. Pregnancy loss was significantly lower in group A (2/85, 2·4%) vs group B (4/11, 36·4%) (P = 0·001). Other pregnancy-related adverse outcomes were similar between groups., Conclusions: Increasing LT4 dose for women with uncontrolled hypothyroidism in the 1st trimester of pregnancy was associated with a decreased risk of pregnancy loss. Given the limitations of our study, this association awaits further confirmation from larger studies., (© 2016 John Wiley & Sons Ltd.)

Study Question: What is an objective approach that employs measurable and reproducible physiologic changes as the basis for the classification of ovarian hyperstimulation syndrome (OHSS) in order to facilitate more accurate reporting of incidence rates within and across clinical trials?, Summary Answer: The OHSS flow diagram is an objective approach that will facilitate consistent capture, classification and reporting of OHSS within and across clinical trials., What Is Known Already: OHSS is a potentially life-threatening iatrogenic complication of the early luteal phase and/or early pregnancy after ovulation induction (OI) or ovarian stimulation (OS). The clinical picture of OHSS (the constellation of symptoms associated with each stage of the disease) is highly variable, hampering its appropriate classification in clinical trials. Although some degree of ovarian hyperstimulation is normal after stimulation, the point at which symptoms transition from those anticipated to those of a disease state is nebulous., Study Design, Size, Duration: An OHSS working group, comprised of subject matter experts and clinical researchers who have significantly contributed to the field of fertility, was convened in April and November 2014., Participants/materials, Setting, Methods: The OHSS working group was tasked with reaching a consensus on the definition and the classification of OHSS for reporting in clinical trials. The group engaged in targeted discussion regarding the scientific background of OHSS, the criteria proposed for the definition and the rationale for universal adoption. An agreement was reached after discussion with all members., Main Results and the Role of Chance: One of the following conditions must be met prior to making the diagnosis of OHSS in the context of a clinical trial: (i) the subject has undergone OS (either controlled OS or OI) AND has received a trigger shot for final oocyte maturation (e.g. hCG, GnRH agonist [GnRHa] or kisspeptin) followed by either fresh transfer or segmentation (cryopreservation of embryos) or (ii) the subject has undergone OS or OI AND has a positive pregnancy test. All study patients who develop symptoms of OHSS should undergo a thorough examination. An OHSS flow diagram was designed to be implemented for all subjects with pelvic or abdominal complaints, such as lower abdominal discomfort or distention, nausea, vomiting and diarrhea, and/or for subjects suspected of having OHSS. The diagnosis of OHSS should be based on the flow diagram., Limitations, Reasons for Caution: This classification system is primarily intended to address the needs of the clinical investigator undertaking clinical trials in the field of OS and may not be applicable for the use in clinical practice or with OHSS occurring under natural circumstances., Wider Implications of the Findings: The proposed OHSS classification system will enable an accurate estimate of the incidence and severity of OHSS within and across clinical trials performed in women with infertility., Study Funding/competing Interests: Financial support for the advisory group meetings was provided by Merck & Co., Inc., Kenilworth, NJ, USA. P.H. reports unrestricted research grants from MSD, Merck and Ferring, and honoraria for lectures from MSD, Merck and IBSA. S.M.N. reports that he has received fees and grant support from the following companies (in alphabetic order): Beckman Coulter, Besins, EMD Serono, Ferring Pharmaceuticals, Finox, MSD and Roche Diagnostics over the previous 5 years. P.D., C.C.C., J.L.F., H.M.F., and P.L. report no relationships that present a potential conflict of interest. B.C.T., Reports: grants and honorarium from Merck Serono; unrestricted research grants, travel grants and honorarium, and participation in a company-sponsored speaker's bureau from Merck Sharp & Dohme; grants, travel grants, honoraria and advisory board membership from IBSA; travel grants from Ferring; and advisory board membership from Ovascience. L.B.S. reports current employment with Merck & Co, Inc., Kenilworth, NJ, USA, and owns stock in the company. K.G. and B.J.S. report prior employment with Merck & Co., Inc., Kenilworth, NJ, USA, and own stock in the company. All reported that competing interests are outside the submitted work. No other relationships or activities exist that could appear to have influenced the submitted work., Trial Registration Number: Not applicable., (Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The Society for Assisted Reproductive Technology (SART) was established within a few years of assisted reproductive technology (ART) in the United States, and has not only reported on the evolution of infertility care, but also guided it toward improved success and safety. Moving beyond its initial role as a registry, SART has expanded its role to include quality assurance, data validation, practice and advertising guidelines, research, patient education and advocacy, and membership support. The success of ART in this country has greatly benefited from SART's role, as highlighted by a series of graphs. SART continues to set the standard and lead the way., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Subclinical hypothyroidism (SCH) has been associated with increased risk of adverse pregnancy outcomes in some, but not all, studies. Uncertainty remains regarding the impact of levothyroxine (LT4) therapy on improving health outcomes in pregnant women with SCH. The objective of this study was to assess the potential benefits of LT4 therapy in pregnant women with SCH., Methods: The medical records were reviewed of pregnant women with SCH, defined as an elevated serum thyrotropin (TSH) of >2.5 mIU/L for the 1st trimester or >3 mIU/L for the 2nd and 3rd trimesters, but ≤10 mIU/L. Pregnant women were divided into two groups depending on whether they received LT4 (group A) or not (group B). Pregnancy loss and other pre-specified adverse outcomes were evaluated during follow-up., Results: There were 82 women in group A and 284 in group B. Group A had a higher body mass index (p = 0.04) and a higher serum TSH level (p < 0.0001) compared with group B. Group A had fewer pregnancies lost (n = 5 [6.1%] vs. n = 25 [8.8%]; p = 0.12), low birth weight (LBW) offspring (1.3% vs. 10%; p < 0.001), and no neonates with a five-minute Apgar score ≤7 (0% vs. 7%; p < 0.001) compared with group B. Other pregnancy-related adverse outcomes were similar between the two groups. Inferences remained unchanged after considering different models to adjust for potential predictors of outcome., Conclusions: LT4 therapy is associated with a decreased risk of LBW and a low Apgar score among women with SCH. This association awaits confirmation in randomized trials before the widespread use of LT4 therapy in pregnant women with SCH.

Background: The impact of subclinical hypothyroidism (SCH) and of levothyroxine replacement in pregnant women with SCH is unclear. The aims of this study were to assess (i) the impact of SCH during pregnancy on maternal and neonatal outcomes, and (ii) the effect of levothyroxine replacement therapy in these patients., Methods: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, the Cochrane Controlled Trials Register, Ovid EMBASE, Web of Science, and Scopus were searched from inception to January 2015. Randomized trials and cohort studies of pregnant women with SCH that examined adverse pregnancy and neonatal outcomes were included. Reviewers extracted data and assessed methodological quality in duplicate. Eighteen cohort studies at low-to-moderate risk of bias were included. Compared with euthyroid pregnant women, pregnant women with SCH were at higher risk for pregnancy loss (relative risk [RR] 2.01 [confidence interval (CI) 1.66-2.44]), placental abruption (RR 2.14 [CI 1.23-3.70]), premature rupture of membranes (RR 1.43 [CI 1.04-1.95]), and neonatal death (RR 2.58 [CI 1.41-4.73]). One study at high risk of bias compared pregnant women with SCH who received levothyroxine to those who did not and found no significant decrease in the rate of pregnancy loss, preterm delivery, gestational hypertension, low birth weight, or low Apgar score., Conclusions: SCH during pregnancy is associated with multiple adverse maternal and neonatal outcomes. The value of levothyroxine therapy in preventing these adverse outcomes remains uncertain.

Objective: To evaluate the impact of cessation of fertility services on patients with infertility., Study Design: A cross-sectional, anonymous mail survey was conducted in a university hospital setting. A total of 281 female infertility patients treated from 2003-2006 were mailed surveys. The main outcome measures of the study were the Perceived Stress Scale 10 (PSS-10) and the Impact of Events Scale (IES)., Results: Of the 281 patients, 175 (62.3%) responded to the questionnaire. Of those, 51 (29.1%) reported being affected by the closure. The majority (58.9%) reported a somewhat or very negative impact on their perceived quality of life. Affected patients were more likely than unaffected patients to have an elevated PSS-10 result (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.04-4.3). No significant difference was seen in IES results, with 90.2% of affected and 81.5% of unaffected patients scoring in the high distress range (OR 2.1, 95% CI 0.77-5.65). Self-reported average stress levels were reduced following news of resumption of services (3.3, scale 1-10) as compared to both prior to (5.1) and during (7.4) the closure., Conclusion: When fertility services are discontinued, there may be significant emotional distress among the population affected. Health care providers should be aware of the impact infertility has on stress-coping and quality of life and be prepared to offer psychological services.

Objective: To determine practice patterns for insulin resistance (IR) evaluation and management in women with polycystic: ovary syndrome (PCOS) among physician members of the American Society for Reproductive Medicine (ASRM)., Study Design: Cross-sectional survey using a web-based questionnaire., Results: A total of 205 members responded. Respondents were board-certified (94%), or board-eligible (6%), in obstetrics and gynecology. Sixty-four percent of the respondents use the Rotterdam 2003 Criteria for a diagnosis of PCOS. Two-thirds (68%) screenfor IR in women with PCOS. Respondents who screen for IR were more likely to also screen for diabetes and impaired glucose tolerance (OR 3.37, 95% CI 1.48-7.21). The 2-hour oral glucose tolerance test with glucose and insulin concentrations was the most common IR screening test used (45%). Metformin therapy was used by 33% of respondents for, "all women with PCOS who have IR." The majority (68%) responded that there is a need for a committee opinion from ASRM on IR testing in PCOS., Conclusion: Two-thirds of ASRM physician members surveyed screen women with PCOS for IR in spite of the lack of general consensus on the need for such screening from endocrine societies.

Background: HP1γ, a well-known regulator of gene expression, has been recently identified to be a target of Aurora A, a mitotic kinase which is important for both gametogenesis and embryogenesis. The purpose of this study was to define whether the Aurora A-HP1γ pathway supports cell division of gametes and/or early embryos, using western blot, immunofluorescence, immunohistochemistry, electron microscopy, shRNA-based knockdown, site-directed mutagenesis, and Affymetrix-based genome-wide expression profiles., Results: We find that the form of HP1γ phosphorylated by Aurora A, P-Ser83 HP1γ, is a passenger protein, which localizes to the spermatozoa centriole and axoneme. In addition, disruption in this pathway causes centrosomal abnormalities and aberrations in cell division. Expression profiling of male germ cell lines demonstrates that HP1γ phosphorylation is critical for the regulation of mitosis-associated gene expression networks. In female gametes, we observe that P-Ser83-HP1γ is not present in meiotic centrosomes of M2 oocytes, but after syngamy, it becomes detectable during cleavage divisions, coinciding with early embryonic genome activation., Conclusions: These results support the idea that phosphorylation of HP1γ by Aurora A plays a role in the regulation of gene expression and mitotic cell division in cells from the sperm lineage and in early embryos. Combined, this data is relevant to better understanding the function of HP1γ in reproductive biology.

Objective: The purpose of this study was to use a validated prediction model to examine whether single embryo transfer (SET) over 2 cycles results in live birth rates (LBR) comparable with 2 embryos transferred (DET) in 1 cycle and reduces the probability of a multiple birth (ie, multiple birth rate [MBR])., Study Design: Prediction models of LBR and MBR for a woman considering assisted reproductive technology developed from linked cycles from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System for 2006-2012 were used to compare SET over 2 cycles with DET in 1 cycle. The prediction model was based on a woman's age, body mass index (BMI), gravidity, previous full-term births, infertility diagnoses, embryo state, number of embryos transferred, and number of cycles., Results: To demonstrate the effect of the number of embryos transferred (1 or 2), the LBRs and MBRs were estimated for women with a single infertility diagnosis (male factor, ovulation disorders, diminished ovarian reserve, and unexplained); nulligravid; BMI of 20, 25, 30, and 35 kg/m2; and ages 25, 35, and 40 years old by cycle (first or second). The cumulative LBR over 2 cycles with SET was similar to or better than the LBR with DET in a single cycle (for example, for women with the diagnosis of ovulation disorders: 35 years old; BMI, 30 kg/m2; 54.4% vs 46.5%; and for women who are 40 years old: BMI, 30 kg/m(2); 31.3% vs 28.9%). The MBR with DET in 1 cycle was 32.8% for women 35 years old and 20.9% for women 40 years old; with SET, the cumulative MBR was 2.7% and 1.6%, respectively., Conclusion: The application of this validated predictive model demonstrated that the cumulative LBR is as good as or better with SET over 2 cycles than with DET in 1 cycle, while greatly reducing the probability of a multiple birth., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To evaluate pregnancy rates based on the route of progesterone replacement in frozen embryo transfer (FET) cycles., Study Design: A randomized controlled trial and retrospective analysis. In the randomized group 76 FET cycles were randomized. In the retrospective group 508 FET cycles were reviewed. Intramuscular (IM) proges-erone in oil 100 mg daily or oral micronized progesterone prior to transfer followed by compounded vaginal proges-erone 200 mg 3 times daily (OV). The main outcome measure was the clinical pregnancy rate (CPR)., Results: Baseline characteristics did not vary be-ween groups in either cohort. In the randomized group there were no significant differences in CPR (31.43% vs. 21.05%) or live birth rate (LBR) (31.43% vs. 18.92%) for IM and OV progesterone replacement, respectively. In the retrospective cohort patients there wore also no significant differences in CPR (35.56% vs. 32.35%) or LBR (32.23% vs. 28.51%)f or the IM and OVp rogester-ne replacement groups, respectively., Conclusion: This study demonstrates that either OV or IM progesterone is effective for luteal phase support for FETs.

Background: Cervical ectopic pregnancies (CEPs) are increasingly being managed conservatively. However, the efficacy of specific conservative approaches such as the single-dose intramuscular (IM) methotrexate (MTX) therapy has not been evaluated. We reportthe successful management of 2 consecutive CEPs in the same patient with single-dose IM MTX therapy, and review published cases of CEPs treated with a similar regimen, to determine the efficacy of this approach., Case: In our case, both CEPs resolved with single-dose IM MTX, and the patient subsequently had a successful term delivery. A Medline/OVID English language search, covering the period 1982-2012, identified 38 additional cases of CEPs treated with single-dose IM MTX. Of the total 40 cases analyzed, including our 2 cases, 30 (75%) were successfully treated, with complete remission. Of the 27 cases with no embryonic cardiac activity, 25 (93%) were successfully treated with single-dose IM MTX., Conclusion: Appropriately selected cases of CEPs can be successfully managed with single-dose IM MTX with very low complication rates and preservation of future fertility potential.

Early diagnosis of uterine hemangiomas may direct management decisions improving long-term outcome in children, adolescents and adulthood., (Copyright © 2014 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Objective: To develop a model predictive of live-birth rates (LBR) and multiple birth rates (MBR) for an individual considering assisted reproduction technology (ART) using linked cycles from Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) for 2004-2011., Design: Longitudinal cohort., Setting: Clinic-based data., Patient(s): 288,161 women with an initial autologous cycle, of whom 89,855 did not become pregnant and had a second autologous cycle and 39,334 did not become pregnant in the first and second cycles and had a third autologous cycle, with an additional 33,598 women who had a cycle using donor oocytes (first donor cycle)., Intervention(s): None., Main Outcome Measure(s): LBRs and MBRs modeled by woman's age, body mass index, gravidity, prior full-term births, infertility diagnoses by oocyte source, fresh embryos transferred, and cycle, using backward-stepping logistic regression with results presented as adjusted odds ratios (AORs) and 95% confidence intervals., Result(s): The LBRs increased in all models with prior full-term births, number of embryos transferred; in autologous cycles also with gravidity, diagnoses of male factor, and ovulation disorders; and in donor cycles also with the diagnosis of diminished ovarian reserve. The MBR increased in all models with number of embryos transferred and in donor cycles also with prior full-term births. For both autologous and donor cycles, transferring two versus one embryo greatly increased the probability of a multiple birth (AOR 27.25 and 38.90, respectively)., Conclusion(s): This validated predictive model will be implemented on the Society for Assisted Reproductive Technology Web site (www.sart.org) so that patients considering initiating a course of ART can input their data on the Web site to generate their expected outcomes., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the effect of unilateral oophorectomy (UO) by assessing ovarian reserve (OVR) and the response to gonadotropin stimulation in women with UO undergoing in vitro fertilization (IVF) compared with the response of the ipsilateral ovary of women without UO., Design: Historical cohort study., Setting: Academic fertility clinic., Patient(s): Fifty-one women with single ovary compared with a referent group with both ovaries in a 1:2 fashion., Intervention(s): None., Main Outcome Measure(s): Day-3 follicle-stimulating hormone (FSH), estradiol, and antral follicle counts as measures of OVR, and IVF outcomes including number of follicles aspirated and oocytes retrieved., Result(s): The baseline demographics and serum markers of OVR were not different. Referent women had greater follicular yield and oocyte numbers when compared with women with UO; however, when compared with the ipsilateral ovary of the referents, women with UO had a higher antral follicle count and greater follicle and oocyte numbers. In multivariate analyses, the ovary from women with UO was more likely to yield more than the median number of follicles and oocytes than the ipsilateral ovary in referent women. Live-birth rates in both groups were similar., Conclusion(s): Our results suggest that the remaining ovary appears to compensate in follicular yield after UO in women, confirming the animal data. Women with UO can be reassured and appropriately counseled regarding IVF., (Published by Elsevier Inc.)

Objective: To determine whether there is a correlation between preovulatory endometrial stripe thickness (EST) and pregnancy rates in clomiphene citrate (CC)/IUI cycles., Design: Retrospective cohort., Setting: Infertility clinic of an academic medical center., Patient(s): A total of 262 patients completed 562 transvaginal ultrasound-monitored CC/IUI cycles from January 2005 through December 2012., Intervention(s): All patients received oral CC. In 362 of the cycles, a single dose of gonadotropin was administered on cycle day 9 (MinStim). A transvaginal ultrasound was performed on cycle day 10, 11, or 12., Main Outcome Measure(s): Pregnancy rate per initiated cycle., Result(s): A total of 91 pregnancies ensued, yielding a pregnancy rate of 16.2% per initiated cycle. Pregnancy rates did not vary with EST <6 mm, 6-9 mm, and >9 mm (14.8%, 16.3%, and 19.0%, respectively). There was no significant difference in mean EST between stimulation types (6.8 mm for CC vs. 6.7 mm for MinStim). When conception and nonconception cycles were compared, no difference in mean EST (6.9 mm vs. 6.8 mm, respectively) was observed. Area under the receiver operating characteristic curve for the probability of pregnancy based on EST was 0.51., Conclusion(s): Preovulatory EST had no significant correlation with pregnancy rates in CC/IUI cycles. The decision to switch from CC to another treatment strategy should be influenced by factors other than thin endometrial stripe., (Published by Elsevier Inc.)