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Apico-basal polarization of cells within the embryo is critical for the segregation of distinct lineages during mammalian development. Polarized cells become the trophectoderm (TE), which forms the placenta, and apolar cells become the inner cell mass (ICM), the founding population of the fetus. The cellular and molecular mechanisms leading to polarization of the human embryo and its timing during embryogenesis have remained unknown. Here, we show that human embryo polarization occurs in two steps: it begins with the apical enrichment of F-actin and is followed by the apical accumulation of the PAR complex. This two-step polarization process leads to the formation of an apical domain at the 8–16 cell stage. Using RNA interference, we show that apical domain formation requires Phospholipase C (PLC) signaling, specifically the enzymes PLCB1 and PLCE1, from the eight-cell stage onwards. Finally, we show that although expression of the critical TE differentiation marker GATA3 can be initiated independently of embryo polarization, downregulation of PLCB1 and PLCE1 decreases GATA3 expression through a reduction in the number of polarized cells. Therefore, apical domain formation reinforces a TE fate. The results we present here demonstrate how polarization is triggered to regulate the first lineage segregation in human embryos.

Introduction This study examined obstetric outcomes in patients diagnosed with uterine adenomyosis. Material and methods This historical cohort study queried the Healthcare Cost and Utilization Project's National Inpatient Sample. The study population was all hospital deliveries in women aged 15–54 years between January 2016 and December 2019. The exposure was a diagnosis of uterine adenomyosis. The main outcome measures were obstetric characteristics, including placenta previa, placenta accreta spectrum, and placental abruption. Secondary outcomes were delivery complications including severe maternal morbidity. Analytic steps to assess these outcomes included (i) a 1‐to‐N propensity score matching to mitigate and balance prepregnancy confounders to assess obstetric characteristics, followed by (ii) an adjusting model with preselected pregnancy and delivery factors to assess maternal morbidity. Sensitivity analyses were also performed with restricted cohorts to account for prior uterine scar, uterine myoma, and extra‐uterine endometriosis. Results After propensity score matching, 5430 patients with adenomyosis were compared to 21 720 patients without adenomyosis. Adenomyosis was associated with an increased odds of placenta accreta spectrum (adjusted‐odds ratio [aOR] 3.07, 95% confidence interval [CI] 2.01–4.70), placenta abruption (aOR 3.21, 95% CI: 2.60–3.98), and placenta previa (aOR 5.08, 95% CI: 4.25–6.06). Delivery at <32 weeks of gestation (aOR 1.48, 95% CI: 1.24–1.77) and cesarean delivery (aOR 7.72, 95% CI: 7.04–8.47) were both increased in women with adenomyosis. Patients in the adenomyosis group were more likely to experience severe maternal morbidity at delivery compared to those in the nonadenomyosis group (aOR 1.86, 95% CI: 1.59–2.16). Results remained robust in the aforementioned several sensitivity analyses. Conclusions This national‐level analysis suggests that a diagnosis of uterine adenomyosis is associated with an increased risk of placental pathology (placenta accreta spectrum, placenta abruption, and placental previa) and adverse maternal outcomes at delivery. The results of this nationwide assessment suggest that pregnant patient with a diagnosis of adenomyosis may be associated with increased risk of placental pathology (placenta accreta spectrum, placenta abruption, and placental previa) and adverse maternal outcomes at delivery.

Introduction Since malignancy during pregnancy is uncommon, information regarding contraception selection or sterilization at delivery is limited. The objective of this study was to examine the type of long‐acting reversible contraception or surgical sterilization procedure chosen by pregnant patients with malignancy at delivery. Material and methods This cross‐sectional study queried the Healthcare Cost and Utilization Project's National Inpatient Sample in the USA. The study population was vaginal and cesarean deliveries in a hospital setting from January 2017 to December 2020. Pregnant patients with breast cancer (n = 1605), leukemia (n = 1190), lymphoma (n = 1120), thyroid cancer (n = 715), cervical cancer (n = 425) and melanoma (n = 400) were compared with 14 265 319 pregnant patients without malignancy. The main outcome measures were utilization of long‐acting reversible contraception (subdermal implant or intrauterine device) and performance of permanent surgical sterilization (bilateral tubal ligation or bilateral salpingectomy) during the index hospital admission for delivery, assessed with a multinomial regression model controlling for clinical, pregnancy and delivery characteristics. Results When compared with pregnant patients without malignancy, pregnant patients with breast cancer were more likely to proceed with bilateral salpingectomy (adjusted odds ratio [aOR] 2.30) or intrauterine device (aOR 1.91); none received the subdermal implant. Pregnant patients with leukemia were more likely to choose a subdermal implant (aOR 2.22), whereas those with lymphoma were more likely to proceed with bilateral salpingectomy (aOR 1.93) and bilateral tubal ligation (aOR 1.76). Pregnant patients with thyroid cancer were more likely to proceed with bilateral tubal ligation (aOR 2.21) and none received the subdermal implant. No patients in the cervical cancer group selected long‐acting reversible contraception, and they were more likely to proceed with bilateral salpingectomy (aOR 2.08). None in the melanoma group chose long‐acting reversible contraception. Among pregnant patients aged <30, the odds of proceeding with bilateral salpingectomy were increased in patients with breast cancer (aOR 3.01), cervical cancer (aOR 2.26) or lymphoma (aOR 2.08). The odds of proceeding with bilateral tubal ligation in pregnant patients aged <30 with melanoma (aOR 5.36) was also increased. Conclusions The results of this nationwide assessment in the United States suggest that among pregnant patients with malignancy, the preferred contraceptive option or method of sterilization at time of hospital delivery differs by malignancy type. The Healthcare Cost and Utilization Project's National Inpatient Sample was examined to assess contraceptive use and surgical sterilization choice at in‐hospital delivery. The results suggest that among pregnant patients with malignancy, the preferred contraceptive option or method of sterilization at time of hospital delivery differs by malignancy type.

PurposeTyrosine kinase inhibitors (TKIs) such as imatinib are commonly used chemotherapeutics, but the effects of long-term treatments on reproductive outlook for cancer survivors are unknown. The purpose of this study was to examine the effects of long-term imatinib treatments on follicle development and embryo quality. Since prospective studies are not possible in healthy humans, we have incorporated a commonly used mouse model.MethodsAdult female mice were treated with daily IP injections of imatinib for 4–6 weeks. Liquid chromatography-mass spectrometry was used to measure imatinib in serum and ovarian tissues. At the end of treatments, females were superovulated and mated to yield fertilized embryos. Oocytes and embryos were collected from oviducts, assessed for development by microscopy, and fertilized embryos were cultured in vitro. Blastocysts were fixed and stained for differential cell counts.ResultsLong-term imatinib treatments caused a shift in follicle development, with imatinib-treated females having fewer primordial follicles, but an increase in primary and secondary follicles (P < 0.05). There was no effect on ovulation or fertilization rates. However, blastocysts from imatinib-treated females had fewer total cells (P < 0.05) and a significant shift from inner cell mass to increased trophectoderm cells.ConclusionThis pilot study indicates that long-term TKI treatments may have significant impact on ovarian reserve and embryo developmental capacity. More studies are needed in other model systems to determine the long-term impact of TKIs in patients. Knowing the potential effects of chemotherapeutics on reproductive outlook is critical for quality of life and more research is needed.

PurposeTo examine patient and hospital characteristics related to seasonal fluctuation in in vitro fertilization (IVF).MethodsThis retrospective cohort study examined 33,077 oocyte retrievals identified in the National Ambulatory Surgery Sample. Exposure assignment was monthly IVF encounters: low-volume months (<25%ile), mid-volume months (≥25/<75%ile), and high-volume months (>75%ile). Main outcomes were patient and hospital characteristics related to the exposure groups, assessed with a multinomial regression model.ResultsThe median IVF encounters were 977 per month, ranging from 657 to 1074 (absolute-difference 417). January, July, and December were the lowest-quartile volume months, ranging from 657 to 710 encounters per month (low-volume months). May, August, and November were the top-quartile volume months, ranging from 1049 to 1074 encounters per month (high-volume months). In a multivariable analysis, patients undergoing IVF in the low-volume months were younger and less likely to have infertility or comorbidities. Patients undergoing IVF in the high-volume months were more likely to have lower household income and receive IVF at urban teaching facilities. Northeastern residents were less likely to have IVF in the low-volume months but more likely to have IVF in the high-volume months. Sensitivity analyses showed that the lowest-to-highest variability in monthly IVF encounters was higher in Northeast region compared to other regions (320 vs 50–128); infertility patients compared to those without (317 vs 190); privately insured patients compared to self-pay (227 vs 156); and older patients compared to younger (234 vs 192).ConclusionThis study suggests substantial seasonal fluctuation in IVF oocyte retrieval in the USA based on patient and hospital factors.

Purpose Clomiphene citrate (CC) is often utilized as an adjunct in in vitro fertilization (IVF) protocols during the first 5 days of stimulation for endogenous FSH release. However, due to its antiestrogenic mechanism of action, CC may also effectively prevent the LH surge, and hence premature ovulation, if continued until the day of trigger. The objective of this study was to evaluate a “long CC” protocol, in which CC is continued throughout the entire cycle in-lieu of GnRH antagonist, and to compare IVF outcomes with a standard 5-day CC + GnRH antagonist protocol in patients with diminished ovarian reserve (DOR) undergoing IVF with high-dose gonadotropins. Methods This is a retrospective cohort study of all CC-based IVF cycles at a single institution between 9/2020 and 9/2022. Mild stimulation protocols were excluded. The long CC group received CC throughout the entire cycle without GnRH antagonist. The CC + GnRH antagonist group received CC for the first 5 days of stimulation followed by GnRH antagonist when the lead follicle reached 14 mm. The primary outcome was mature oocyte yield. Results There were 361 cycles (77%) in the long CC group and 108 (23%) in the 5-day CC + GnRH antagonist group. Age and AMH levels were similar between the two groups. There was no significant difference in mature oocyte yield between the long CC and 5-day CC + GnRH antagonist groups (median 5 (IQR 5) vs. 4.5 (IQR 5), respectively, ( P  = 0.922)). MII oocytes/AFC did not differ (0.69 vs. 0.56, respectively, P  = 0.16). Premature ovulation occurred in 0.3% of cycles in the long CC group vs. 3.0% of cycles in the 5-day CC + GnRH antagonist group ( P  = 0.019). Conclusions In DOR patients undergoing IVF, a long CC protocol is an effective and patient-friendly approach associated with non-inferior oocyte yield.

Imatinib is an oral chemotherapeutic used primarily to treat chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). The potential effects of cancer treatments on a patient’s future fertility  are a major concern affecting the quality of life for cancer survivors. The effects of imatinib on future fertility are unknown. It is teratogenic. Therefore, patients are advised to stop treatment before pregnancy. Unfortunately, CML and GIST have high rates of recurrence in the absence of the drug, therefore halting imatinib during pregnancy endangers the mother. Possible long-term (post-treatment) effects of imatinib on reproduction have not been studied. We have used a mouse model to examine the effects of imatinib on the placenta and implantation after long-term imatinib exposure. We found significant changes in epigenetic markers of key imprinted genes in the placenta. There was a significant decrease in the labyrinth zone and vasculature of the placenta, which could impact fetal growth later in pregnancy. These effects on placental growth occurred even when imatinib was stopped prior to pregnancy. These results indicate potential long-term effects of imatinib on pregnancy and implantation. A prolonged wash-out period prior to pregnancy or extra monitoring for possible placental insufficiency may be advisable.

Purpose To assess national trends, characteristics, and delivery outcomes associated with gestational carriers (GC) pregnancies. Methods This cross-sectional study queried the Healthcare Cost and Utilization Project’s National Inpatient Sample. The study population was 14,312,619 deliveries between 2017 and 2020. Obstetric characteristics and outcomes associated with GC pregnancies were assessed with inverse probability of treatment weighting propensity score. Results There were 1965 GCs (13.7 per 100,000) included for national estimates. The prevalence rate of GC pregnancies increased by 55.0% over a 4-year period from 11.8 to 18.2 per 100,000 deliveries ( P -trend < .001). In the weighted model, GCs were more likely to have a multiple gestation pregnancy (14.7% vs 1.8%, adjusted odds ratio [aOR] 7.83, 95% confidence interval [CI] 6.54–9.38, P  < .001), placental abruption (3.5% vs 1.1%, aOR 2.98, 95%CI 2.12–4.19), and low-lying placenta (1.6% vs 0.2%, aOR 5.14, 95%CI 3.10–8.52). Among singleton delivery, odds of late-preterm (10.8% vs 6.4%, aOR 1.79, 95%CI 1.44–2.23) and periviable (1.1% vs 0.4%, aOR 2.54, 95%CI 1.32–4.89) deliveries and postpartum hemorrhage (12.2% vs 4.1%, aOR 3.27, 95%CI 2.67–4.00) were increased for GC compared to non-GCs whereas odds of cesarean delivery (23.6% vs 31.6%, aOR 0.59, 95%CI 0.51–0.69) were decreased. These associations were less robust in multi-fetal gestations. Conclusion The results of the current nationwide assessment suggest that GC pregnancies are rare but gradually increasing in the United States. This study shows that GC pregnancies have usually favorable pre-pregnancy patient characteristics compared to non-GC pregnancies, with mixed obstetric outcomes including increased odds of preterm delivery, placental abnormalities, and postpartum hemorrhage and decreased odds of cesarean delivery in singleton pregnancies.

PurposeIntracytoplasmic sperm injection (ICSI) for initially immature oocytes that mature in vitro is controversial and practice varies widely. While it may increase the number of usable embryos, it may also be time-intensive and potentially low-yield. This study sought to elucidate which patients may benefit from ICSI of initially immature oocytes that matured in vitro.MethodsA retrospective study comparing fertilization, cleavage, blastulation, and embryo usage rates between sibling initially immature and mature oocytes that underwent ICSI between 2015 and 2019 was performed. Outcomes of initially immature oocytes were stratified by initial maturation stage, timing of progression to metaphase II (MII) in vitro, percentage of mature oocytes in the cycle, and female age.ResultsTen thousand eight hundred seventeen oocytes from 889 cycles were included. Of 3137 (29.0%) initially immature oocytes, 418 (13.3%) reached MII later on the day of retrieval (day 0) and 1493 (47.6%) on day 1. Overall, embryos originating from initially immature oocytes had lower cleavage and blastulation rates compared to those from initially mature oocytes (P<0.05, all groups). However, embryos from oocytes that matured later on day 0 comprised a unique subset that had clinically similar cleavage (75% vs 80%, RR 0.93, P=0.047) and blastulation rates (41% vs 50%, RR 0.81, P=0.024) compared to initially mature oocytes. Women with low percentages of mature oocytes in the cycle overall and women ≥40 in cleavage cycles derived the highest relative benefit from the use of immature oocytes.ConclusionICSI of immature oocytes, particularly those that mature later on the day of retrieval, may improve numbers of usable embryos. This study supports routine reassessment of immature oocytes for progression to MII and ICSI on day 0. An additional reassessment on day 1 may also be of use in older women or those with low percentage of mature oocytes.

IntroductionPrevious studies have suggested that metformin use may enhance the therapeutic effect of progestin therapy for endometrial hyperplasia or malignancy. However, it is not known how the impact of concurrent metformin may be altered by route of progestin therapy, either locally via an intrauterine device or systemically. This study examined the effectiveness of concurrent metformin use and progestin therapy for women with complex atypical hyperplasia stratified by progestin route (systemic vs local).MethodsThis single-institution retrospective study examined consecutive women with complex atypical hyperplasia who received progestin therapy from 2003 to 2018. Time-dependent analyses for complete response rate were performed comparing concurrent metformin users versus non-users in the oral progestin group and in the levonorgestrel-releasing intrauterine device group.ResultsAcross the study cohort (n=245), there were 137 (55.9%) women who responded to progestin therapy. In the oral progestin group (n=176), the median age and body mass index were 36 years and 37.7 kg/m2, respectively. 36 (20.5%) of women on oral progestins also took metformin. After controlling for diabetes status, women taking both oral progestins and metformin had a complete response rate similar to those not taking metformin (6 month cumulative rates, 23.1% vs 27.8%, adjusted hazard ratio (aHR) 0.71, 95% confidence interval (95% CI) 0.36 to 1.41). In the levonorgestrel-releasing intrauterine device group (n=69), the median age and body mass index were 35 years and 39.9 kg/m2, respectively. There were 15 (21.7%) women who took metformin in addition to the levonorgestrel-releasing intrauterine device. After controlling for diabetes status, women who had the levonorgestrel-releasing intrauterine device and took metformin had a significantly higher complete response rate compared with those not taking metformin (6 month cumulative rates, 86.7% vs 58.9%, aHR 2.31, 95% CI 1.09 to 4.89).ConclusionIn a predominantly obese population, concurrent metformin may possibly offer treatment benefit when used with the levonorgestrel-releasing intrauterine device.