Assisted reproductive technology use and outcomes in childhood cancer survivors.

BACKGROUND: Treatment exposures for childhood cancer reduce ovarian reserve. However, the success of assisted reproductive technology (ART) among female survivors is not well established. METHODS: Five-year survivors of childhood cancer in the Childhood Cancer Survivor Study were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, which captures national ART outcomes. The authors assessed the live birth rate, the relative risk (RR) with 95% confidence intervals (95% CIs), and associations with treatment exposure using generalized estimating equations to account for multiple ovarian stimulations per individual. Siblings from a random sample of survivors were recruited to serve as a comparison group. RESULTS: Among 9885 female survivors, 137 (1.4%; median age at diagnosis, 10 years [range, 0-20 years]; median years of follow-up after age 18 years, 11 years [range, 2-11 years]) underwent 224 ovarian stimulations using autologous or donor eggs and/or gestational carriers (157 autologous ovarian stimulation cycles, 67 donor ovarian stimulation cycles). In siblings, 33 (1.4%) underwent 51 autologous or donor ovarian stimulations. Of those who used embryos from autologous eggs without using gestational carriers, 97 survivors underwent 155 stimulations, resulting in 49 live births, for a 31.6% chance of live birth per ovarian stimulation (vs. 38.3% for siblings; p = .39) and a 43.9% chance of live birth per transfer (vs. 50.0%; p = .33). Prior treatment with cranial radiation therapy (RR, 0.44; 95% CI, 0.20-0.97) and pelvic radiation therapy (RR, 0.33; 95% CI, 0.15-0.73) resulted in a reduced chance of live birth compared with siblings. The likelihood of live birth after ART treatment in survivors was not affected by alkylator exposure (cyclophosphamide-equivalent dose, ≥8000 mg/m2 vs. none; RR, 1.04; 95% CI, 0.52-2.05). CONCLUSIONS: Childhood cancer survivors are as likely to undergo treatment using ART as sibling controls. The success of ART treatment was not reduced after alkylator exposure. The results from the current study provide needed guidance on the use of ART in this population.

Premature progesterone elevation during the early and mid-follicular phases in fresh in vitro fertilization (IVF) cycles is associated with lower live birth, clinical pregnancy, and implantation rates.

PURPOSE: Evaluate follicular phase progesterone elevation (≥ 1.5 ng/mL) prior to trigger during IVF stimulation and its effects on live birth rate (LBR), clinical pregnancy rate (CPR), and implantation rate (IR) in fresh IVF cycles. METHODS: This was a retrospective cohort study within an academic clinic. A total of 6961 fresh IVF and IVF/ICSI cycles from October 1, 2015 to June 30, 2021 were included and grouped by progesterone (PR) prior to trigger: PR < 1.5 ng/mL (low PR group) and PR ≥ 1.5 ng/mL (high PR group). Main outcome measures included LBR, CPR, and IR. RESULTS: Among all cycle starts, 1568 (22.5%) were in the high PR group and 5393 (77.5%) were in the low PR group. Of the cycles which proceeded to an embryo transfer, 416 (11.1%) were in the high PR group and 3341 (88.9%) were in the low PR group. The high PR group had significantly lower IR (RR 0.75; 95% CI 0.64-0.88), CPR (aRR 0.74; 95% CI 0.64-0.87), and LBR (aRR 0.71; 95% CI 0.59-0.85) compared to the low PR group. When stratified by progesterone on the day of trigger (TPR), there was a clinically notable decrease in IR (16.8% vs 23.3%), CPR (28.1% vs 36.0%), and LBR (22.8% vs 28.9%) in the high PR group compared to the low PR group even when TPR < 1.5 ng/mL. CONCLUSIONS: In fresh IVF cycles in which TPR < 1.5 ng/mL, progesterone elevation ≥ 1.5 ng/mL at any point in time prior to trigger negatively impacts IR, CPR, and LBR. This data supports testing of serum progesterone in the follicular phase prior to trigger, as these patients may benefit from a freeze-all approach.

Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms.

Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.

Incidence and risk factors of intrauterine adhesions after myomectomy.

Objective: To determine the incidence and risk factors for intrauterine adhesions (IUAs) after minimally invasive and open myomectomy and hysteroscopic myomectomy (HM). Design: Retrospective cohort study. Setting: University-affiliated fertility center. Patients: Patients aged ≥18 years undergoing robotic-assisted or conventional laparoscopic minimally invasive myomectomy, abdominal myomectomy, or HM between January 2007 and January 2017. Only patients who underwent uterine cavity evaluation within 12 months of surgery via hysteroscopy or hysterosalpingography were included. Patients were excluded if they had a history of IUA before myomectomy. Interventions: Not applicable. Main Outcome Measures: The primary outcomes of this study were the presence and severity of IUA. The secondary outcomes were the identification of risk factors for IUA formation. The severity of IUAs was scored by 2 investigators using a previously published grading system by March et al. Results: Of 1,315 patients who underwent myomectomy, 173 (13.2%) met the inclusion criteria. Intrauterine adhesions were identified in 9.3% of all patients, 75.0% of which were classified as minimal. The incidence of IUA did not vary by modality: 8.6%, minimally invasive myomectomy; 7.8%, abdominal myomectomy; and 11.8%, HM. There were no differences in incidence of IUA by the number or size of fibroids removed. Of patients with IUA, 87.5% had submucosal fibroids resected compared with 58.6% without IUA. Conclusions: The incidence of postoperative IUA in women undergoing myomectomy of any modality is relatively low (9.3%) and does not vary by modality alone. Most IUAs are of minimal degree. The presence of submucosal fibroids is associated with an increased risk of IUA in all modalities.

Blown out of proportion? Induction Foley balloon ruptures associated with overinflation.

BACKGROUND: Larger volume Foley catheters are occasionally used for labor induction. In some instances the balloon is overinflated to obtain this volume. Neither the risk or rate of rupture are known for this practice. OBJECTIVE: The purpose of this study was to evaluate the use of overinflated Foley catheter balloons and the rate of rupture in prospective trials and to describe rupture events in our institutions. STUDY DESIGN: Clinical trials and prospective cohorts were identified through a search of MEDLINE from 2000 through May 1, 2017; prospective studies were examined for the use of overinflated Foley catheters. Reports of overinflated balloons were then reviewed in detail to determine if rupture occurred and to record any reported maternal, neonatal, or gynecologic outcomes. Internal reports to the Obstetric Safety Report System were used to describe the local cases at our institutions. RESULTS: We reviewed 296 abstracts. Seventeen prospective cohorts or randomized trials used larger balloon volumes (≥50 mL), of which 12 abstracts confirmed routine overinflation of the balloon. Within these studies, 19 patients who underwent cervical ripening with overinflated Foley catheters experienced balloon rupture during use. The incidence of rupture in these studies was 0.9%. No adverse maternal or fetal effects were noted. Internal safety reporting yielded an additional case. One gynecologic case was identified internally. The patient had an overinflated Foley catheter balloon used to tamponade excessive uterine bleeding after uterine evacuation. Balloon rupture was noted, and hysteroscopy was needed to remove fragments of the balloon. CONCLUSION: Overinflation of Foley catheter balloons in obstetric and gynecologic applications may cause rupture. Because of possible underreporting, the extent of complications that may result from balloon rupture is unknown.

Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes.

CONTEXT: The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening. OBJECTIVE: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. SUBJECTS: Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes. MAIN OUTCOME MEASURES: Reproductive and nonreproductive phenotypes within each genetic group were measured. RESULTS: Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors. CONCLUSIONS: Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening.