The impact of increasing body mass index on in vitro fertilization treatment, obstetrical, and neonatal outcomes.

BACKGROUND: Citing the risks of administering anesthesia to patients with obesity, few fertility centers offer in vitro fertilization as a treatment modality for patients with body mass indexes ≥40 kg/m2. Although previous studies have assessed clinical pregnancy and cumulative live birth rates in patients who spontaneously conceive with body mass indexes ≥50 kg/m2, there is a paucity of in vitro fertilization, obstetrical, and neonatal outcome data in patients with severe obesity who conceive after in vitro fertilization. OBJECTIVE: This study aimed to evaluate the impact of increasing body mass index on in vitro fertilization, obstetrical, and neonatal outcomes in patients with obesity undergoing in vitro fertilization. STUDY DESIGN: This was a retrospective cohort study within an academic fertility center including 2069 fresh in vitro fertilization/intracytoplasmic sperm injection and frozen embryo transfer cycles from January 1, 2012 to April 30, 2020; this cohort was used to determine in vitro fertilization treatment outcomes. A second embedded cohort of 867 fresh in vitro fertilization/intracytoplasmic sperm injection and frozen embryo transfer cycles that resulted in ongoing clinical pregnancies and deliveries within a single tertiary hospital system was used to determine pregnancy, maternal, and neonatal outcomes. All patients with a body mass index ≥40 kg/m2 underwent consultation with a maternal-fetal medicine specialist before starting treatment and a preoperative evaluation with an anesthesiologist before oocyte retrieval. Cycles were grouped by body mass index at cycle start (30-34.9, 35-39.9, 40-44.9, 45-49.9, and ≥50 kg/m2). Log-binomial regression and Poisson regression with an offset were fitted with body mass index of 30 to 34.9 kg/m2 as the reference group, adjusting for potential confounders including oocyte age, patient age, embryo quality, transfer type, and coexisting comorbidities. The primary outcome was live birth rate. Secondary outcomes included fertilization rate, blastulation rate, miscarriage rate, incidence of preeclampsia with severe features, gestational diabetes, labor induction, cesarean delivery, preterm delivery, and birthweight. RESULTS: There were 2069 fresh in vitro fertilization/intracytoplasmic sperm injection and frozen embryo transfer cycle starts from January 1, 2012 to April 30, 2020. Of these, 1008 cycles were in the 30 to 34.9 kg/m2 group, 547 in the 35 to 39.9 kg/m2 group, 277 in the 40 to 44.9 kg/m2 group, 161 in the 45 to 49.9 kg/m2 group, and 76 in the ≥50 kg/m2 body mass index group. Live birth rate was not significantly different between groups. The body mass index ≥50 kg/m2 group was significantly more likely to experience preeclampsia with severe features when compared with the 30 to 34.9 kg/m2 body mass index group (absolute risk reduction, 2.75; 95% confidence interval, 1.13-6.67). Fertilization rate, blastulation rate, miscarriage rate, incidence of gestational diabetes, labor induction, cesarean delivery, preterm delivery, and neonatal birthweights were not significantly different between groups. CONCLUSION: Among patients with body mass indexes from 30 to 60 kg/m2 who conceived via in vitro fertilization and received comprehensive prenatal care at a tertiary care hospital, in vitro fertilization, obstetrical, and neonatal outcomes were largely comparable. These data support a collaborative care approach with maternal-fetal medicine specialists and skilled anesthesiologists, reinforcing the notion that in vitro fertilization should not be withheld as a treatment modality from patients with obesity.

Utility of Office Hysteroscopy in Diagnosing Retained Products of Conception Following Early Pregnancy Loss After In Vitro Fertilization.

OBJECTIVE: To evaluate the utility of office hysteroscopy in diagnosing and treating retained products of conception in patients with infertility who experience early pregnancy loss (EPL) after in vitro fertilization (IVF). METHODS: We evaluated a retrospective cohort of 597 pregnancies that ended in EPL in patients aged 18-45 years who conceived through fresh or frozen embryo transfer at an academic fertility practice between January 2016 and December 2021. All patients underwent office hysteroscopy after expectant, medical, or surgical management of the EPL. The primary outcome was presence of retained products of conception at the time of office hysteroscopy. Secondary outcomes included incidence of vaginal bleeding, presence of intrauterine adhesions, treatment for retained products of conception, and duration of time from EPL diagnosis to resolution. Log-binomial regression and Poisson regression were performed, adjusting for potential confounders including oocyte age, patient age, body mass index, prior EPL count, number of prior dilation and curettage procedures, leiomyomas, uterine anomalies, and vaginal bleeding. RESULTS: Of the 597 EPLs included, 129 patients (21.6%) had retained products of conception diagnosed at the time of office hysteroscopy. The majority of individuals with EPL were managed surgically (n=427, 71.5%), in lieu of expectant management (n=140, 23.5%) or medical management (n=30, 5.0%). The presence of retained products of conception was significantly associated with vaginal bleeding (relative risk [RR] 1.72, 95% CI 1.34-2.21). Of the 41 patients with normal pelvic ultrasonogram results before office hysteroscopy, 10 (24.4%) had retained products of conception detected at the time of office hysteroscopy. When stratified by EPL management method, retained products of conception were significantly more likely to be present in individuals with EPL who were managed medically (adjusted RR 2.66, 95% CI 1.90-3.73) when compared with those managed surgically. Intrauterine adhesions were significantly less likely to be detected in individuals with EPL who underwent expectant management when compared with those managed surgically (RR 0.14, 95% CI 0.04-0.44). Of the 127 individuals with EPL who were diagnosed with retained products of conception at the time of office hysteroscopy, 30 (23.6%) had retained products of conception dislodged during the office hysteroscopy, 34 (26.8%) chose expectant or medical management, and 63 (49.6%) chose surgical management. The mean number of days from EPL diagnosis to resolution of pregnancy was significantly higher in patients who elected for expectant management (31 days; RR 1.18, 95% CI 1.02-1.37) or medical management (41 days; RR 1.54, 95% CI 1.25-1.90) when compared with surgical management (27 days). CONCLUSION: In patients with EPL after IVF, office hysteroscopy detected retained products of conception in 24.4% of those with normal pelvic ultrasonogram results. Due to the efficacy of office hysteroscopy in diagnosing and treating retained products of conception, these data support considering office hysteroscopy as an adjunct to ultrasonography in patients with infertility who experience EPL after IVF.

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.

Sonographic Predictors of Ovarian Torsion in Premenarchal Girls.

STUDY OBJECTIVE: To identify preoperative transabdominal sonographic predictors of surgically confirmed ovarian torsion (OT) in premenarchal girls METHODS: We conducted a retrospective case-control study of 32 premenarchal girls aged 0-12 undergoing surgery for OT (cases) or a non-torsed ovarian mass (controls) from 2006 to 2017 at a single academic center. Cases had ICD-9/10 codes for torsion of the ovary, adnexa, ovarian pedicle, or fallopian tube and surgically confirmed OT; controls had codes for ovarian mass or cyst and surgically confirmed absence of OT. Preoperative transabdominal ultrasounds were analyzed by 3 radiologists blinded to final diagnosis. We used χ2, Fisher[s exact, and Student's t tests for statistical comparisons. RESULTS: From 2016 to 2017, 32 patients presented with acute abdominal pain or symptoms concerning for ovarian mass requiring ultrasound imaging and subsequent diagnostic laparoscopy; 24 (75.0%) had confirmed OT by laparoscopy, and 8 (25.0%) did not. The mean age in both groups was similar (7.3 ± 2.9 years). Preoperative sonographic variables significantly associated with OT included presence of a simple cyst (20.8% vs 12.5%), ovarian heterogeneity (100% vs 12.5%), presence of peripheralized follicles (70.8% vs 0%), and asymmetry of color Doppler (75.0% vs 37.5%; all P < .05). Presence of free fluid, arterial color Doppler, and a whirlpool sign were not predictive of OT. CONCLUSION: In premenarchal patients, although certain variables on transabdominal sonography predicted surgically confirmed OT, only the presence of peripheralized follicles was unique to girls with OT. The decision to proceed with diagnostic laparoscopy for suspected OT can be aided by these specific sonographic findings but should ultimately be based on high clinical suspicion.

The impact of insurance mandates on donor oocyte utilization: an analysis of 39,338 donor oocyte cycles from the Society for Assisted Reproductive Technology registry.

BACKGROUND: A total of 19 states passed legislation mandating insurance coverage of assisted reproductive technology, and out-of-pocket costs associated with in vitro fertilization vary significantly depending on the region. Consequently, it has been observed that assisted reproductive technology utilization differs regionally and is associated with the presence of an insurance mandate. However, it is unknown whether regional differences exist among patients using donor oocytes. OBJECTIVE: This study aimed to determine the patient and cycle-specific parameters associated with the use of donor oocytes according to the insurance mandate status of the Society for Assisted Reproductive Technology clinic in which the assisted reproductive technology cycle was performed. STUDY DESIGN: This study was a retrospective cohort study using national data collected from the Society for Assisted Reproductive Technology registry for 39,338 donor oocyte cycles and 242,555 autologous oocyte cycles performed in the United States from January 1, 2014, to December 31, 2016. Cycles were stratified by insurance mandate of the state in which the assisted reproductive technology cycle was performed: comprehensive (coverage for at least 4 cycles of assisted reproductive technology), limited (coverage limited to 1-3 assisted reproductive technology cycles), offer (insurance mandates exist but exclude assisted reproductive technology treatment), and no mandate. The primary outcome was the number of previous autologous assisted reproductive technology cycles of the recipient. The secondary outcomes included age, serum follicle stimulating hormone level, frozen donor oocyte utilization, day of embryo transfer, number of embryos transferred, clinical pregnancy rate, and live birth rate. Analyses were adjusted for day of transfer, number of embryos transferred, and age of the recipient. RESULTS: Patients in no mandate states underwent fewer autologous assisted reproductive technology cycles (mean, 1.1; standard deviation, 1.6) before using donor oocytes than patients in offer (mean, 1.7; standard deviation, 2.5; P<.01), limited (mean, 1.5; standard deviation, 2.5; P<.01), and comprehensive (mean, 1.7; standard deviation, 2.0; P<.01) states. Patients in no mandate states were more likely to use frozen oocytes than patients in offer (relative risk, 0.54; 95% confidence interval, 0.52-0.57), limited (relative risk, 0.50; 95% confidence interval, 0.46-0.54), and comprehensive (relative risk, 0.94; 95% confidence interval, 0.89-0.99) states. Clinical pregnancy and live birth rates were similar among recipients of donor oocytes, regardless of insurance mandate. CONCLUSION: Despite similar ages and ovarian reserve parameters, patients without state-mandated insurance coverage of assisted reproductive technology were more likely to use frozen donor oocytes and undergo fewer autologous in vitro fertilization cycles than their counterparts in partial or comprehensive insurance coverage states. These differences in donor oocyte utilization highlight the financial barriers associated with pursuing assisted reproductive technology in uninsured states.

Mouse oocyte vitrification with and without dimethyl sulfoxide: influence on cryo-survival, development, and maternal imprinted gene expression.

PURPOSE: Oocytes and embryos can be vitrified with and without dimethyl sulfoxide (DMSO). Objectives were to compare no vitrification (No-Vitr), vitrification with DMSO (Vitr + DMSO), and vitrification without DMSO (Vitr - DMSO) on fresh/warmed oocyte survival, induced parthenogenetic activation, parthenogenetic embryo development, and embryonic maternal imprinted gene expression. METHODS: In this prospective controlled laboratory study, mature B6C3F1 female mouse metaphase II oocytes were treated as: i) No-Vitr, ii) Vitr + DMSO/warmed, and iii) Vitr - DMSO/warmed with subsequent parthenogenetic activation and culture to the blastocyst stage. Oocyte cryo-survival, parthenogenetic activation and embryo development, parthenogenetic embryo maternal imprinted gene expression were outcome measures. RESULTS: Oocyte cryo-survival was significantly improved in Vitr + DMSO versus Vitr - DMSO at initial warming and 2 h after warming. Induced parthenogenetic activation was similar between all three intervention groups. While early preimplantation parthenogenetic embryo development was similar between control, Vitr + DMSO, Vitr - DMSO oocytes, the development to blastocysts was significantly inferior in the Vitr - DMSO oocytes group compared to the control and Vitr + DMSO oocyte groups. Finally, maternal imprinted gene expression was similar between intervention groups at both the 2-cell and blastocyst parthenogenetic embryo stage. CONCLUSION(S): Inclusion of DMSO in oocyte vitrification solutions improved cryo-survival and developmental potential of parthenogenetic embryos to the blastocyst stage without significantly altering maternal imprinted gene expression.

Comparison of Short-Duration and Chronic Premenarchal Vulvar Complaints.

STUDY OBJECTIVE: To compare clinical characteristics, treatment histories, and microbiology of premenarchal girls who presented to a pediatric gynecology specialty clinic with short-duration and chronic vulvar symptoms. DESIGN: Retrospective cohort study. SETTING: Pediatric and adolescent gynecology clinic at a tertiary care children's hospital. PARTICIPANTS: One hundred eighty-two premenarchal patients ages 2-14 years who presented to a pediatric gynecology specialty clinic with vulvar complaints and who were evaluated with a yeast and/or bacterial culture. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Chronic and short-duration vulvar symptoms, microbiology, and diagnosis. RESULTS: Patients with chronic symptoms were more likely to present with itching (59/102 (57.8%) vs 34/80 (42.5%); P = .04), redness or rash (53/102 (52.0%) vs 22/80 (27.5%); P = .0009), and discomfort (59/102 (57.8%) vs 30/80 (37.5%); P = .006), compared with patients with short-duration symptoms. Overall, 44.5% of patients had a history of antifungal treatment, with a greater proportion of patients with chronic symptoms having received antifungal treatment compared with those with short-duration symptoms (53/102 (52.0%) vs 28/80 (35.0%); P = .02). Despite a history of antifungal treatment in nearly half of the patients, Candida albicans was isolated in only 3/144 (2.1%) yeast cultures. Bacterial vulvar cultures were positive in 75/159 (47.2%), and there was no difference among the symptom duration groups (38/71 (53.5%) vs 37/88 (42.1%); P = .15). CONCLUSION: Vulvovaginitis is a common gynecological diagnosis among premenarchal girls with short-duration and chronic vulvar symptoms. Regardless of symptom duration, yeast cultures are rarely positive. Antifungal treatment should be avoided in toilet-trained prepubertal girls.

Adolescents Presenting to the Emergency Department with Heavy Menstrual Bleeding.

STUDY OBJECTIVE: To describe the adolescent population that seeks care in the emergency department (ED) for heavy menstrual bleeding (HMB), and to compare those who are discharged to those who are admitted to the hospital. DESIGN: Retrospective study. SETTING: Emergency department and inpatient unit at a national tertiary care hospital from 2006-2018. PARTICIPANTS: Adolescents 11-19 years old with ICD-9 and ICD-10 codes for HMB. INTERVENTIONS: Chart abstraction for demographic data, symptoms, laboratory tests, outcomes, and treatments. MAIN OUTCOME MEASURE: Adolescents who were admitted were compared to girls who were treated as outpatients. RESULTS: There were 258 adolescents who sought care for HMB in the ED during the study period. A total of 44 patients (17%) were admitted to the hospital, whereas 214 (83%) were discharged. The average age of those admitted was 15 years, compared to 17 years for those discharged (P < .001). In the admitted group, the mean initial hemoglobin (Hgb) was 6.3 g/dL compared to 12.0 g/dL in the discharged group (P < .0001). Only 23% of the discharged patients were released with medications; the remainder did not receive treatment. Anovulation was the etiology of HMB in the majority (56%) of both inpatients and outpatients. Of the 44 adolescents admitted to the hospital for HMB, 12 (27%) had a bleeding disorder (BD) and 32 (73%) did not. CONCLUSION: The majority of adolescents who presented to the emergency department for HMB were not anemic and did not receive any treatment. Of those admitted, almost one-third had an underlying BD, which is higher than previously reported.

The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of ß Cells.

Although glucose uniquely stimulates proinsulin biosynthesis in ß cells, surprisingly little is known of the underlying mechanism(s). Here, we demonstrate that glucose activates the unfolded protein response transducer inositol-requiring enzyme 1 alpha (IRE1α) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary ß cells. Using mRNA sequencing (mRNA-Seq), we show that unconventional Xbp1 mRNA splicing is required to increase and decrease the expression of several hundred mRNAs encoding functions that expand the protein secretory capacity for increased insulin production and protect from oxidative damage, respectively. At 2 wk after tamoxifen-mediated Ire1α deletion, mice develop hyperglycemia and hypoinsulinemia, due to defective ß cell function that was exacerbated upon feeding and glucose stimulation. Although previous reports suggest IRE1α degrades insulin mRNAs, Ire1α deletion did not alter insulin mRNA expression either in the presence or absence of glucose stimulation. Instead, ß cell failure upon Ire1α deletion was primarily due to reduced proinsulin mRNA translation primarily because of defective glucose-stimulated induction of a dozen genes required for the signal recognition particle (SRP), SRP receptors, the translocon, the signal peptidase complex, and over 100 other genes with many other intracellular functions. In contrast, Ire1α deletion in ß cells increased the expression of over 300 mRNAs encoding functions that cause inflammation and oxidative stress, yet only a few of these accumulated during high glucose. Antioxidant treatment significantly reduced glucose intolerance and markers of inflammation and oxidative stress in mice with ß cell-specific Ire1α deletion. The results demonstrate that glucose activates IRE1α-mediated Xbp1 splicing to expand the secretory capacity of the ß cell for increased proinsulin synthesis and to limit oxidative stress that leads to ß cell failure.

Chaperone activation by unfolding.

Conditionally disordered proteins can alternate between highly ordered and less ordered configurations under physiological conditions. Whereas protein function is often associated with the ordered conformation, for some of these conditionally unstructured proteins, the opposite applies: Their activation is associated with their unfolding. An example is the small periplasmic chaperone HdeA, which is critical for the ability of enteric bacterial pathogens like Escherichia coli to survive passage through extremely acidic environments, such as the human stomach. At neutral pH, HdeA is a chaperone-inactive dimer. On a shift to low pH, however, HdeA monomerizes, partially unfolds, and becomes rapidly active in preventing the aggregation of substrate proteins. By mutating two aspartic acid residues predicted to be responsible for the pH-dependent monomerization of HdeA, we have succeeded in isolating an HdeA mutant that is active at neutral pH. We find this HdeA mutant to be substantially destabilized, partially unfolded, and mainly monomeric at near-neutral pH at a concentration at which it prevents aggregation of a substrate protein. These results provide convincing evidence for direct activation of a protein by partial unfolding.