Shear wave elastography to assess stiffness of the human ovary and other reproductive tissues across the reproductive lifespan in health and disease†.

The ovary is one of the first organs to show overt signs of aging in the human body, and ovarian aging is associated with a loss of gamete quality and quantity. The age-dependent decline in ovarian function contributes to infertility and an altered endocrine milieu, which has ramifications for overall health. The aging ovarian microenvironment becomes fibro-inflammatory and stiff with age, and this has implications for ovarian physiology and pathology, including follicle growth, gamete quality, ovulation dynamics, and ovarian cancer. Thus, developing a non-invasive tool to measure and monitor the stiffness of the human ovary would represent a major advance for female reproductive health and longevity. Shear wave elastography is a quantitative ultrasound imaging method for evaluation of soft tissue stiffness. Shear wave elastography has been used clinically in assessment of liver fibrosis and characterization of tendinopathies and various neoplasms in thyroid, breast, prostate, and lymph nodes as a non-invasive diagnostic and prognostic tool. In this study, we review the underlying principles of shear wave elastography and its current clinical uses outside the reproductive tract as well as its successful application of shear wave elastography to reproductive tissues, including the uterus and cervix. We also describe an emerging use of this technology in evaluation of human ovarian stiffness via transvaginal ultrasound. Establishing ovarian stiffness as a clinical biomarker of ovarian aging may have implications for predicting the ovarian reserve and outcomes of Assisted Reproductive Technologies as well as for the assessment of the efficacy of emerging therapeutics to extend reproductive longevity. This parameter may also have broad relevance in other conditions where ovarian stiffness and fibrosis may be implicated, such as polycystic ovarian syndrome, late off target effects of chemotherapy and radiation, premature ovarian insufficiency, conditions of differences of sexual development, and ovarian cancer. Summary sentence:  Shear Wave Elastography is a non-invasive technique to study human tissue stiffness, and here we review its clinical applications and implications for reproductive health and disease.

Changes in Age Distribution and Maternal Mortality in a Subset of the U.S., 2014-2021.

INTRODUCTION: This study aimed to determine the association between changes in age distribution and maternal mortality rates (MMR) in a subset of the United States between 2014 and 2021. METHODS: A serial cross-sectional analysis of birthing individuals aged 15-44 years from 2014 to 2021 was performed. States that had not adopted the pregnancy checkbox as of 2014 were excluded from the primary analysis. A significant inflection point in MMR was identified in 2019 with the Joinpoint Regression Program, so all analyses were stratified: 2014-2019 and 2019-2021. The Kitagawa decomposition was applied to quantify the contribution from (1) changes in age distribution and (2) changes in age-specific MMR (ASMR) to total MMR. Data analysis occurred between 2022 and 2023. RESULTS: From 2014 to 2021, the mean (standard deviation) age of birthing individuals changed from 28.3 (5.8) to 29.4 (5.7) years. The MMR (95% CI) increased significantly from 16.5 (15.8-18.5) to 18.9 (17.4-20.5) per 100,000 live births from 2014 to 2019 with acceleration in MMR to 31.8 (30.0-33.8) by 2021. The change in maternal age distribution contributed to 36% of the total change in the MMR from 2014 to 2019 and 4% from 2019 to 2021. Age-specific MMR components increased significantly for those aged 25-29 years and 30-34 years from 2014 to 2019. All 5-year age strata except the 15-19 year old group saw increases in age-specific MMR from 2019 to 2021. CONCLUSIONS: MMR increased significantly from 2014 to 2021 with rapid increase after 2019. However, older age of birthing individuals explained only a minority of the increased MMR in both periods. The greatest contribution to MMR arose from increases in age-specific MMR.

Antimüllerian hormone level predicts ovulation in women with polycystic ovary syndrome treated with clomiphene and metformin.

OBJECTIVE: To describe the serum anti-Müllerian hormone (AMH) concentrations in a large, well-phenotyped cohort of women with polycystic ovary syndrome (PCOS) and evaluate whether AMH predicts successful ovulation induction in women treated with clomiphene and metformin. DESIGN: Secondary analysis of randomized controlled trial. SETTING: Not applicable. PATIENT(S): A total of 333 women with anovulatory infertility attributed to PCOS who participated in the double-blind randomized trial entitled the Pregnancy in Polycystic Ovary Syndrome I (PPCOS I) study (registration number, NCT00068861) who had serum samples from baseline laboratory testing available for further serum analysis were studied. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The association between the baseline AMH levels in each of the 3 treatment groups and ovulation, pregnancy, and live birth rates were assessed. RESULT(S): A total of 322 individuals had a baseline AMH concentration available, of which the mean AMH was 11.7 ± 8.3 ng/mL (range 0.1-43.0 ng/mL). With each unit (1 ng/mL) increase in baseline AMH, the odds of ovulation decreased by 10% (odds ratio, 0.90; 95% confidence interval, 0.86-0.93); this effect did not differ by treatment group. Women with a high baseline AMH concentration (>8 ng/mL) were significantly less likely to ovulate compared with those with a normal baseline AMH concentration (<4 ng/mL) (odds ratio, 0.23; 95% confidence interval, 0.05-0.68). This remained statistically significant when controlling for confounders, including age, body mass index, time in study, and Homeostatic Model Assessment for Insulin Resistance score. Ovulation occurred even at very high AMH concentrations; there was no maximum level noted at which no ovulation events occurred. Baseline AMH concentration was not associated with pregnancy or live birth rates when controlling for confounders. CONCLUSION(S): These AMH values in well-phenotyped individuals with PCOS add to the literature and will aid in identifying AMH criteria for the diagnosis of PCOS. In women with infertility and PCOS, a higher AMH concentration was associated with reduced odds of ovulation with ovulation induction with clomiphene, clomiphene + metformin, and metformin. CLINICAL TRIAL REGISTRATION NUMBER: The original trial from which this analysis is derived was entitled "Pregnancy in Polycystic Ovary Syndrome: A 30 Week Double-Blind Randomized Trial of Clomiphene Citrate, Metformin XR, and Combined Clomiphene Citrate/Metformin XR For the Treatment of Infertility in Women With Polycystic Ovary Syndrome" and was registered on ClinicalTrials.gov as number NCT00068861. The URL for the trial is https://clinicaltrials.gov/study/NCT00068861. The first subject was enrolled in November 2002.

Undergraduate students have low fertility knowledge and high anxiety regarding future fertility: An opportunity for education.

Objectives: To assess childbearing intentions, concerns about future fertility, knowledge about the age-related decline in fertility, and interest in receiving fertility education among undergraduate students. Design: From March to April 2021, a cross-sectional, web-based survey with 42 reproductive and fertility-related questions was administered to and completed by actively enrolled undergraduates at Northwestern University in the United States. Results: The survey was completed by 291 students (mean age 20.2 years). Of all participants, 62.5% plan to have children and 68.3% intend to delay childbearing. Significantly more females than males (70.7% vs 40.9%, P = 0.004) and premedical students compared to non-premedical students (78.2% vs 60.1%, P = 0.002) reported planning to delay childbearing due to educational or career aspirations. Significantly more females than males (43.5% vs 4.5%, P < 0.001) and premedical compared to non-premedical students (50.4% vs 31.5%, P = 0.002) also reported having anxiety about future fertility due to career aspirations.When surveyed about fertility knowledge, 31.1% of participants reported that females are as fertile in their forties as they are in their thirties, and 25.4% stated that female fertility does not dramatically decline until age 40 or later. When asked to estimate the oldest age a woman has conceived using autologous oocytes, 83.3% reported age 48 or older. Of all participants, 72.3% were interested in learning about fertility. Conclusions: The majority of surveyed undergraduates plan to delay childbearing, yet they have concerns about how career goals will impact future fertility. Notably, females and premedical students reported higher rates of anxiety when compared to their male and non-premedical counterparts. Knowledge about the age-related decline in fertility was limited, but students have a strong interest in learning about fertility, highlighting an opportunity for educational intervention at the undergraduate level. With education, students may be empowered to make informed decisions about future reproductive strategy earlier in time, potentially decreasing future anxiety.

Genetic contributions to risk of adverse pregnancy outcomes.

Purpose of Review: Adverse pregnancy outcomes (APOs), including hypertensive disorders of pregnancy (HDP), low birthweight (LBW), and preterm birth (PTB), along with peripartum cardiomyopathy (PPCM) are associated with short- and long-term maternal and fetal cardiovascular risks. This review focuses on the genetic contributions to the risk of APOs and PPCM. Recent Findings: The expansion of genome-wide association studies (GWAS) has led to better understanding of the biologic mechanisms underpinning APO, PPCM, and the predisposition to cardiovascular disease across the life course. Genetic loci known to be involved with the risk of hypertension (FTO, ZNF831) have been associated with the development of overall HDP and preeclampsia. Additionally, four loci significantly associated with type 2 diabetes have been associated with GDM (CDKAL1, MTNR1B, TCF7L2, CDK2NA-CDKN2B). Variants in loci known to affect genes coding for proteins involved in immune cell function and placental health (EBF1, EEFSEC, AGTR2, 2q13) have been implicated in the development of PTB and future cardiovascular risks for both the mother and the offspring. Genetic similarities in rare variants between PPCM and dilated cardiomyopathy have been described suggesting shared pathophysiologic origins as well as predisposition for future risk of heart failure, highlighting the need for the development PPCM genetic counseling guidelines. Summary: Genetics may inform mechanisms, risk, and counseling for individuals after an APO or PPCM. Through recent advances in genetic techniques and analytic approaches, new insights into the underlying biologic mechanisms and genetic variants leading to these risks have been discovered.

Early ß-hCG levels predict live birth after single embryo transfer.

PURPOSE: Specific serum beta human chorionic gonadotropin (ß-hCG) parameters that can predict live birth after an embryo transfer have yet to be defined. METHODS: We performed a retrospective cohort study of 1,028 patients with a detectable ß-hCG who underwent a single embryo transfer between 2002 and 2019 at a large academic center. Two ß-hCG parameters were examined in relation to live birth: 1) "doubling" defined as ß-hCG doubling over 48 h and 2) "reaching 100" defined as a ß-hCG ≥ 100 mIU/mL by 15 days after oocyte retrieval (AOR). RESULTS: One thousand three hundred forty cycles involving a single embryo were analyzed. Two thirds were frozen embryos and 86% were blastocyst transfers. Preimplantation genetic testing was performed in almost 30% of cycles. When ß-hCG levels "doubled," a live birth occurred in 80.7% of cycles and when ß-hCG levels "reached 100" by 15 days AOR, live birth occurred in 81.6% of cycles. When ß-hCG levels both doubled and reached 100 by 15 days, AOR 85.4% cycles resulted in live birth. A multiple logistic regression model to control for patient and cycle level factors revealed a live birth odds ratio (OR) of 8.0 (95% CI 5.7-11.1) when ß-hCG "doubled" and an OR of 21.2 (95% CI 14.3-31.5) when ß-hCG "reached 100." When both these latter parameters were met, the OR was 12.5 (95% CI 8.9-17.8). CONCLUSION: ß-hCG parameters of "doubling" and "reaching 100" by 15 days AOR are robust predictors of live birth and can aid in patient counseling regarding pregnancy outcomes soon after single embryo transfer.

Relationship between paternal factors and embryonic aneuploidy of paternal origin.

OBJECTIVE: To determine if there is a relationship between paternal factors and embryonic aneuploidy of paternal origin using preimplantation genetic testing for aneuploidy (PGT-A). DESIGN: Retrospective cohort. SETTING: Academic. PARTICIPANTS: Couples undergoing in vitro fertilization with PGT-A. INTERVENTIONS: None. MAIN OUTCOME MEASURE: To determine if there is an association between paternal age, body mass index (BMI), or semen analysis parameters and paternal aneuploidy. RESULTS: From January 2015-2020, 453 in vitro fertilization cycles (1,720 embryos) underwent PGT-A using single nucleotide polymorphism microarrays with parental support bioinformatics. The mean (±SD) was 36.5 (±3.5) years for maternal age, 39.5 (±5.5) years for paternal age, 24.7 (±5.0) kg/m2 for maternal BMI, and 27.6 (±4.3) kg/m2 for paternal BMI. Embryonic aneuploidy of paternal origin was found in 8.4% (144/1,720) embryos. There were 1,533 embryos with a recorded paternal BMI. Rates of embryonic aneuploidy of paternal origin were similar between men across BMI groups: BMI 18-24.9 kg/m2 was 7.2% (referent); BMI 25-29.9 kg/m2 was 8.4% (odds ratio [OR], 1.12; 95% confidence interval [CI], 0.79-1.82); and BMI ≥30 kg/m2 was 9.1% (OR, 1.31; 95% CI, 0.83-2.08). There were 854 embryos from men with a normal and 866 from men with an abnormal semen analysis. No differences were found in the rate of embryonic aneuploidy of paternal origin between men with normal and abnormal sperm concentration, total count, motility, progressive motility, or morphology. No significant difference was seen in rates of aneuploidy between men aged <50 years and those aged ≥50 years (OR, 1.69; 95% CI, 0.96-2.98). CONCLUSION: No association was found between paternal age, BMI, or semen analysis parameters and paternal aneuploidy.

Maternal body mass index is not associated with increased rates of maternal embryonic aneuploidy.

OBJECTIVE: To evaluate the relationship between maternal body mass index (BMI) and embryonic aneuploidy of maternal origin. DESIGN: Retrospective cohort analysis. SETTING: University hospital-based reproductive center. PATIENTS: Maternal origin of aneuploidy was available for 453 cycles and 1,717 embryos. INTERVENTIONS: Data regarding BMI were collected before egg retrieval. Comparison groups included underweight (BMI, <18.5 kg/m2), normal weight (BMI, 18.5-24.9 kg/m2), overweight (BMI, 25-29.9 kg/m2), and obese (BMI, ≥30 kg/m2). Overall embryonic aneuploidy and maternal aneuploidy rates were compared. The aneuploidy rate was the number of embryos with either maternal or mixed (maternal and paternal) aneuploidy divided by the total number of embryos tested. MAIN OUTCOME MEASURES: Overall embryonic aneuploidy and maternal aneuploidy rates. RESULTS: Maternal aneuploidy rate was 51.5% for BMI of ≥30 kg/m2 and 39.3% for BMI of <30 kg/m2. Female age as well as several in vitro fertilization characteristics were significantly different across groups and were included in the adjusted model. Both the overall embryonic aneuploidy rate (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.11-1.59) and the maternal aneuploidy rate (OR, 1.64; 95% CI, 1.25-2.16) increased with increasing maternal BMI. However, after controlling for significant confounders, BMI did not significantly predict the rate of maternal aneuploidy (OR, 1.16; 95% CI, 0.85-1.59). CONCLUSIONS: Maternal BMI did not correlate with embryonic aneuploidy of maternal origin after adjusting for confounders.