Malathion exposure may increase infertility risk among US Adults: Results from the 2015-2016 NHANES.

BACKGROUND AND PURPOSE: Organophosphate pesticides such as malathion are the most widely used pesticides. Despite endocrine-disrupting effects, there is a paucity of information regarding chronic exposure to non-persistent organopesticides such as malathion. The purpose of this study is to describe the exposure burden among U.S. residents as well as possible impacts on fertility. METHODS: Population-based data collected by the National Health and Nutrition Examination Survey (NHANES) between 2015 and 2016 were used to perform a retrospective analysis on urinary concentrations of malathion diacid. Samples were assessed from 1703 adult participants, statistically weighted to represent over 231 million individuals. General linear models were used to examine associations between exposure and reproductive health measures among pre-menopausal women. RESULTS: Detectable concentrations of malathion diacid were identified in 16.1 % (n = 254) of samples. Concentrations were higher among women who reported seeing a physician due to difficulties becoming pregnant (P < 0.001; r2 = 0.12) as well as among women who reported trying for at least a year to become pregnant (P < 0.001; r2 = 0.06). CONCLUSIONS: Exposure to malathion is associated with a history of reproductive health challenges among women.

Association of duration of embryo culture with risk of large for gestational age delivery in cryopreserved embryo transfer cycles.

OBJECTIVE: To examine the relationship between the day of embryo cryopreservation and large for gestational age (LGA) infants in women undergoing frozen embryo transfers (FETs) after cryopreservation on days 2-7 after fertilization and to compare the risk of the day of embryo cryopreservation to other possible risk factors of LGA after FET cycles. DESIGN: Retrospective cohort study. SETTING: Society of Assisted Reproduction Clinical Outcomes Reporting System. PATIENTS: Women undergoing FET cycles. INTERVENTION: Day of cryopreservation. MAIN OUTCOME MEASURE: Singleton LGA infant. RESULTS: A total of 33,030 (18.2%) FET cycles in the study group (n = 181,592) resulted in LGA infants during the study period of 2014-2019. There was an increase in LGA risk when cryopreservation was performed from day 2 (13.7%) to days 3-7 (14.4%, 15.0%, 18.2%, 18.5%, and 18.9%). In the log-binomial model, the risk increased compared with days 2-3 combined when cryopreservation was performed on days 5-7 (adjusted relative risk [aRR] 1.32, 95% confidence interval [CI] 1.22-1.44 for day 5, aRR 1.34, 95% CI 1.23-1.46 for day 6, and aRR 1.42, 95% CI 1.25-1.61 for day 7). Other factors most associated with LGA risk in the log-binomial model were preterm parity of >3 compared with 0 (aRR 1.82, 95% CI 1.24-2.69) and body mass index (BMI) of >35 kg/m2 compared with normal weight (aRR 1.94, 95% CI 1.88-2.01). Increasing gravity, parity, BMI, number of oocytes, and embryo grade were also associated with LGA in this model. Asian, Black, Hispanic, and combined Hawaiian and Pacific Islander were protective factors in the model compared with White patients. Low BMI (<18.5 kg/m2) was also considered a protective factor in the model compared with normal BMI. CONCLUSION: Duration of embryo culture was associated with an increased risk of LGA in this study cohort when controlling for known confounders such as maternal BMI and parity. This study sheds new light on the possible link between FET and LGA infants.

An Assessment of Physician Well-Being and Burnout Among Army Obstetricians and Gynecologists.

INTRODUCTION: Physician burnout is associated with unsafe patient care and poor patient satisfaction. Civilian studies show burnout rates of 46% among obstetricians/gynecologists (OB/GYNs). Army Active Duty (A-AD) physician burnout rates range from 7.7% to 26% across specialties, but no studies have assessed A-AD OB/GYN burnout. The objective of this study was to quantify well-being of A-AD OB/GYNs by determining rates of professional fulfillment (wellness) and burnout and detect factors of potential protective or risk for wellness and burnout. METHODS: A cross-sectional survey-based study was designed to determine well-being of A-AD OB/GYNs. This Institutional Review Board-approved study used the validated Professional Fulfillment Index. The survey was shared anonymously via email to 197 A-AD OB/GYNs. Additional questions asked as possible risk factors for burnout include location, training status, fellowship training, and remaining active duty service obligation (ADSO). Wellness and burnout rates were determined using published scales. Mean rates of wellness and burnout were reported, and chi-square tests detected associations between wellness/burnout and other variables. RESULTS: Eighty-three A-AD OB/GYNs responded to the survey (42%), with 73 available for full analysis. 26.5% had positive wellness, and 50% reported burnout. Completing fellowship training and shorter ADSO (of 0-2 years compared to >5 years) had higher rates of wellness. There were no differences in burnout among groups. CONCLUSIONS: Burnout rates in A-AD OB/GYNs appear higher than A-AD physicians of other specialties but are similar to civilian OB/GYNs. Fellowship training may confer higher rates of wellness. Further research is needed regarding improvements in A-AD OB/GYN well-being and burnout.

Factors associated with large-for-gestational-age infants born after frozen embryo transfer cycles.

Objective: To examine trends of frozen embryo transfer (FET) proportions and large-for-gestational-age (LGA) incidence and determine risk factors for LGA infants after FET. Design: Retrospective cohort study. Setting: Not applicable. Patients: Frozen embryo transfer cycles. Interventions: None. Main Outcome Measures: Singleton LGA infant. Results: The percentage of FETs increased from 20%-74% of transfers, whereas the rate of LGA among FET singleton births decreased from 18%-12% during 2004-2018. In a subanalysis of 127,525 FET-associated singleton live births during 2016-2018, patient factors associated with LGA were higher-than-normal maternal body mass index (body mass index [BMI], 25.0-29.9 kg/m2; adjusted relative risk [aRR], 1.31; 95% confidence interval [CI], 1.26-1.36; BMI, 30.0-34.9 kg/m2; aRR, 1.48; 95% CI, 1.41-1.55; and BMI, >35 Kg/m2; aRR, 1.68; 95% CI, 1.59-1.77) and ≥1 prior birth vs. none. Low maternal BMI (<18.5 vs. 18.5-24.9 kg/m2) and cycles involving patients who were non-Hispanic (NH) Asian/Native Hawaiian/Pacific Islander, NH Black, or Hispanic (compared with NH White) were at lower risk of LGA infants. Cycle factors associated with LGA included gestational carrier use (aRR, 1.25; 95% CI, 1.16-1.34) and donor sperm (aRR, 1.17; 95% CI, 1.10-1.25). Conclusions: Although the number and proportion of FET cycles increased from 2004-2018, the rate of LGA after FET decreased. Maternal BMI, parity, and race/ethnicity were the strongest risk factors for LGA infants after FET.

A Comparison of Prostaglandin Profile in Human Follicular Fluid Between White and Black/Hispanic Women.

The aim of the study is to compare prostaglandin (PG) profiles in human follicular fluid between White and Black/Hispanic women using data from a previously published study. A retrospective cohort study of 5 White and 5 Black/Hispanic women who underwent oocyte retrieval was conducted. Human follicular fluid was obtained from the first follicle entered at time of oocyte retrieval for patients undergoing in vitro fertilization cycles (IVF). PG levels were compared using mass spectroscopy with known standards to quantify PG levels. Five White women were matched with 5 Black/Hispanic women with diagnosis. Both cohorts had similar levels of age, body mass index, and IVF cycle characteristics. There were no statistical differences in PG profiles (PGE2, PGF1α, PGF2α, or 8 iso-PGF1α). In this small repeat analysis of previously studied data, there were no differences noted in PG profiles in follicular fluid. Larger studies are needed to verify this finding. This study further demonstrates the lack of representation of minority patients in studies.

Effects of different frozen embryo transfer regimens on abnormalities of fetal weight: a systematic review and meta-analysis.

BACKGROUND: Reported increases in maternal and perinatal morbidity (including macrosomia, large for gestational age (LGA), cesarean section, hemorrhage and hypertensive disorders of pregnancy) following frozen embryo transfer (FET) cycles may be associated with the lack of a corpus luteum seen in programmed FET. Given the growing number of studies comparing outcomes between natural FET and programmed FET cycles, a meta-analysis would prove useful to detect the presence of abnormalities in fetal birth weight in patients undergoing natural and programmed FET cycles. OBJECTIVE AND RATIONALE: The aim of this study was to provide a systematic review and meta-analysis of the effects of natural versus programmed methods of endometrial preparation for FET cycles on fetal weight and the risks of LGA and macrosomia. SEARCH METHODS: A literature search using MEDLINE, SCOPUS, EMBASE and clinicaltrials.gov was conducted for published research comparing neonatal outcomes in natural FET and programmed FET cycles. Primary outcomes of interest were fetal weight, macrosomia and LGA. Studies were included if the following criteria were met: study contained cohorts of NFET and programmed FET with outcome data of birth weight, large for gestational data and/or macrosomia. The data are presented as average weight and odds ratio (OR) with 95% confidence interval (CI) with fixed- or random-effects meta-analysis between cohorts of NFET and programmed FET cycles. Bias was assessed using Newcastle-Ottawa quality assessment scale for the 14 included studies. Multiple subgroup analyses were performed to assess for effect of the true natural cycle (defined as no ovulation trigger medication use) and the day of embryo transfer on fetal weight parameters compared with programmed cycle FET. OUTCOMES: A total of 879 studies were identified, with 15 meeting inclusion the criteria. The studies varied with respect to country of origin, definition of natural cycle FET and type of progesterone supplementation used. The included studies had similar gestational ages at the time of birth. Programmed FET cycles resulted in a higher fetal weight compared with natural FET cycles (mean difference 47.38 gp = 0.04). Programmed FET cycles were also at higher risk for macrosomia (OR 1.15, 95% CI 1.06-1.26) and LGA (OR 1.10, 95% CI 1.02-1.19) compared with natural FET cycles. Subgroup analyses demonstrated that programmed FET cycles resulted in a higher fetal weight compared with true natural FET (mean difference 62.18 gp = 0.0001) cycles. Cleavage stage embryo transfers had an increased risk of LGA (OR 1.27, 95% CI 1.00-1.62) and an increased risk of macrosomia (OR 1.25, 95% CI 1.08-1.44) in programmed FET cycles compared with natural FET cycles. Blastocyst transfer in programmed FET cycles resulted in no difference in risk of macrosomia but an increased risk of LGA (OR 1.13, 95% CI 1.06-1.21) compared with natural FET cycles. WIDER IMPLICATIONS: Programmed endometrial preparation for FET cycles had a significant effect, causing increased fetal birth weight and increased risks of LGA and macrosomia. The numbers of studies in the subgroup analyses were too low to determine reliable results. Further prospective randomized trials are needed to determine whether the changes seen in the observational trials are indeed accurate.

Elevated Serum Estradiol Levels Do Not Inhibit Implantation During Frozen Embryo Transfer Cycles.

The aim of the study is to determine if the magnitude of serum estradiol levels in blastocyst frozen embryo transfer cycles are associated with clinical pregnancy. A retrospective cohort study of female patients 18-43 years old, who underwent vitrified blastocyst embryo transfers at Tripler Army Medical Center from October 1, 2006, to October 1, 2016, was evaluated to determine the impact of estradiol levels on ongoing pregnancy rates in frozen embryo transfer cycles. The study included 173 total frozen embryo transfer cycles during the 10-year study period. The mean age at time of transfer was 34.5 years old (±4.4) with a majority of women undergoing double embryo transfer (70%). There was no statistical difference in ongoing pregnancy rates across estradiol levels (p = 0.80). However, at estradiol levels >3000 pg/mL, a statistically significant ongoing pregnancy rate was observed (p = 0.009). Ongoing pregnancy rate in frozen embryo transfer cycles is not negatively impacted by elevated estradiol levels.

Frozen-thawed embryo transfers: time to adopt a more "natural" approach?

The increasing use of frozen-thawed embryo transfer (FET) cycles has magnified the focus on endometrial preparation protocols in assisted reproduction. Emerging evidence suggests that natural cycle (NC) FETs are associated with improved outcomes, and that providers should consider increasing the utilization of NC FET at the expense of the currently favored artificial cycle (AC) FET as primary method for endometrial preparation.

Single Embryo Transfer Versus Double Embryo Transfer: A Cost-Effectiveness Analysis in a Non-IVF Insurance Mandated System.

INTRODUCTION: Because of increased morbidity seen in multiple gestations, the American Society of Reproductive Medicine recommends transfer of blastocysts one at a time for most patients. While cost-effectiveness models have compared single embryo transfer (SET) versus double embryo transfer (DET), few incorporate maternal and neonatal morbidity, and none have been performed in U.S. Military facilities. The purpose of this study was to determine the cost effectiveness of sequential SET versus DET in a U.S. Military treatment facility. MATERIALS AND METHODS: A cost-effectiveness model was created based on 250 patients between the ages of 20-44 who previously underwent in vitro fertilization (IVF) at our facility. The model consisted of patients pursuing either SET or DET with two total embryos. Cycle outcomes were determined using the published SARTCORS success calculator. Neonatal and obstetrical outcomes were simulated based on singleton and twin IVF pregnancies. Neonatal and obstetrical cost estimates were based on internal data as well. RESULTS: If 250 model patients pursue SET, 140 live births would occur, with total cost of $5.7 million, and cost per delivery of $40,500. If the model patients pursued DET, 117 live births would occur, with total cost of $9.2 million and a cost per delivery of $77.700. DET would lead to more total infants (207 vs. 143 in SET cohort). Personal costs are higher in SET versus DET cohorts ($23,036 vs. $20,535). CONCLUSIONS: SET in a system with no infertility coverage saves approximately $3.5 million per 250 patients. Higher personal costs as seen with SET may incentivize patients to seek DET. The total savings should encourage alteration to practice patterns with the U.S Military Healthcare System.

Azoospermia Secondary to a Novel X-Autosomal Reciprocal Translocation: 46,Y, t(X:16)(p22.1:p11.2).

Chromosomal translocations occur in 10 to 15% of men with azoospermia. Thirty distinct X-autosomal balanced reciprocal translocations have been reported in the literature thus far. We present a novel case of azoospermia with a karyotype of 46,Y,t(X:16)(p22.1:p11.2). A 26-year-old, healthy, active duty male Solider presented with his dependent female partner for primary infertility. Female anatomical and endocrine evaluations were normal. Initial male evaluation revealed azoospermia on multiple semen analyses. Further evaluation with a detailed physical exam and laboratory tests were normal except for an abnormal karyotype with a reciprocal translocation at chromosomes X and 16. An open testicular biopsy demonstrated 75% late spermatid maturation arrest confirming reproductive potential although significantly reduced. Men who present with azoospermia should undergo a full endocrine and genetic evaluation with a thorough physical evaluation by an urologist. They can have limited but successful reproductive outcomes if spermatozoa can be isolated during testicular biopsy. Given the high risk of producing genetically unbalanced embryos, genetic counseling and preimplantation genetic testing is essential before pursuing assisted reproductive technology. This case is the first X-autosomal balanced reciprocal translocations involving chromosome 16 and highlights the importance of the X chromosome during spermatogenesis.

Large, Non-Cavity Distorting Intramural Leiomyomas Decrease Leukemia Inhibitory Factor in the Secretory Phase Endometrium.

Despite mounting evidence that large intramural leiomyomas decrease fecundity during in vitro fertilization cycles, few studies have demonstrated a mechanism for this impact. We hypothesize that large intramural leiomyomas (IM) decrease the expression of endometrial implantation factors during the window of implantation. We prospectively recruited sub-fertile patients with IM 3 cm or greater in size planning myomectomy and performed endometrial biopsies the day of planned myomectomy (n = 9). Preoperative screening demonstrated no intercavitary lesions. Control endometrial samples were obtained from young, normally menstruating women free of uterine leiomyomas (n = 8). Endometrial samples were obtained in the mid-secretory phase (average cycle day for control patients and intramural leiomyoma patients were 24.5 and 21.3, respectively). Expression of implantation markers HOXA10, leukemia inhibitory factor (LIF), ER-α, and PR was compared using quantitative immunohistochemistry. Standard descriptive statistics were used to compare H-scores between the cohorts. Patients with intramural leiomyomas were found to have decreased LIF compared to controls (p value < 0.001). Expressions of HOXA10 and PR were no different between cohorts; however, ER-α showed a trend toward increased expression in the fibroid cohort (p value 0.07). LIF is downregulated in the endometrium of patients with large IM. This study is among the first to show decreased LIF expression in patients with uterine leiomyomas. We hypothesize that this difference from previously published work is due to sampling the endometrium at the height of LIF expression. Further work is needed to show if LIF downregulation is corrected with leiomyoma resection.

Low antimüllerian hormone (AMH) is associated with decreased live birth after in vitro fertilization when follicle-stimulating hormone and AMH are discordant.

OBJECTIVE: To evaluate which factor, AMH or FSH, was superior in predicting live birth after assisted reproductive technologies (ART) when the tests are discordant, using data from the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System database. DESIGN: Retrospective cohort. SETTING: Clinic-based data. PATIENT(S): The study population included 44,696 fresh embryo transfer cycles using autologous oocytes. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth (≥22 wk gestation and ≥300 g birth weight). RESULT(S): Live birth rate per started cycle was lower in patients with low AMH and normal FSH than in patients with normal AMH and elevated FSH (26% vs. 39%). A multivariate analysis was performed on patients with normal FSH and low AMH, and the following factors were independently associated with live birth: AMH, age >40 years, body mass index >30 kg/m2, race African-American or Asian, IVF clinic region West, uterine factor infertility diagnosis, agonist suppression, and FSH dosage. IVF cycle cancellation rate was higher in patients with low AMH and normal FSH (30%). CONCLUSION(S): AMH is a superior predictor of live birth in patients undergoing IVF when FSH and AMH values are discordant. Lower AMH is independently associated with lower live birth and higher IVF cycle cancellation rates than elevated FSH in patients with discordant values.

Comprehensive profiling of prostaglandins in human ovarian follicular fluid using mass spectrometry.

Prostaglandins are formed by enzymatic and non-enzymatic mechanisms. They have been detected in human ovarian follicular fluid (HFF), a medium rich in growth factors and nutrients important for oocyte growth and fertility. However, the comprehensive identification of HFF prostaglandins has not been addressed. Here we use hybrid triple quadrupole time-of-flight and triple quadrupole mass spectrometers to comprehensively analyze prostaglandins in HFF. We identified PGE1, PGE2, PGF2α, and other prostaglandins synthesized via prostaglandin-endoperoxide synthase (i.e. Cox) cascades. We also identified specific PGF2α isomers (F2-isoprostanes) and PGF3α analogs whose structures are inconsistent with Cox-dependent formation. A prospective cohort pilot study of infertility patient subtypes revealed two potential associations. F2-isoprostanes are decreased in the diminished ovarian reserve subtype and elevated PGF2α may be associated with decreased live birth. Other than PGF2α, only body mass index >25kg/m2 correlated with poor in vitro fertilization outcome. Our studies suggest that HFF contains prostaglandins formed from at least two mechanisms, which may correlate with distinct clinical parameters.

Potential causes of subfertility in patients with intramural fibroids.

BACKGROUND: Intramural leiomyomas have been long debated as a potential cause of infertility and pregnancy loss. FINDINGS: Previous research has linked intramural fibroids to defective implantation, as well as to abnormal peristaltic events of the uterine smooth muscle. Previous reports describe the effects of intramural fibroids on normal human fertility and early pregnancy loss, specifically in regards to implantation failure. CONCLUSION: A thorough understanding of prior research may direct new research focus, leading to better understanding of leiomyoma-associated infertility.

Effect of cigarette smoking on human oviductal ciliation and ciliogenesis.

OBJECTIVE: To investigate the effect of cigarette smoke exposure on ciliation and ciliogenesis in human oviductal epithelium. DESIGN: Molecular analysis using human tubal segments. SETTING: Academic medical center. PATIENT(S): Twenty women undergoing elective tubal sterilization procedure. INTERVENTION(S): Expression of ciliated cell-specific markers was compared in tubal segments from smokers and nonsmokers using quantitative immunohistochemistry and Western blot analysis. The expression of transcription factors in the motile ciliogenesis program was compared using quantitative polymerase chain reaction and quantitative immunohistochemistry. MAIN OUTCOME MEASURE(S): Oviductal ciliation and expression of transcription factors involved in ciliogenesis. RESULT(S): No significant differences were detected in density of ciliation between groups. Neither number of years of smoking nor pack-year history correlated with density of ciliation. Expression of ciliogenic transcription factors FOXJ1, RFX2, and RFX3 was consistent between groups. CONCLUSION(S): Few studies have evaluated the relationship between smoking and ciliated epithelium in human oviducts. Cigarette smoking does not seem to result in quantitative differences in the density of ciliation nor expression of ciliogenesis factors. Our findings suggest that pathophysiologic mechanisms other than ciliation account for the increased risk of ectopic pregnancy in women who smoke.

Practice and perceptions of obstetrics and gynecology providers and the treatment of overweight and obese women.

OBJECTIVE: To verify how frequently obstetrics-gynecology providers documented the diagnosis and treatment of overweight/obese patients during routine examinations. These results were compared to a survey administered to this group of providers that measured their perceived practice patterns regarding weight management. STUDY DESIGN: A retrospective chart review was performed of well woman and routine postpartum exams of patients with a body mass index (BMI) > 25. Patient encounters were reviewed for a diagnosis of overweight or obese and weight management interventions offered. In addition, a survey was administered to obstetrics-gynecology providers who performed these exams in order to measure their perceived obesity diagnosis and treatment patterns. RESULTS: A total of 1,145 patient encounters were reviewed of patients with a BMI > 25. Providers documented 77 of the 1,145 (6.7%) as overweight or obese. Only 70 of 1,145 (6.1%) had documented interventions (i.e., recommending weight loss or exercise). In contrast, a majority of providers surveyed reported they appropriately diagnosed and counseled patients with obesity. CONCLUSION: The majority of obstetrics and gynecology providers surveyed perceived that weight management was an important part of their clinical practice; however documentation of patient encounters did not match their perceived clinical