Developing an Adjunct Services Approach to Identify the Use of Procedures Not Covered by Health Insurance: The Case of In Vitro Fertilization.

BACKGROUND: Health care claims have an inherent limitation in that noncovered services are unreported. This limitation is particularly problematic when researchers wish to study the effects of changes in the insurance coverage of a service. In prior work, we studied the change in the use of in vitro fertilization (IVF) after an employer added coverage. To estimate IVF use before coverage began, we developed and tested an Adjunct Services Approach that identified patterns of covered services cooccurring with IVF. METHODS: Based on clinical expertise and guidelines, we developed a list of candidate adjunct services and used claims data after IVF coverage began to assess associations of those codes with known IVF cycles and whether any additional codes were also strongly associated with IVF. The algorithm was validated by primary chart review and was then used to infer IVF in the precoverage period. RESULTS: The selected algorithm included pelvic ultrasounds and either menotropin or ganirelix, yielding a sensitivity of 93.0% and specificity of >99.9%. DISCUSSION: The Adjunct Services Approach effectively assessed the change in IVF use postinsurance coverage. Our approach can be adapted to study IVF in other settings or to study other medical services experiencing coverage changes (eg, fertility preservation, bariatric surgery, and sex confirmation surgery). Overall, we find that an Adjunct Services Approach can be useful when (1) clinical pathways exist to define services delivered adjunct to the noncovered service, (2) those pathways are followed for most patients receiving the service, and (3) similar patterns of adjunct services occur infrequently with other procedures.

Emergency department utilization for ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is a rare, but serious, risk of assisted reproductive technologies. In severe cases, patients may present to the emergency department (ED) for assessment, treatment of related complications, and even in-patient admission. Significant effort has been made to reduce the incidence and complications of OHSS; however, it is unknown if these strategies have decreased patient presentation for treatment in the ED. PURPOSE: To assess ED utilization for OHSS over time and to examine admission rates, patient demographics, and charges. METHODS: Retrospective longitudinal study utilizing data from the Nationwide Emergency Department Sample Database and the National ART Surveillance System. All ED visits between 2006 and 2016 with an ICD-9 or -10 diagnosis of OHSS were included. Demographics including age, geographic location, and income quartile and alternative diagnoses, admission rates, overall charges, and number of stimulation cycles annually were assessed. RESULTS: The number of ovarian stimulation cycles steadily increased from 2006 (n = 110,183) to 2016 (n = 157,721), while the number of OHSS-related ED visits remained relatively stable (APC 2.08, p = 0.14). Admission rates for OHSS decreased from 52.7% in 2006 to 33.1% in 2016 (APC -4.43%, p < 0.01). The average charge for OHSS-related ED visits almost doubled from 2006 to 2016 (APC 8.53, p < 0.01) and was significantly higher than charges for non-OHSS-related visits for age-matched controls (p < 0.01). CONCLUSION: Despite an increase in total stimulation cycles, there was no significant change in the estimated number of patients presenting to the ED; however, admission rates significantly declined. These observations suggest a possible shift in the severity and/or management of OHSS during the study period.

Association of Maternal-Neonatal Steroids With Early Pregnancy Endocrine Disrupting Chemicals and Pregnancy Outcomes.

CONTEXT: Steroids play an important role in fetal development and parturition. Gestational exposures to endocrine-disrupting chemicals (EDCs) affect steroidal milieu and pregnancy outcomes, raising the possibility of steroids serving as biomarkers. Most studies have not addressed the impact of EDC mixtures, which are reflective of real life scenarios. OBJECTIVE: Assess the association of maternal and neonatal steroids with pregnancy outcomes and early pregnancy EDC levels. DESIGN: Prospective analysis of mother-infant dyads. SETTING: University hospital. PARTICIPANTS: 121 mother-infant dyads. MAIN OUTCOME MEASURES: The associations of maternal and neonatal steroidal hormones from 121 dyads with pregnancy outcomes, the associations of first trimester EDCs individually and as mixtures with maternal and neonatal steroids in a subset of 56 dyads and the influence of body mass index (BMI), age, and offspring sex in modulating the EDC associations with steroids were determined. RESULTS: Steroid-specific positive or negative associations with pregnancy measures were evident; many maternal first trimester EDCs were negatively associated with estrogens and positively with androgen/estrogen ratios; EDC-steroid associations were influenced by maternal age, pre-pregnancy BMI, and fetal sex; and EDCs individually and as mixtures showed direct and inverse fetal sex-dependent associations with maternal and neonatal steroids. CONCLUSIONS: This proof-of-concept study indicates association of steroids with pregnancy outcomes depending on maternal age, prepregnancy BMI, and fetal sex, with the effects of EDCs differing when considered individually or as mixtures. These findings suggest that steroidal hormonal measures have potential to serve as biomarkers of impact of EDC exposures and pregnancy outcome.

Secondary Prevention of Intrauterine Adhesions Following Hysteroscopic Surgery in Women With Asherman Syndrome: Is Something Better Than Nothing?

Asherman syndrome is a reproductive disorder characterized by intrauterine adhesions and amenorrhea, infertility, abnormal placentation, or pregnancy loss. Treatment of Asherman syndrome involves hysteroscopic lysis of adhesions. Many surgeons utilize postoperative measures such as hormone therapy, solid mechanical devices, or barrier gels to prevent recurrent adhesions in this setting. However, there is limited high-quality evidence to support their use. Additional research is needed on the safety and efficacy of these commonly used methods to guide patient care.

Co-morbidity of type 1 diabetes and endometriosis: bringing a new paradigm into focus.

Type 1 diabetes mellitus and endometriosis separately affect millions of women worldwide. Reproductive-age women diagnosed with type 1 diabetes may also suffer from endometriosis, but the asymptomatic pre-clinical period of highly variable duration for each condition can lead to challenges in the timely recognition of co-morbid disease onset and misdiagnosis. While knowledge of the pathogenesis of each condition has grown substantially, co-morbid endometriosis and type 1 diabetes has not been widely considered and much less addressed. This review discusses the molecular rationale for the likelihood of their co-existence, and prospects for improvements in therapeutic strategies and reduced complications, if this paradigm is included as a significant variable in disease management.

Prenatal Testosterone Excess Disrupts Placental Function in a Sheep Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common condition of reproductive-aged women. In a well-validated sheep model of PCOS, testosterone (T) treatment of pregnant ewes culminated in placental insufficiency and intrauterine growth restriction of offspring. The purpose of this study was to explore specific mechanisms by which T excess compromises placental function in early, mid, and late gestation. Pregnant Suffolk sheep received T propionate 100 mg intramuscularly or control vehicle twice weekly from gestational days (GD) 30 to 90 (term = 147 days). Placental harvest occurred at GD 65, 90, and 140. Real-time RT-PCR was used to assess transcript levels of proinflammatory (TNF, IL1B, IL6, IL8, monocyte chemoattractant protein-1/chemokine ligand 2, cluster of differentiation 68), antioxidant (glutathione reductase and superoxide dismutase 1 and 2), and angiogenic [vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF1A)] genes. Lipid accumulation was assessed using triglyceride assays and Oil Red O staining. Placental measures of oxidative and nitrative stress included the thiobarbituric acid reactive substance assay and high-pressure liquid chromatography. Tissue fibrosis was assessed with Picrosirius Red staining. Student t tests and Cohen effect-size analyses were used for statistical analysis. At GD 65, T-treated placentomes showed increased lipid accumulation and collagen deposition. Notable findings at GD 90 were a significant increase in HIF1A expression and a large effect increase in VEGF expression. At GD 140, T-treated placentomes displayed large effect increases in expression of hypoxia and inflammatory markers. In summary, T treatment during early pregnancy induces distinct gestational age-specific effects on the placental milieu, which may underlie the previously observed phenotype of placental insufficiency.

A Narrative Review of Placental Contribution to Adverse Pregnancy Outcomes in Women With Polycystic Ovary Syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women. In pregnancy, women with PCOS experience increased risk of miscarriage, gestational diabetes, preeclampsia, and extremes of fetal birth weight, and their offspring are predisposed to reproductive and cardiometabolic dysfunction in adulthood. Pregnancy complications, adverse fetal outcomes, and developmental programming of long-term health risks are known to have placental origins. These findings highlight the plausibility of placental compromise in pregnancies of women with PCOS. EVIDENCE SYNTHESIS: A comprehensive PubMed search was performed using terms "polycystic ovary syndrome," "placenta," "developmental programming," "hyperandrogenism," "androgen excess," "insulin resistance," "hyperinsulinemia," "pregnancy," and "pregnancy complications" in both human and animal experimental models. CONCLUSIONS: There is limited human placental research specific to pregnancy of women with PCOS. Gestational androgen excess and insulin resistance are two clinical hallmarks of PCOS that may contribute to placental dysfunction and underlie the higher rates of maternal-fetal complications observed in pregnancies of women with PCOS. Additional research is needed to prevent adverse maternal and developmental outcomes in women with PCOS and their offspring.

Disparities in accessing infertility care in the United States: results from the National Health and Nutrition Examination Survey, 2013-16.

OBJECTIVE: To investigate infertility rates and access to infertility care among women in the United States. DESIGN: Retrospective cross-sectional. SETTING: Not applicable. PATIENT(S): Women between 20 and 44 years-old who participated in the National Health and Nutrition Examination Survey between 2013 and 2016 and answered questions RHQ074 ("have you ever attempted to become pregnant over a period of at least a year without becoming pregnant?") and RHQ076 ("have you ever been to a doctor or other medical provider because you were unable to become pregnant?"). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rates of infertility and accessing infertility care. RESULT(S): Women reported infertility at a rate of 12.5% (95% confidence interval, 10.8-14.4). Higher infertility rates were noted with increasing age and body mass index. There were no differences in infertility rates by race/ethnicity, education, income, U.S. citizenship, insurance, or primary location of health care. However, women with less than a high school diploma accessed infertility care less than women with a college degree (5.0% vs. 11.6%). Women with incomes less than $25,000 sought infertility care less than those with incomes above $100,000 (5.4% vs. 11.6%). Non-U.S. citizens accessed infertility care less than U.S. citizens (6.9% vs. 9.4%), and uninsured women reported fewer visits for infertility than insured women (5.9% vs. 9.9%). Women who used the emergency department as their primary medical location reported accessing infertility care less than those who relied on a hospital outpatient unit (1.4% vs. 14.9%). CONCLUSION(S): These nationally representative findings highlight the need to address disparities in access to infertility care.

Early pregnancy exposure to endocrine disrupting chemical mixtures are associated with inflammatory changes in maternal and neonatal circulation.

Endocrine disrupting chemicals (EDCs) are ubiquitous, and pregnancy is a sensitive window for toxicant exposure. EDCs may disrupt the maternal immune system, which may lead to poor pregnancy outcomes. Most studies investigate single EDCs, even though "real life" exposures do not occur in isolation. We tested the hypothesis that uniquely weighted mixtures of early pregnancy exposures are associated with distinct changes in the maternal and neonatal inflammasome. First trimester urine samples were tested for 12 phthalates, 12 phenols, and 17 metals in 56 women. Twelve cytokines were measured in first trimester and term maternal plasma, and in cord blood after delivery. Spearman correlations and linear regression were used to relate individual exposures with inflammatory cytokines. Linear regression was used to relate cytokine levels with gestational age and birth weight. Principal component analysis was used to assess the effect of weighted EDC mixtures on maternal and neonatal inflammation. Our results demonstrated that maternal and cord blood cytokines were differentially associated with (1) individual EDCs and (2) EDC mixtures. Several individual cytokines were positively associated with gestational age and birth weight. These observed associations between EDC mixtures and the pregnancy inflammasome may have clinical and public health implications for women of childbearing age.

Body mass index restrictions in fertility treatment: a national survey of OB/GYN subspecialists.

PURPOSE: To explore the attitudes of reproductive endocrinology and infertility (REI) and maternal-fetal medicine (MFM) subspecialists regarding the necessity and appropriateness of body mass index (BMI) cutoffs for women seeking fertility treatment. METHODS: Members of the Society for Reproductive Endocrinology and Infertility (SREI) and the Society for Maternal Fetal Medicine (SMFM) were invited to participate in a survey querying their knowledge of existing institutional or clinic BMI policies and personal opinions regarding upper and lower BMI cutoffs for a range of fertility treatments, including oral ovulation agents, gonadotropins, and in vitro fertilization. RESULTS: Respondents included 398 MFMs and 201 REIs. The majority of REI and MFM providers agreed with upper limit BMI cutoffs (72.5% vs 68.2%, p = 0.29), but REIs were twice as likely to support lower limit BMI restrictions compared to MFMs (56.2% vs 28.4%, p < 0.0001). Those who supported upper BMI restrictions were more likely to be female and report existing institutional BMI cutoffs. The majority of respondents (99.3%) believed that an official statement to guide clinicians should be issued by a national professional organization. CONCLUSIONS: Although practice patterns widely vary, the majority of REIs and MFMs believe that there should be a BMI cutoff above which women should not be offered immediate fertility treatment. Furthermore, there is a reported need for a written statement by a national professional organization to guide clinical practice and to ensure that OB/GYN subspecialists are providing consistent, fair, and safe recommendations to infertile women at the extremes of BMI.

Postmenopausal hormone treatment alters neural pathways but does not improve verbal cognitive function.

OBJECTIVE: Cognitive outcomes in trials of postmenopausal hormone treatment have been inconsistent. Differing outcomes may be attributed to hormone formulation, treatment duration and timing, and differential cognitive domain effects. We previously demonstrated treatment benefits on visual cognitive function. In the present study, we describe the effects of hormone treatment on verbal outcomes in the same women, seeking to understand the effects of prior versus current hormone treatment on verbal function. METHODS: This is a cross-sectional evaluation of 57 women (38 hormone users [25 prior long-term users and 13 current users] and 19 never-users). Hormone users took identical formulations of estrogen or estrogen + progestin (0.625 mg/d conjugated equine estrogens with or without medroxyprogesterone acetate) for at least 10 years, beginning within 2 years of menopause. Women were evaluated with tests of verbal function and functional magnetic resonance imaging (fMRI) of a verbal discrimination task. RESULTS: All women scored similarly on assessments of verbal function (Hopkins Verbal Learning Test and a verbal discrimination task performed during the fMRI scanning session); however, women ever treated with hormones had more left inferior frontal (T = 3.72; P < 0.001) and right prefrontal cortex (T = 3.53; P < 0.001) activation during the verbal task. Hormone-treated women performed slightly worse on the verbal discrimination task (mean accuracy 81.72 ±â€Š11.57 ever-treated, 85.30 ±â€Š5.87 never-treated, P = 0.14), took longer to respond (mean reaction time 1.10 ±â€Š0.17 s ever-treated, 1.02 ±â€Š0.11 never-treated, P = 0.03), and remembered fewer previously viewed words (mean accuracy 62.21 ±â€Š8.73 ever-treated, 65.45 ±â€Š7.49 never-treated, P = 0.18). Increased posterior cingulate activity was associated with longer response times (R = 0.323, P = 0.015) and worse delayed verbal recall (R = -0.328, P = 0.048), suggesting that increased activation was associated with less efficient cognitive processing. We did not detect between group differences in activation in the left prefrontal cortex, superior frontal cortex, thalamus, or occipital/parietal junction. CONCLUSIONS: Although current and past hormone treatment was associated with differences in neural pathways used during verbal discrimination, verbal function was not higher than never-users.

Outpatient Narcotic Use After Minimally Invasive Urogynecologic Surgery.

OBJECTIVES: To quantify outpatient narcotic use in the first 2 weeks after urogynecologic surgery. METHODS: Using a convenience sample, women who underwent minimally invasive urogynecologic surgery between May and October 2014 were contacted by telephone 2 weeks postoperatively and given a questionnaire regarding their postoperative pain experience. To quantify narcotic use, patients were asked to count the tablets remaining from their discharge narcotic prescription. Postoperative pain scores and pain expectations were also assessed. Women using more than 30 narcotics were in the top quartile for use; therefore, those using 30 or fewer versus more than 30 were compared. Logistic regression was used to identify independent factors associated with women in the top quartile for postoperative narcotic use. RESULTS: Fifty women were included in the study. Median number of narcotics used was 13 (interquartile range (IQR), 1-30) versus 40 (IQR, 35-60) prescribed. Compared to women who used 30 or fewer narcotics (n=38), those using more than 30 (n=12) more frequently were taking narcotics before surgery (13.2% vs 41.7%; P=0.03) and had a chronic pain diagnosis (15.8% vs 58.3%; P=0.003). Although pain scores were similar, women who took more than 30 narcotics more frequently reported their postoperative pain to be much worse or worse than expected (7.9% vs 33.3%; P=0.048). In logistic regression, chronic pain remained the only factor associated with using more than 30 narcotics (odds ratio, 7.36; 95% confidence interval, 1.00-54.03; P=0.0496). CONCLUSIONS: Women used one third of the narcotics they were prescribed after minimally invasive urogynecologic surgery. These data may be useful for establishing narcotic prescription guidelines.

Reversal of fortune: estrogen receptor-ß in endometriosis.

Enhanced inflammation and reduced apoptosis sustain the growth of endometriotic lesions. Alterations in the expression of estrogen receptor-alpha (ERα) and estrogen receptor-beta (ERß) accompany the conversion of resident endometrial cells within the normal uterine environment to ectopic lesions located in extrauterine sites. Recent studies highlighted in this focused review linked ERß to dysregulation of apoptotic and inflammatory networks involving novel interacting partners in endometriosis. The elucidation of these nongenomic actions of ERß using human cells and mouse models is an important step in understanding key regulatory pathways that are disrupted leading to disease establishment and progression.