Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility.

It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child per woman). In the United States, where TFR has also declined, there are ethnic differences. Caucasians have rates below replacement, while TFRs among African-Americans and Hispanics are higher. We review possible links between TFR and trends in a range of male reproductive problems, including testicular cancer, disorders of sex development, cryptorchidism, hypospadias, low testosterone levels, poor semen quality, childlessness, changed sex ratio, and increasing demand for assisted reproductive techniques. We present evidence that several adult male reproductive problems arise in utero and are signs of testicular dysgenesis syndrome (TDS). Although TDS might result from genetic mutations, recent evidence suggests that it most often is related to environmental exposures of the fetal testis. However, environmental factors can also affect the adult endocrine system. Based on our review of genetic and environmental factors, we conclude that environmental exposures arising from modern lifestyle, rather than genetics, are the most important factors in the observed trends. These environmental factors might act either directly or via epigenetic mechanisms. In the latter case, the effects of exposures might have an impact for several generations post-exposure. In conclusion, there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. We highlight a number of topics that need attention by researchers in human physiology, pathophysiology, environmental health sciences, and demography.

Racial and Ethnic Disparities in Genetic Testing at a Hereditary Breast and Ovarian Cancer Center.

BACKGROUND: Prior studies suggest that referral to genetic counseling and completion of genetic testing vary by race/ethnicity; however, the data are limited. OBJECTIVE: We sought to evaluate patterns of genetic testing and clinical outcomes across race/ethnicity at a hereditary breast and ovarian cancer center. DESIGN: The medical records for all patients undergoing genetic assessment at a hereditary breast and ovarian cancer center were reviewed and stratified by self-reported race/ethnicity (non-Hispanic White, Hispanic, non-Hispanic Black, and Asian). PARTICIPANTS: A total of 1666 patients met inclusion criteria (non-Hispanic Whites, 1367; Hispanics, 85, non-Hispanic Blacks, 101; Asians, 113). MAIN MEASURES: Demographics, patient characteristics, and referral patterns for patients who underwent genetic testing were analyzed using Kruskal-Wallis tests, chi-square test, or Fisher's exact tests, stratifying by self-reported race/ethnicity. Pathogenic mutations and variants of unknown significance (VUS) were reviewed. Outcomes of patients with genetic mutations and personal history of breast and/or gynecologic malignancies were compared. KEY RESULTS: Non-Hispanic Whites were more likely to be referred due to family cancer history compared to all other ethnicities while Non-Hispanic Blacks, Hispanics, and Asians were more likely to be referred due to personal history of cancer (p < 0.001). Non-Hispanic Blacks and Hispanics were more likely to have advanced-stage cancer at the time of genetic testing (p < 0.02). Rates of mutations did not differ by race/ethnicity when Ashkenazi Jewish patients were excluded (p = 0.08). Among patients found to have a BRCA1/2 mutation, Non-Hispanic Whites were more likely to undergo cancer screening and risk-reducing surgery compared with all other ethnicities (p = 0.04). CONCLUSIONS: Minority patients were more likely to utilize genetic services following a cancer diagnosis and less likely due to family cancer history, suggesting a missed opportunity for mutation detection and cancer prevention in this population. Efforts to eradicate racial/ethnic disparities in early access to genetic testing and guided cancer prevention strategies are essential.

Time-Varying Effects of Signs and Symptoms on Pregnancy Loss <20 Weeks: Findings from a Preconception Prospective Cohort Study.

BACKGROUND: Although pregnancy loss affects one-third of pregnancies, the associated signs/symptoms have not been fully described. Given the dynamic nature of maternal physiologic adaptation to early pregnancy, we posited the relationships between signs/symptoms and subsequent loss would vary weekly. METHODS: In a preconception cohort with daily follow-up, pregnancies were ascertained by self-administered sensitive home pregnancy tests on day of expected menses. We evaluated the effects of weekly time-varying signs/symptoms (including vaginal bleeding, lower abdominal cramping, and nausea and/or vomiting) on pregnancy loss <20 weeks in Cox proportional hazards models and calculated the week-specific probability of loss by the presence/absence of each sign/symptom. RESULTS: Of 341 pregnancies ascertained by home pregnancy test, 95 (28%) ended in loss. Relationships between signs/symptoms and loss varied across time since first positive pregnancy test. In the first week following pregnancy confirmation, when many losses occurred, bleeding [hazard ratio (HR) 8.7, 95% confidence interval (CI) 4.7, 16.0] and cramping (HR 1.8, 95% CI 1.2, 2.7) were associated with loss even when accompanied by nausea and/or vomiting (HR 5.2, 95% CI 2.6, 10.5). After the second week, new relationships emerged with nausea and/or vomiting inversely associated (HR range 0.6-0.3, all 95% CI upper bounds <1.00) and bleeding no longer associated with loss. Probabilities of loss of ranged from 78% (95% CI 59%, 96%) with bleeding present in week 1 to 8% (95% CI 5%, 12%) with nausea/vomiting present in week 5. CONCLUSIONS: Relationships between signs/symptoms and pregnancy loss vary in early pregnancy possibly reflecting maternal physiologic response.

Group B Streptococcus and the Vaginal Microbiota.

Background: Streptococcus agalactiae (group B Streptococcus [GBS]) is an important neonatal pathogen and emerging cause of disease in adults. The major risk factor for neonatal disease is maternal vaginal colonization. However, little is known about the relationship between GBS and vaginal microbiota. Methods: Vaginal lavage samples from nonpregnant women were tested for GBS, and amplicon-based sequencing targeting the 16S ribosomal RNA V3-V4 region was performed. Results: Four hundred twenty-eight of 432 samples met the high-quality read threshold. There was no relationship between GBS carriage and demographic characteristics, α-diversity, or overall vaginal microbiota community state type (CST). Within the non-Lactobacillus-dominant CST IV, GBS positive status was significantly more prevalent in CST IV-A than CST IV-B. Significant clustering by GBS status was noted on principal coordinates analysis, and 18 individual taxa were found to be significantly associated with GBS carriage by linear discriminant analysis. After adjusting for race/ethnicity, 4 taxa were positively associated with GBS, and 6 were negatively associated. Conclusions: Vaginal microbiota CST and α-diversity are not related to GBS status. However, specific microbial taxa are associated with colonization of this important human pathogen, highlighting a potential role for the microbiota in promotion or inhibition of GBS colonization.

Is human fecundity changing? A discussion of research and data gaps precluding us from having an answer.

Fecundity, the biologic capacity to reproduce, is essential for the health of individuals and is, therefore, fundamental for understanding human health at the population level. Given the absence of a population (bio)marker, fecundity is assessed indirectly by various individual-based (e.g. semen quality, ovulation) or couple-based (e.g. time-to-pregnancy) endpoints. Population monitoring of fecundity is challenging, and often defaults to relying on rates of births (fertility) or adverse outcomes such as genitourinary malformations and reproductive site cancers. In light of reported declines in semen quality and fertility rates in some global regions among other changes, the question as to whether human fecundity is changing needs investigation. We review existing data and novel methodological approaches aimed at answering this question from a transdisciplinary perspective. The existing literature is insufficient for answering this question; we provide an overview of currently available resources and novel methods suitable for delineating temporal patterns in human fecundity in future research.

Multigene panels in Ashkenazi Jewish patients yield high rates of actionable mutations in multiple non-BRCA cancer-associated genes.

OBJECTIVE: To evaluate the results of multigene panel testing among Ashkenazi Jewish compared with non-Ashkenazi Jewish patients. METHODS: We reviewed the medical records for all patients who underwent multigene panel testing and targeted BRCA1/2 testing at a single institution between 6/2013-1/2015. Clinical actionability for identified pathogenic mutations was characterized based on the National Comprehensive Cancer Network (NCCN) guidelines and consensus statements and expert opinion for genes not addressed by these guidelines. RESULTS: Four hundred and fifty-four patients underwent multigene panel screening, including 138 Ashkenazi Jewish patients. The median patient age was fifty-two years. Three hundred and fifty-four patients (78%) had a personal history of cancer. Two hundred and fifty-one patients had breast cancer, 49, ovarian cancer, 26, uterine cancer and 20, colorectal cancer. We identified 62 mutations in 56 patients and 291 variants of uncertain significance in 196 patients. Among the 56 patients with mutations, 51 (91%) had actionable mutations. Twenty mutations were identified by multigene panels among Ashkenazi Jewish patients, 18 of which were in genes other than BRCA1/2. A review of targeted BRCA1/2 testing performed over the same study period included 103 patients and identified six mutations in BRCA1/2, all of which occurred in Ashkenazi Jewish patients. Among all Ashkenazi Jewish patients undergoing genetic testing, 25/183 (14%) had a mutation, 24/25 of which were actionable (96%) and 17/25 patients (68%) had mutations in non BRCA1/2 genes. CONCLUSIONS: With the rapid acceptance of multigene panels there is a pressing need to understand how this testing will affect patient management. While traditionally many Ashkenazi Jewish patients have undergone targeted BRCA1/2 testing, our data suggest consideration of multigene panels in this population as the majority of the results are clinically actionable and often in genes other than BRCA1/2.

Planned home births: the need for additional contraindications.

BACKGROUND: Planned home births in the United States are associated with fewer interventions but with increased adverse neonatal outcomes such as perinatal and neonatal deaths, neonatal seizures or serious neurologic dysfunction, and low 5-minute Apgar scores. The American College of Obstetricians and Gynecologists' Committee on Obstetric Practice states that, to reduce perinatal death and to improve outcomes at planned home births, strict criteria are necessary to guide the selection of appropriate candidates for planned home birth. The committee lists 3 absolute contraindications for a planned home birth: fetal malpresentation, multiple gestations, and a history of cesarean delivery. OBJECTIVE: The aim of this study was to evaluate whether there are risk factors that should be considered contraindications to planned home births in addition to the 3 that are listed by the American College of Obstetricians and Gynecologists. STUDY DESIGN: We conducted a population-based, retrospective cohort study of all term (≥37 weeks gestation), normal weight (≥2500 grams), singleton, nonanomalous births from 2009-2013 using the Centers for Disease Control and Prevention's period-linked birth-infant death files that allowed for identification of intended and unintended home births. We examined neonatal deaths (days 0-27 after birth) across 3 groups (hospital-attended births by certified nurse midwives, hospital-attended births by physicians, and planned home births) for 5 risk factors: 2 of the 3 absolute contraindications to home birth listed by the American College of Obstetricians and Gynecologists (breech presentation and previous cesarean delivery) and 3 additional risk factors (parity [nulliparous and multiparous], maternal age [women <35 and ≥35 years old], and gestational age at delivery [37-40 and ≥41 weeks]). RESULTS: The overall risk of neonatal death was significantly higher in planned home births (12.1 neonatal death/10,000 deliveries; P<.001) compared with hospital births by certified nurse midwives (3.08 neonatal death/10,000 deliveries) or physicians (5.09 neonatal death/10,000 deliveries). Neonatal mortality rates were increased significantly at planned home births, with the following individual risk factors: breech presentation (neonatal mortality rate, 127.52/10.000 births), nulliparous pregnant women (neonatal mortality rate, 22.5/10,000), previous cesarean delivery (18.91/10,000 births), and a gestational age ≥41 weeks (neonatal mortality rate, 17.17/10,000 births). Planned home births with ≥1 of the 5 risk factors had significantly higher neonatal death risks compared with deliveries with none of the risks. Neonatal death risk was further increased when a woman's age of ≥35 years was combined with either a first-time birth or a gestational age of ≥41 weeks. CONCLUSIONS: In this study, we show 2 risk factors with significantly increased neonatal mortality rates at planned home births in addition to the 3 factors that are listed by the American College of Obstetricians and Gynecologists. These additional risks factors have neonatal mortality rates that are approaching or exceeding those for planned home birth after cesarean delivery: first-time births and a gestational age of ≥ 41 weeks. Therefore, 2 additional risk factors (first-time births and a gestational age of ≥41 weeks) should be added to the 3 absolute contraindications of planned home births that are listed by the American College of Obstetricians and Gynecologists (previous cesarean delivery, malpresentation, multiple gestations) for a total of 5 contraindications for planned home births.

Reconstructing a Pregnancy Cohort to Examine Potential Selection Bias in Studies on Racial Disparities in Preterm Delivery.

BACKGROUND: Epidemiologic studies examining preconception risk factors on perinatal outcomes are typically restricted to livebirths. By including only non-terminated pregnancies, estimates for the underlying pregnancy cohort may be subject to selection bias. We examined if potential selection bias due to induced termination by maternal race may result in different estimates of the non-Hispanic black - non-Hispanic white risk ratio (RR) for preterm delivery (PTD) among a reconstructed pregnancy cohort ('pseudo-pregnancy cohort'). METHODS: Using New York City registries of 1.6 million livebirths, spontaneous terminations, and induced terminations among non-Hispanic black and non-Hispanic white women (2000-12), we multiply imputed PTD (<37 weeks) and early PTD (<32 weeks) outcomes for induced terminations based on maternal race, age, parity, marital status, nativity, and medical care payer to construct the pseudo-pregnancy cohort. RESULTS: Among non-Hispanic black and non-Hispanic white women, 55% and 19% of pregnancies ended in induced termination and 13% and 8% resulted in PTD, respectively. Although several factors were associated with both PTD and induced termination, PTD RRs in the birth (RR 1.64, 95% confidence interval (CI) 1.62, 1.66) and pseudo-pregnancy (RR 1.63, 95% CI 1.56, 1.71) cohorts were similar. However, early PTD RR was somewhat larger in the birth (RR 2.80, 95% CI 2.71, 2.89) than pseudo-pregnancy (RR 2.47, 95% CI 2.23, 2.73) cohort. CONCLUSIONS: Using birth certificate data - thereby excluding induced terminations - to estimate the PTD racial disparity did not produce biased estimates. Our data suggest observed PTD disparities likely are not artefacts of selection bias due to induced termination.

Time-to-Pregnancy Associated With Couples' Use of Tobacco Products.

INTRODUCTION: Previous studies suggest female smoking increases time-to-pregnancy (TTP), a couple-dependent reproductive outcome, while associations with male smoking are more ambiguous. Furthermore, despite small increases in smokeless tobacco use in the United States, no prior study has evaluated TTP among smokeless tobacco users. METHODS: Using population-based sampling in 16 counties in Michigan and Texas, 501 couples discontinuing contraception to become pregnant were followed until positive pregnancy test or 12 months of trying. Participants were interviewed on lifetime and current cigarette, cigar, and chew/snuff (smokeless) use and provided blood samples for quantification of heavy metals and cotinine. Fecundability odds ratios (FORs) and 95% confidence intervals (95% CIs) were estimated, adjusted for demographics/lifestyle. FORs less than 1 reflect longer TTP. RESULTS: Eleven percentage of females and 15% of males smoked cigarettes. Among men, 14% smoked cigars, 9% used snuff, and 2% used chew. Compared with never tobacco users, male (FOR: 0.41, 95% CI: 0.24, 0.68) and female (FOR: 0.53, 95% CI: 0.33, 0.85) smoking were individually associated with longer TTP; males' smoking remained significant (FOR: 0.46, 95% CI: 0.27, 0.79) when modeling partners together. Cadmium levels were higher in smokers than smokeless tobacco and never users; adjusting for cadmium attenuated the cigarette-TTP association, particularly among women. TTP was shorter among smokeless tobacco users relative to smokers (FOR: 2.86, 95% CI: 1.47, 5.57). CONCLUSIONS: Compared with never users, smokeless tobacco did not alter TTP in our cohort; however, TTP was shorter compared with smokers. We observed longer TTP in male and female smokers; cadmium may partially contribute. IMPLICATIONS: Both partners' preconception smoking contributed to longer TTP, highlighting the importance of both partners' lifestyles in healthy reproduction and underscores the need for couple-based preconception guidance. The male's contribution is a new finding. Higher cadmium levels may partially contribute to longer TTP in smokers, particularly among females. Though we do not observe longer TTP among a small sample of smokeless tobacco users compared with never tobacco users, we observe shorter TTP compared with smokers. Further work is needed to more thoroughly delineate the relationship between smokeless tobacco use and TTP and possible mechanisms of tobacco use's effects on reproduction.

Urinary concentrations of benzophenone-type ultraviolet radiation filters and couples' fecundity.

Concern has arisen about benzophenone (BP) ultraviolet (UV) radiation filters, given their use in sunscreen and personal-care products and their reported estrogenic and antiandrogenic activity. We recruited 501 couples who were discontinuing use of contraceptives in order to become pregnant for the Longitudinal Investigation of Fertility and the Environment (LIFE) Study (Michigan and Texas, 2005-2009). Couples provided urine specimens and completed daily journals until they either achieved pregnancy or had tried for 12 months. Women used fertility monitors to time sexual intercourse and digital pregnancy tests. Urinary concentrations of 5 UV filters (ng/mL) were determined using triple-quadrupole mass spectrometry: 2,4-dihydroxybenzophenone (also called BP-1); 2,2',4,4'-tetrahydroxybenzophenone (BP-2); 2-hydroxy-4-methoxybenzophenone (BP-3); 2,2'-dihydroxy-4-methoxybenzophenone (BP-8); and 4-hydroxybenzophenone. Fecundability odds ratios were estimated for each UV filter (dichotomized at the 75th percentile) and adjusted for age, creatinine concentration, body mass index (weight (kg)/height (m)(2)), cotinine concentration, season, and site, while accounting for time off contraception. Separate models were fitted for each UV filter and partner; final models included partners' concentrations. Male partners' concentrations of BP-2 and 4-hydroxybenzophenone were associated with reduced fecundity in adjusted models (fecundability odds ratio (FOR) = 0.69 (95% confidence interval (CI): 0.50, 0.95) and FOR = 0.74 (95% CI: 0.54, 1.00), respectively). In models adjusting for both partners' concentrations, male BP-2 concentration remained associated with reduced fecundity (FOR = 0.69, 95% CI: 0.49, 0.97). These data suggest that male exposure to select UV filters may diminish couples' fecundity, resulting in a longer time to pregnancy.

Early and total neonatal mortality in relation to birth setting in the United States, 2006-2009.

OBJECTIVE: We examined neonatal mortality in relation to birth settings and birth attendants in the United States from 2006 through 2009. STUDY DESIGN: Data from the Centers for Disease Control and Prevention-linked birth and infant death dataset in the United States from 2006 through 2009 were used to assess early and total neonatal mortality for singleton, vertex, and term births without congenital malformations delivered by midwives and physicians in the hospital and midwives and others out of the hospital. Deliveries by hospital midwives served as the reference. RESULTS: Midwife home births had a significantly higher total neonatal mortality risk than deliveries by hospital midwives (1.26 per 1000 births; relative risk [RR], 3.87 vs 0.32 per 1000; P < .001). Midwife home births of 41 weeks or longer (1.84 per 1000; RR, 6.76 vs 0.27 per 1000; P < .001) and midwife home births of women with a first birth (2.19 per 1000; RR, 6.74 vs 0.33 per 1000; P < .001) had significantly higher risks of total neonatal mortality than deliveries by hospital midwives. In midwife home births, neonatal mortality for first births was twice that of subsequent births (2.19 vs 0.96 per 1000; P < .001). Similar results were observed for early neonatal mortality. The excess total neonatal mortality for midwife home births compared with midwife hospital births was 9.32 per 10,000 births, and the excess early neonatal mortality was 7.89 per 10,000 births. CONCLUSION: Our study shows a significantly increased total and early neonatal mortality for home births and even higher risks for women of 41 weeks or longer and women having a first birth. These significantly increased risks of neonatal mortality in home births must be disclosed by all obstetric practitioners to all pregnant women who express an interest in such births.

Apgar score of 0 at 5 minutes and neonatal seizures or serious neurologic dysfunction in relation to birth setting.

OBJECTIVE: To examine the occurrence of 5-minute Apgar scores of 0 and seizures or serious neurologic dysfunction for 4 groups by birth setting and birth attendant (hospital physician, hospital midwife, free-standing birth center midwife, and home midwife) in the United States from 2007-2010. METHODS: Data from the United States Centers for Disease Control's National Center for Health Statistics birth certificate data files were used to assess deliveries by physicians and midwives in and out of the hospital for the 4-year period from 2007-2010 for singleton term births (≥37 weeks' gestation) and ≥2500 g. Five-minute Apgar scores of 0 and neonatal seizures or serious neurologic dysfunction were analyzed for 4 groups by birth setting and birth attendant (hospital physician, hospital midwife, freestanding birth center midwife, and home midwife). RESULTS: Home births (relative risk [RR], 10.55) and births in free-standing birth centers (RR, 3.56) attended by midwives had a significantly higher risk of a 5-minute Apgar score of 0 (P < .0001) than hospital births attended by physicians or midwives. Home births (RR, 3.80) and births in freestanding birth centers attended by midwives (RR, 1.88) had a significantly higher risk of neonatal seizures or serious neurologic dysfunction (P < .0001) than hospital births attended by physicians or midwives. CONCLUSION: The increased risk of 5-minute Apgar score of 0 and seizures or serious neurologic dysfunction of out-of-hospital births should be disclosed by obstetric practitioners to women who express an interest in out-of-hospital birth. Physicians should address patients' motivations for out-of-hospital delivery by continuously improving safe and compassionate care of pregnant, fetal, and neonatal patients in the hospital setting.

Health Care Leaders' Perspectives on the Maryland All-Payer Model.

Importance: Since 2014, all hospitals in Maryland have operated under an all-payer global budget system. Hospital global budgets have gained renewed attention as a strategy for constraining cost growth, improving patient outcomes, and preserving health care access in rural and underserved communities. Lessons from the implementation of the Maryland All-Payer Model (MDAPM) may have implications for policy makers, payers, and hospitals in other settings seeking to adopt global budgets or other value-based payment models. Objective: To examine perspectives on the implementation of the MDAPM among health care leaders who participated in its design and execution. Design Setting and Participants: This qualitative study with semistructured telephone interviews was conducted from November 1, 2019, to February 11, 2020. The purposive sample of Maryland health care leaders represents diverse stakeholder groups, including hospitals, state government and regulatory agencies, the federal government, and payers. Main Outcomes and Measures: Key high-level themes were extracted from interviews using qualitative content analysis, with barriers and facilitators to implementation specified within each theme. Results: A total of 20 interviews were conducted with hospital leaders (n = 6), state regulators (n = 4), federal regulators (n = 4), payer representatives (n = 3), and state leaders (n = 3). Key themes were labeled as (1) expectations (setting bold yet achievable goals), (2) autonomy (allowing hospitals to follow individual strategies within MDAPM parameters), (3) communication (encouraging early and ongoing communication between stakeholders), (4) actionable data (sharing useful hospital and patient-level data between stakeholders), (5) global budget calibration (anticipating technical challenges when negotiating budgets for individual hospitals), and (6) shared commitment to change (harnessing collective motivation for system change). Together, these themes suggest that implementing the payment model followed an evolving and collaborative process that requires stakeholder communication, data to guide decisions, and commitment to operating within the new payment system. Conclusions and Relevance: The implementation of hospital global budgets in the state of Maryland offers generalizable lessons that can inform the evolution and expansion of this approach to value-based payment in other states and settings.

Identifying High-Cost Medicare Beneficiaries: Impact of Neighborhood Socioeconomic Disadvantage.

The objective of this observational longitudinal study of Maryland fee-for-service Medicare beneficiaries (2015-2016) was to investigate whether using data on neighborhood socioeconomic disadvantage in addition to individual clinical risk data improves identification of high-cost Medicare beneficiaries. Neighborhood socioeconomic disadvantage is measured using the Area Deprivation Index (ADI), a validated composite measure based on publically-available US census data (2011-2015) for Maryland census block groups. Hierarchical Condition Categories (HCC) score, health care utilization, and spending were obtained from Centers for Medicare & Medicaid Services Chronic Condition Warehouse beneficiary file and Part A and Part B claims data (2015). Total cost of care (TCOC) was calculated for 2016. Descriptive and multivariate analyses were performed to examine the relationship of residency in neighborhoods with high ADI and subsequent year health care spending. Among 615,637 Maryland Medicare fee-for-service beneficiaries, those living in neighborhoods with the greatest disadvantage vs. the least disadvantage incur significantly greater costs in the subsequent year (ADI Quintile 5 $12,439 versus Quintile 1 $8920, P < .001). Clinical risk exacerbates this disparity. Among beneficiaries in the highest HCC score quintile, costs are 27% ($5458, P < .001) higher among beneficiaries in the highest compared with the lowest ADI quintiles without risk adjustment and 24% ($4599, P < .001) higher with risk adjustment. Several sensitivity analyses found the relationship between ADI and TCOC robust. Association between neighborhood socioeconomic disadvantage and health care cost is most pronounced among the most clinically complex Maryland Medicare beneficiaries. Using ADI in combination with HCC score may facilitate more precise targeting of care management resources.

Semen quality and pregnancy loss in a contemporary cohort of couples recruited before conception: data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study.

OBJECTIVE: To study the relationship between semen quality and pregnancy loss in a cohort of couples attempting to conceive. DESIGN: Observational prospective cohort. SETTING: Not applicable. PATIENT(S): Three hundred and forty-four couples with a singleton pregnancy observed daily through 7 postconception weeks of gestation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Association between semen quality and pregnancy loss. RESULT(S): Ninety-eight (28%) of the couples experienced a pregnancy loss after singleton pregnancy. No differences were observed in semen volume, sperm concentration, total sperm count, sperm viability, or sperm morphology (World Health Organization [WHO] and strict criteria) by couple's pregnancy loss status irrespective of whether they were analyzed continuously or as dichotomous variables per the WHO 5th edition semen criteria. A dichotomous DNA fragmentation measure of ≥30% was statistically significantly associated with pregnancy loss. No association was identified with other sperm morphometric or movement measures. Of the 70 couples who re-enrolled after a pregnancy loss, 14 experienced a second loss. Similar findings were identified when examining semen quality from couples with recurrent pregnancy loss. CONCLUSION(S): Although a few trends were identified (e.g., DNA fragmentation), general semen parameters seemed to have little relation with risk of pregnancy loss or recurrent pregnancy loss at the population level. However, given that 30% of pregnancies end in miscarriage and half the fetal genome is paternal in origin, the findings await corroboration.

Signs and Symptoms of Early Pregnancy Loss.

Approximately one-third of pregnancies end in loss; however, the natural history of early pregnancy loss, including signs and symptoms preceding loss, has yet to be fully described and its underlying mechanisms fully understood. We searched PubMed/MEDLINE and Embase to identify articles with prospective ascertainment of signs and symptoms, including vaginal bleeding, nausea, and vomiting, of pregnancy loss < 20 weeks gestation in spontaneous conceptions to ascertain existing literature on symptomatology of pregnancy loss. Two preconception and 16 pregnancy cohort studies that ascertained information on bleeding and/or nausea/vomiting prior to pregnancy loss ascertainment were included. Data from these studies indicated increased risk of loss with vaginal bleeding and decreased risk of loss with nausea/vomiting, though these studies were mostly comprised of pregnancies surviving into late first trimester. While such associations are biologically plausible, these study designs are subject to bias, given recruitment of women at later gestational ages and reliance on women presenting to care. Reporting symptoms to clinicians and over long periods may introduce reporting error. Data gaps remain regarding (1) relationships between signs and symptoms and losses occurring very early, prior to care entry; (2) empirical testing of whether relationships between signs and symptoms and loss differ across gestational age; (3) whether similar relationships between signs and symptoms and loss are observed in populations using assisted reproductive technologies; (4) the patterning of multiple signs and symptoms in relation to loss; and (5) how hormonal and physiologic adaptions to early pregnancy relate to symptomatology and pregnancy loss.

Preconception stress and the secondary sex ratio in a population-based preconception cohort.

OBJECTIVE: To examine the association between preconception parental stress and the secondary sex ratio, defined as the ratio of males to females at birth. DESIGN: A population-based preconception cohort. SETTING: Not applicable. PATIENT(S): A total of 235 couples who were enrolled before conception in Michigan and Texas between 2005 and 2009 and who had a singleton birth during the follow-up period. Couples were interviewed separately at baseline to obtain information on perceived stress (Cohen's Perceived Stress Scale) and lifetime history of physician-diagnosed anxiety and/or mood disorders. Female partners were also trained to collect basal saliva samples for the measurement of salivary stress markers, alpha-amylase and cortisol. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Birth outcome data including infant sex were collected upon delivery. Modified Poisson regression models were used to estimate the relative risks (RRs) of a male birth for each stress marker. RESULT(S): After adjusting for potential confounders, we observed a 76% increase in the risk of fathering a male infant (RR 1.76; 95% confidence interval 1.17-2.65) in men diagnosed with anxiety disorders compared with those who were not diagnosed. When lifetime history of physician-diagnosed anxiety disorders was modeled jointly for the couple, the association was slightly strengthened (RR 2.03; 95% confidence interval 1.46-2.84). CONCLUSION(S): This prospective cohort study suggests that paternal lifetime history of physician-diagnosed anxiety disorders may be associated with an increase in the secondary sex ratio, resulting in an excess of male births.

Low-level environmental metals and metalloids and incident pregnancy loss.

Environmental exposure to metals and metalloids is associated with pregnancy loss in some but not all studies. We assessed arsenic, cadmium, mercury, and lead concentrations in 501 couples upon trying for pregnancy and followed them throughout pregnancy to estimate the risk of incident pregnancy loss. Using Cox proportional hazard models, we estimated hazard ratios (HR) and 95% confidence intervals (CIs) for pregnancy loss after covariate adjustment for each partner modeled individually then we jointly modeled both partners' concentrations. Incidence of pregnancy loss was 28%. In individual partner models, the highest adjusted HRs were observed for female and male blood cadmium (HR=1.08; CI 0.81, 1.44; HR=1.09; 95% CI 0.84, 1.41, respectively). In couple based models, neither partner's blood cadmium concentrations were associated with loss (HR=1.01; 95% CI 0.75, 1.37; HR=0.92; CI 0.68, 1.25, respectively). We observed no evidence of a significant relation between metal(loids) at these environmentally relevant concentrations and pregnancy loss.