Racial Disparity in Severe Maternal Morbidity Associated with Hypertensive Disorders in Washington State: A Retrospective Cohort Study.

OBJECTIVES: To evaluate the relationship between hypertensive (HTN) disorders and severe maternal morbidity (SMM). To understand whether there is differential prevalence of HTN disorders by race and whether the relationship between HTN disorders and SMM is modified by race and ethnicity. METHODS: We performed a retrospective cohort study using patient-level rates of SMM for pregnancies at all 61 non-military hospitals in Washington State from 10/2015 to 9/2016. Data were obtained from the Washington State Comprehensive Hospital Abstract Reporting System. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the association of HTN disorders and SMM (with and without transfusion) overall and by race. The population-attributable fraction of HTN disorders on SMM within each racial/ethnic group was calculated. RESULTS: Of 76,965 deliveries, 864 (1.1%) had any SMM diagnosis or procedure. All racial and ethnic minorities, except white and Asian, were disproportionally affected by preeclampsia with severe features (SF) and SMM. Overall, and within each racial/ethnic group, the SMM rate was higher among pregnancies with any HTN disorder compared to no HTN disorder (2.8 vs. 0.9%, OR 3.1, 95% CI 2.7-3.6). Race and ethnicity significantly modified the association. Overall and within each racial/ethnic group, there was a dose-response relationship between the type of HTN disorder and SMM, with more severe HTN disorders leading to a greater risk of SMM. The population-attributable fraction of HTN disorders on SMM was 20.6% for Black individuals versus 17.5% overall. The findings were similar when reclassifying transfusion-only SMM as no SMM. CONCLUSIONS: In Washington, HTN disorders are associated with SMM in a dose-dependent fashion with the greatest impact among Black individuals.

Risk Factors Associated with Congenital Syphilis, Georgia, 2008-2015.

Background: Congenital syphilis (CS) is associated with significant perinatal morbidity and mortality. The study objectives were to compare risk factors among women with syphilis infection whose pregnancies did and did not result in CS cases and to evaluate other geographic and socioeconomic characteristics of county of residence as a measure of healthcare inequity. Methods: This study linked maternal and congenital syphilis data from the Georgia Department of Public Health (DPH), 2008-2015. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline was followed. Demographic, behavioral, and case characteristics were compared among women with syphilis infection who did and did not have an infant with CS. Chi-square, Fisher's exact, and multivariate regression analyses were performed using STATA 14.2 (College Station, TX). Results: Of 505 women with syphilis infection, 23% had an infant with CS, while 77% did not. After adjusting for race/ethnicity, factors associated with CS outcome were age greater than 35 years (adjusted odds ratio (aOR) 3.88; 95% confidence interval (CI) 1.01-14.89), hospital/emergency department diagnosis of syphilis (aOR 3.43; 95% CI 1.54-7.62), and high-risk behaviors such as exchanging sex for money or drugs (aOR 3.25; 95% CI 1.18-8.98). There were no associations between characteristics of county of residence and CS outcome. Conclusions: This study highlights risk factors that may be associated with CS incidence and the adverse pregnancy outcomes associated with CS. Further work is needed to study improved data collection systems, contributing factors related to CS as well as prevention measures in the United States.

Breastfeeding Among People With Human Immunodeficiency Virus in North America: A Multisite Study.

BACKGROUND: In North American countries, national guidelines have strongly recommended formula over breastmilk for people with human immunodeficiency virus (HIV) because of concern for HIV transmission. However, data from resource-limited settings suggest the risk is <1% among virally suppressed people. Information regarding breastfeeding experience in high-resource settings is lacking. METHODS: A retrospective multisite study was performed for individuals with HIV who breastfed during 2014-2022 in the United States (8 sites) and Canada (3 sites). Descriptive statistics were used for data analysis. RESULTS: Among the 72 cases reported, most had been diagnosed with HIV and were on antiretroviral therapy prior to the index pregnancy and had undetectable viral loads at delivery. Most commonly reported reasons for choosing to breastfeed were health benefits, community expectations, and parent-child bonding. Median duration of breastfeeding was 24 weeks (range, 1 day to 72 weeks). Regimens for infant prophylaxis and protocols for testing of infants and birthing parents varied widely among institutions. No neonatal transmissions occurred among the 94% of infants for whom results were available ≥6 weeks after weaning. CONCLUSIONS: This study describes the largest cohort to date of people with HIV who breastfed in North America. Findings demonstrate high variability among institutions in policies, infant prophylaxis, and infant and parental testing practices. The study describes challenges in weighing the potential risks of transmission with personal and community factors. Finally, this study highlights the relatively small numbers of patients with HIV who chose to breastfeed at any 1 location, and the need for further multisite studies to identify best care practices.

Antiretroviral Regimen and Pregnancy Outcomes of Women Living with HIV in a US Cohort.

Women who are pregnant and living with HIV have traditionally been excluded from clinical trials regarding new pharmacotherapy. Immediate initiation of antiretroviral therapy (ART) is recommended for women who are pregnant and living with HIV. Integrase inhibitors (INSTIs) are first-line recommended agents as they lead to more rapid HIV viral load reduction. We conducted a retrospective study of women who are pregnant and living with HIV who received prenatal care at the University of Washington. Mothers were categorized by ART class: INSTI, protease inhibitors (PI), and non-nucleoside reverse transcriptase inhibitors (NNRTI). Chi-square and t-tests were used for the analysis of baseline characteristics, and generalized estimating equations were used to adjust for HIV viral suppression between groups. There were a total of 234 mother-infant pairs whose pregnancies progressed beyond 20 weeks. The study demonstrated that women on INSTI regimens were more likely to have a shorter time to viral load suppression than women on NNRTI regimens. Additionally, seven congenital anomalies were identified in this cohort, none of which were neural tube defects. There was no perinatal transmission of HIV to any of the infants. This small cohort of women provides high-quality data regarding the safety and efficacy of INSTI use for both mothers and infants in resource-rich settings.

Cabergoline for postpartum lactation suppression: Effect on blood pressure and pulse.

OBJECTIVE: To evaluate the effect of cabergoline on maternal blood pressure and pulse immediately postpartum. METHODS: We conducted a retrospective cohort study of 224 post-partum women who delivered at the University of Washington and did not breastfeed. Women who received 1 mg cabergoline within 48 h post-partum were compared to unexposed non-breastfeeding women. Systolic and diastolic blood pressure and pulse were assessed at 4-h intervals up to 24 h after cabergoline administration, and compared to unexposed women using delivery as the reference time point. Mean systolic and diastolic blood pressure and pulse were compared using linear regression and 95% confidence intervals, adjusting for age, indication for lactation suppression and weeks' gestation at delivery. RESULTS: Cabergoline-exposed women had lower mean systolic blood pressure at all time intervals. The maximum systolic blood pressure decrease with cabergoline was -10.88 mmHg (95% confidence interval -18.15 to -3.61) at >20-24 h. Mean diastolic blood pressure among cabergoline-exposed women decreased by -8.15 mmHg (95% confidence interval -13.94 to -2.36) at >20-24 h only. We found no significant difference in maternal pulse. Cabergoline was well tolerated with no adverse effects observed. CONCLUSION: Cabergoline has minimal clinically-relevant hemodynamic effects and was well tolerated among normotensive postpartum women.

Severe Maternal Morbidity Associated with Hospital NICU Level in Washington State.

OBJECTIVE: Rising maternal mortality and severe maternal morbidity (SMM) rates have drawn increasing public health attention. We evaluated patterns of SMM across the Washington State Perinatal Regional Network, in which neonatal intensive care unit (NICU) levels correlate with maternal level of care. STUDY DESIGN: Retrospective cohort study using de-identified patient and hospital-level rates of SMM diagnoses and procedures for all women who delivered at 58 hospitals from October 2015 to September 2016. Data were obtained from the Washington State Comprehensive Hospital Abstract Reporting System, which includes inpatient diagnosis with associated Present on Admission flags, procedure, and discharge information derived from hospital billing systems. Deliveries were stratified by having or not having SMM. For each SMM diagnosis, POA rates were tabulated. Hospital SMM rates (all SMM, transfusion only, and SMM excluding transfusion) were grouped according to their NICU level of care (critical access [CA] and 1-4). Odds ratios and 95% confidence intervals (CI) were calculated. RESULTS: Of 76,961 deliveries, 908 women (1.2%) had any SMM including 533 with transfusion only and 375 with all other SMM diagnoses/procedures. Rates of SMM were highest at level 1 and level 4 hospitals at 1.3 and 1.5%, respectively. Level 1 and CA hospitals had the highest transfusion rate (1.0%), while level 2, 3, and 4 hospitals had progressively lower rates (0.8, 0.7, and 0.5%, respectively; p < 0.01). Level 4 hospitals had the highest rate of SMM diagnoses/procedures (1.0%). Among SMM diagnoses, the percentage with POA was lowest in level 1/CA hospitals (23%) and similar across level 2, 3, and 4 hospitals (39%). CONCLUSION: SMM diagnoses occur most frequently at the centers providing the highest level of care, likely attributable to the regional referral system. However, transfusion rates are increased in level 1/CA hospitals. Efforts to decrease SMM should focus on equipping level 1/CA hospitals with tools to decrease maternal morbidity and improve referral systems. KEY POINTS: · SMM occurs most frequently at highest level of care.. · Higher transfusion rates occur at lower care level hospitals.. · Most SMM POA occurs at higher level of care..

Low Prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 Among Pregnant and Postpartum Patients With Universal Screening in Seattle, Washington.

We found low prevalence of SARS-CoV-2 (2.7% [5/188]) among pregnant and postpartum patients with universal testing. Prevalence among symptomatic patients was similar under initial targeted screening (22.2% [4/18]) and universal approaches (19.1% [8/42]). Among 170 asymptomatic patients, 2 were positive or inconclusive, respectively; repeat testing at 24 hours was negative.

An enhanced recovery after surgery pathway for cesarean delivery decreases hospital stay and cost.

BACKGROUND: Enhanced recovery after surgery pathways provide a multidisciplinary, evidence-based approach to the care of surgical patients. They have been shown to decrease postoperative length of stay and cost in several surgical subspecialties, including gynecology, but have not been well-studied in obstetric patients who undergo cesarean delivery. OBJECTIVE: We sought to determine whether the implementation of an enhanced recovery after surgery pathway for cesarean delivery would decrease postoperative length of stay and postoperative direct cost compared with historic controls. STUDY DESIGN: We conducted a retrospective cohort study that compared postoperative length of stay and postoperative direct cost among women on the enhanced recovery after surgery cesarean delivery pathway in the first year of implementation (April 1, 2017, to March 31, 2018; n=531) compared with historic controls (March 1, 2016, to February 28, 2017; n=661). Literature review informed the development of a prototype enhanced recovery after surgery pathway for cesarean delivery based on best practices from previous enhanced recovery after surgery experience in obstetrics (if available) or from other surgical disciplines if there were no available data for obstetrics. When there was not relevant published evidence from obstetrics, the taskforce used clinical experience and expert opinion to develop the pathway. The enhanced recovery after surgery cesarean delivery pathway included preadmission patient education and preoperative, intrapartum, and postoperative elements. Some components reflected standard obstetric care, and others were specific to the enhanced recovery after surgery pathway. Women with pregestational diabetes mellitus who were receiving insulin therapy before pregnancy, women with preeclampsia with severe features, women with complex pain needs, and women with surgical complications were excluded from baseline and implementation groups. Enhanced recovery after surgery cesarean delivery pathway participation was determined by order set usage. Analysis was stratified for women who underwent planned (no labor; n=530) and unplanned (labor; n=662) cesarean delivery. Demographic and clinical characteristics, postoperative length of stay, postoperative direct cost, and readmission rates for the baseline and implementation groups were compared with the use of chi-square and t-tests. RESULTS: During the first year of implementation, 531 of 640 eligible women (83%) were included in the enhanced recovery after surgery cesarean delivery pathway. Body mass index was marginally higher in the baseline group for unplanned cesarean delivery (32.5±7.1 vs 31.4±6.7 kg/m2; P=.04). Otherwise there were no significant differences in demographic or maternal clinical characteristics between baseline or implementation groups overall or for planned or unplanned cesarean delivery. Compared with baseline, implementation of the enhanced recovery after surgery cesarean delivery pathway resulted in a significant decrease in postoperative length of stay by 7.8% or 4.86 hours overall (P<.001) and for both planned (P=.001) and unplanned (P=.002) cesarean delivery. Total postoperative direct costs decreased by 8.4% or $642.85 per patient overall (P<.001) and for both planned (P<.001) and unplanned (P<.001) cesarean delivery. There were no significant differences in readmission rates. CONCLUSION: Implementation of an enhanced recovery after surgery pathway for women who had planned or unplanned cesarean delivery was associated with significantly decreased postoperative length of stay and significant direct cost-savings per patient, without an increase in hospital readmissions. Given that cesarean delivery is 1 of the most common surgical procedures performed in the United States, positively impacting postoperative length of stay and direct cost for women who undergo cesarean delivery could have significant healthcare cost-savings.

Phylogenetic Analyses Comparing HIV Sequences from Plasma at Virologic Failure to Cervix Versus Blood Sequences from Antecedent Antiretroviral Therapy Suppression.

Identifying tissue sources of HIV that rebound following "failure" of antiretroviral therapy (ART) is critical to evaluating cure strategies. To assess the role of the uterine cervix and peripheral blood mononuclear cells (PBMC) as viral reservoirs, nearest-neighbor phylogenetic analyses compared genetic relatedness of tissue sequences during ART suppression to those detected in plasma at viral rebound. Blood and genital tract specimens from a natural history cohort of HIV-infected women were collected over 5 years. HIV DNA sequences extracted from PBMC and cervical biopsies during ART suppression and plasma RNA from rebound (defined as HIV RNA >3 log10 copies/mL) were derived by single-genome amplification. Phylogenetic and nearest-neighbor analyses of HIV env sequences and drug resistance in pol sequences were compared between tissues. Nine instances of plasma viral rebound (median HIV RNA 3.6 log10 c/mL; IQR: 3.1-3.8) were detected in 7 of 57 women. Nearest-neighbor analyses found rebound plasma sequences were closer to uterine cervical sequences in 4/9 (44%), closer to PBMC in 3/9 (33%), and ambiguous in 2/9 (22%) cases. Rebound plasma clades (n = 27) shared identical sequences in seven instances with the cervix versus two with PBMC. Novel drug resistance mutations were detected in 4/9 (44%) rebounds. The observed tendency for greater sharing of identical HIV variants and greater nearest-neighbor association between rebounding plasma and uterine cervical versus PBMC sequences suggests that the uterine cervix may be a relevant HIV reservoir. The cervix, a readily accessible tissue in women that can be repeatedly sampled, could help assess the HIV reservoir when evaluating cure strategies.

Contribution of hypertension to severe maternal morbidity.

BACKGROUND: Maternal mortality and severe maternal morbidity are growing public health concerns in the United States. The Centers for Disease Control and Prevention Severe Maternal Morbidity measure provides insight into processes underlying maternal mortality and may highlight modifiable risk factors for adverse maternal health outcomes. OBJECTIVE: The primary objective of this study was to evaluate the association between hypertensive disorders and severe maternal morbidity at a regional perinatal referral center. We hypothesized that women with preeclampsia with severe features would have a higher rate of severe maternal morbidity compared to normotensive women. We also assessed the proportion of severe maternal morbidity diagnoses that were present on admission, in contrast to those arising during the delivery hospitalization. STUDY DESIGN: In this retrospective cross-sectional analysis, we assessed rates of severe maternal morbidity diagnoses (eg, renal insufficiency, shock, and sepsis) and procedures (eg, transfusion and hysterectomy) for all 7025 women who delivered at the University of Washington Medical Center from Oct. 1, 2013, through May 31, 2017. Severe maternal morbidity was determined from prespecified International Classification of Diseases diagnosis and procedure codes; all diagnoses were confirmed by chart review. Present-on-admission rates were calculated for each diagnosis through hospital administrative data provided by the Vizient University Health System Consortium. Maternal demographic and clinical characteristics were compared for women with and without severe maternal morbidity. The χ2 and Fisher exact tests were used to determine statistical significance. Odds ratios and 95% confidence intervals were calculated for the associations between maternal demographic and clinical characteristics and severe maternal morbidity. RESULTS: Of 7025 deliveries, 284 (4%) had severe maternal morbidity; 154 had transfusion only, 27 had other procedures, and 103 women had 149 severe maternal morbidity diagnoses (26 women had multiple diagnoses). Severe preeclampsia occurred in 438 deliveries (6.2%). Notably, hypertension was associated with severe maternal morbidity in a dose-dependent fashion, with the strongest association observed for preeclampsia with severe features (odds ratio, 5.4; 95% confidence interval, 3.9-7.3). Severe maternal morbidity was also significantly associated with preeclampsia without severe features, chronic hypertension, preterm delivery, pregestational diabetes, and multiple gestation. Among women with severe maternal morbidity, over one third of preterm births were associated with maternal hypertension. American Indian/Alaskan Native women had significantly higher severe maternal morbidity rates compared to other racial/ethnic groups (11.7% vs 3.9% for Whites, P < .01). Overall, 39.6% of severe maternal morbidity diagnoses were present on admission. CONCLUSION: Hypertensive disorders in pregnancy are strongly associated with severe maternal morbidity in a dose-dependent relationship, suggesting that strategies to address rising maternal morbidity rates should include early recognition and management of hypertension. Prevention strategies focused on hypertension might also impact medically indicated preterm deliveries. The finding of increased severe maternal morbidity among American Indian/Alaskan Native women, a disadvantaged population in Washington State, underscores the role that socioeconomic factors may play in adverse maternal health outcomes. As 39% of severe maternal morbidity diagnoses were present on admission, this measure should be risk-adjusted if used as a quality metric for comparison between hospitals.

A Comparison of the Nulliparous-Term-Singleton-Vertex and Society of Maternal-Fetal Medicine Cesarean Birth Metrics Based on Hospital Size.

OBJECTIVE: The purpose of this study was to compare the nulliparous-term-singleton-vertex (NTSV) and the Society of Maternal-Fetal Medicine (SMFM) cesarean birth metrics as tools for quality improvement efforts based on hospital size. MATERIALS AND METHODS: Cesarean birth rates from 275 hospitals from six states were used to evaluate the NTSV metric and 81 hospitals from four states for the SMFM metric. Data were assessed based on delivery volume, their use as an effective tool for ongoing quality improvement programs, and their ability to serve as performance-based payline indicators. RESULTS: The average NTSV and SMFM cesarean birth rates were 25.6 and 13.0%, respectively. The number of deliveries included in the NTSV metric was stable across all hospital sizes (33.1-36.2%). With the SMFM metric, there was a progressive decline in the number of deliveries included, 90.0 versus 69.6%, in relatively small to large facilities. Variability was less and precision increased with the SMFM metric, which reduced the number of hospitals that could be incorrectly categorized when using performance-based predefined cesarean birth rate paylines. CONCLUSION: The SMFM metric appears to be better suited as a tool for rapid process improvement programs aimed at reducing cesarean birth rates in low-risk patients.

Effect of severity of illness on cesarean delivery rates in Washington State.

BACKGROUND: Hospitals and providers are increasingly held accountable for their cesarean delivery rates. In the perinatal quality improvement arena, there is vigorous debate about whether all hospitals can be held to the same benchmark for an acceptable cesarean rate regardless of patient acuity. However, the causes of variation in hospital cesarean delivery rates are not well understood. OBJECTIVE: We sought to evaluate the association and temporal trends between severity of illness at admission and the primary term singleton vertex cesarean delivery rate among hospitals in Washington State. We hypothesized that hospitals with higher patient acuity would have higher cesarean delivery rates and that this pattern would persist over time. STUDY DESIGN: In this cross-sectional analysis, we analyzed aggregate hospital-level data for all nonmilitary hospitals in Washington State with ≥100 deliveries/y during federal fiscal years 2010 through 2014 (287,031 deliveries). Data were obtained from the Washington State Comprehensive Hospital Abstract Reporting System, which includes inpatient demographic, diagnosis, procedure, and discharge information derived from hospital billing systems. Age, admission diagnoses and procedure codes were converted to patient-level admission severity-of-illness scores using the All Patient Refined Diagnosis Related Groups classification system. This system is widely used throughout the United States to adjust hospital data for severity of illness. Mean admission hospital-level severity-of-illness scores were calculated for each fiscal year among the term singleton vertex population with no history of cesarean delivery. We used linear regression to evaluate the association between hospital admission severity of illness and the primary term singleton vertex cesarean delivery rate, calculated Pearson correlation coefficients, and compared regression line slopes and 95% confidence intervals for each fiscal year. RESULTS: Hospitals were diverse with respect to delivery volume, level of care, and geographic location within Washington. Hospital aggregate admission severity-of-illness score correlated with primary term singleton vertex cesarean delivery rate in all fiscal years (R2 0.38-0.58, P < .001). For every year in the study interval, as admission severity of illness increased so did the primary term singleton vertex cesarean rate. The slope of the regression line decreased during the study interval, suggesting that statewide decrease in primary term singleton vertex cesarean rate occurred across the range of severity of illness. CONCLUSION: Admission severity-of-illness score is strongly associated with the primary term singleton vertex cesarean delivery rate among hospitals in Washington State. Approximately 50% of variation in hospital primary term singleton vertex cesarean delivery rates appeared to be related to admission severity of illness. This relationship persisted over time despite a statewide decrease in cesarean delivery, suggesting that patient acuity will likely continue to contribute to hospital variation in cesarean delivery rates despite perinatal quality improvement efforts. The major implication of this study is that patient acuity should be considered when determining optimal cesarean delivery rates. High-acuity hospitals are likely to have high cesarean rates because they provide a specific role in serving regional needs. To hold these centers to an arbitrary benchmark may jeopardize the funding necessary to support regional safety net institutions.

Interconception Challenges of Women Who Had Prior Preterm Births.

OBJECTIVE: To describe the interconception challenges of women who had prior preterm births. DESIGN: We used a cross-sectional design and collected data via survey. SETTING: King County, Washington. PARTICIPANTS: Ninety-two women who had prior early preterm births (20-33 weeks gestation) were included. METHODS: Women were recruited from a larger study focused on exploring the infectious pathways for early preterm birth. Participants were interviewed once using open-ended and close-ended surveys. The primary open-ended survey question was What are the five greatest challenges you experience now? We analyzed data using inductive and summative content analysis and descriptive statistics. RESULTS: Ninety-one participants described challenges. One participant had no challenge. We categorized 11 challenges during the interconception period: Mothering (n = 70, 76%), Self-Care Desires (n = 35, 38%), Finances (n = 31, 34%), Employment (n = 31, 34%), Partner Relationships (n = 29, 32%), Individualized Concerns (n = 25, 27%), Mental Health (n = 23, 25%), Balance (n = 22, 24%), Physical Health (n = 19, 21%), Housing (n = 18, 20%), and Family (n = 17, 19%). CONCLUSION: Participants described an array of challenges that often related to their roles as mothers, employees, and partners. Our research advances knowledge by describing contemporary challenges of women during the interconception period.

Please exit safely: maternal and twin pair neonatal outcomes according to delivery mode when twin A is vertex.

OBJECTIVE: To investigate maternal and infant outcomes associated with delivery mode for twins with a cephalic presenting twin. METHODS: Linked birth certificate and ICD hospital discharge data were analyzed retrospectively for 5573 mothers and their respective twin pairs born live at 34-42 weeks' gestation, with twin A vertex, in Washington State from 1997-2007. Relative risks (RR) and 95% confidence intervals of adverse maternal and twin pair outcomes were calculated for vaginal delivery or cesarean during labor in comparison to cesarean without labor. RESULTS: Vaginal delivery or cesarean during labor was associated with significantly elevated rates of maternal hemorrhage (RR = 2.8 [2.2,3.7]), infection (RR = 2.2 [1.5,3.3]), twin pair birth injury (RR = 2.6 [1.2,5.4]) and low 5-min Apgar scores (RR = 1.4 [1.1,1.8]) and with significantly lower rates of ventilation among preterm twin pairs only (RR = 0.8 [0.7,0.9]). The lowest rate of combined poor short-term outcomes occurred in mothers and twin pairs delivered by cesarean without labor (23%) and the highest rates occurred in those with operative vaginal or cesarean during labor (39% and 34%, respectively). Among women in labor, 35% of nulliparas achieved spontaneous vaginal delivery of both twins compared to 63% of non-nulliparas. CONCLUSION: For nulliparous women who carry twins to term, planned cesarean may improve outcomes.

Effects of Lipopolysaccharide and Progesterone Exposures on Embryonic Cerebral Cortex Development in Mice.

Our objective was to determine if progesterone pretreatment could ameliorate the detrimental effects of lipopolysaccharide (LPS)-induced inflammation on cortical neurogenesis. Timed pregnant mouse dams (n = 8) were given intraperitoneal injections of progesterone (42 mg/kg) or vehicle on embryonic day 17.5. Two hours later, mice were given intraperitoneal LPS (140 µg/kg) or vehicle. Mice were sacrificed 16 hours later on embryonic day 18. Two-color immunofluorescence was performed with primary antibodies T-box transcription factor 2 (Tbr2), ionized calcium binding adapter molecule 1 (Iba1), cleaved caspase 3 (CC3), and 5-bromo-2'-deoxyuridine (BrdU). Cells were counted, and statistical analysis was determined using analysis of variance and Tukey-Kramer method. The Tbr2 intermediate neural progenitor cell density decreased after LPS exposure (P = .0022). Pre-exposure to progesterone statistically increased Tbr2 intermediate neural progenitors compared to LPS treatment alone and was similar to controls (P = .0022). After LPS exposure, microglia displayed an activated phenotype, and cell density was increased (P < .001). Cell death rates were low among study groups but was increased in LPS exposure groups compared to progesterone alone (P = .0015). Lipopolysaccharide-induced systemic inflammation reduces prenatal neurogenesis in mice. Pre-exposure with progesterone is associated with increased neurogenesis. Progesterone may protect the preterm brain from defects of neurogenesis induced by inflammation.

Hydrogen Peroxide-Producing Lactobacilli Are Associated With Lower Levels of Vaginal Interleukin-1ß, Independent of Bacterial Vaginosis.

BACKGROUND: The presence of hydrogen peroxide (H2O2)-producing lactobacilli in the vagina is associated with decreased rates of preterm birth and HIV acquisition. We hypothesize that this is due to immunomodulatory effects of these species. METHODS: Concentrations of interleukin (IL)-1ß, IL-6, IL-8, secretory leukocyte protease inhibitor, and human ß-defensin 2 were quantified from vaginal swabs from 4 groups of women: women with and without bacterial vaginosis (BV) by Nugent score, further stratified by detection of H2O2-producing lactobacilli by semiquantitative culture. Ten quantitative polymerase chain reaction assays characterized the presence and quantity of select Lactobacillus and BV-associated species in each group. Levels of immune markers and bacteria were compared between the 4 groups using analysis of variance, Kruskal-Wallis, Mann-Whitney U, or χ tests. RESULTS: Swabs from 110 women from 4 groups were included: 26 had a normal Nugent score (BV-), and no H2O2-producing lactobacilli detected (H2O2-); 47 were BV-, H2O2+; 27 BV+, H2O2-; and 10 BV+, H2O2+. The groups were similar in age, marital status, and reproductive history, but not ethnicity: the BV-, H2O2- group had more white participants (P = 0.02). In women with and without BV, IL-1ß was lower in the H2O2+ groups. Human ß-defensin 2 was lowest in BV+ H2O2- women and highest in BV-, H2O2-. Secretory leukocyte protease inhibitor was lower in women with BV and did not differ by the presence of H2O2-producing lactobacilli. In regression analysis, higher quantities of Lactobacillus crispatus were associated with lower quantities of IL-1ß. Detection and quantity of BV-associated species by quantitative polymerase chain reaction was significantly different between women with and without BV, but not between women with and without H2O2-producing lactobacilli within those groups. CONCLUSIONS: The presence of H2O2-producing lactobacilli is associated with lower levels of some vaginal proinflammatory cytokines, even in women with BV.

HIV-1 shedding from the female genital tract is associated with increased Th1 cytokines/chemokines that maintain tissue homeostasis and proportions of CD8+FOXP3+ T cells.

BACKGROUND: HIV-1 shedding from the female genital tract is associated with increased sexual and perinatal transmission and has been broadly evaluated in cross-sectional studies. However, few longitudinal studies have evaluated how the immune microenvironment effects shedding. METHODS: Thirty-nine HIV-1-infected women had blood, cervicovaginal lavage, and biopsies of the uterine cervix taken quarterly for up to 5 years. Cytokines/chemokines were quantified by Luminex assay in cervicovaginal lavage, and cellular phenotypes were characterized using immunohistochemistry in cervical biopsies. Comparisons of cytokine/chemokine concentrations and the percent of tissue staining positive for T cells were compared using generalized estimating equations between non-shedding and shedding visits across all women and within a subgroup of women who intermittently shed HIV-1. RESULTS: Genital HIV-1 shedding was more common when plasma HIV-1 was detected. Cytokines associated with cell growth (interleukin-7), Th1 cells/inflammation (interleukin-12p70), and fractalkine were significantly increased at shedding visits compared with non-shedding visits within intermittent shedders and across all subjects. Within intermittent shedders and across all subjects, FOXP3 T cells were significantly decreased at shedding visits. However, there were significant increases in CD8 cells and proportions of CD8FOXP3 T cells associated with HIV-1 shedding. CONCLUSIONS: Within intermittent HIV-1 shedders, decreases in FOXP3 T cells at the shedding visit suggests that local HIV-1 replication leads to CD4 T-cell depletion, with increases in the proportion of CD8FOXP3 cells. HIV-1-infected cell loss may promote a cytokine milieu that maintains cellular homeostasis and increases immune suppressor cells in response to HIV-1 replication in the cervical tissues.

Frequency of Antiretroviral Resistance Mutations among Infants Exposed to Single-Dose Nevirapine and Short Course Maternal Antiretroviral Regimens: ACTG A5207.

BACKGROUND: Intrapartum single-dose nevirapine (sdNVP) reduces HIV-1 perinatal transmission but selects NVP resistance among mothers and infants. We evaluated the frequency of antiretroviral resistance among infants with intrauterine HIV-1 infection exposed to sdNVP and maternal antenatal or breastfeeding antiretroviral therapy. METHODS: This analysis included 429 infants from sub-Saharan Africa, India and Haiti whose 422 mothers received sdNVP plus maternal study treatment. At entry mothers had CD4>250/µL and were ART-naïve except for antenatal ZDV per local standard of care. Maternal study treatment started intrapartum and included ZDV/3TC, TDF/FTC or LPV/r for 7 or 21 days in a randomized factorial design. Infants received sdNVP study treatment and ZDV if local standard of care. Infant HIV RNA or DNA PCR and samples for genotype were obtained at birth and weeks 2, 4 and 12; infants who ever breast-fed were also tested at weeks 16, 24, 48 and 96. Samples from HIV-1-infected infants were tested for drug resistance by population genotype (ViroSeq). NVP or NRTI resistance mutations were assessed using the IAS-USA mutation list. RESULTS: Perinatal HIV-1 transmission occurred in 17 (4.0%) infants including 12 intrauterine infections. Resistance mutations were detected among 5 (42%) intrauterine-infected infants; of these, 3 had mutations conferring resistance to NVP alone, 1 had resistance to NRTI alone, and 1 had dual-class resistance mutations. Among the 2 infants with NRTI mutations, one (K70R) was likely maternally transmitted and one (K65R) occurred in the context of breastfeeding exposure to maternal antiretroviral therapy. CONCLUSIONS: Infants with intrauterine HIV infection are at risk of acquiring resistance mutations from exposure to maternal antiretroviral medications intrapartum and/or during breastfeeding. New approaches are needed to lower the risk of antiretroviral resistance in these infants.

A hemolytic pigment of Group B Streptococcus allows bacterial penetration of human placenta.

Microbial infection of the amniotic fluid is a significant cause of fetal injury, preterm birth, and newborn infections. Group B Streptococcus (GBS) is an important human bacterial pathogen associated with preterm birth, fetal injury, and neonatal mortality. Although GBS has been isolated from amniotic fluid of women in preterm labor, mechanisms of in utero infection remain unknown. Previous studies indicated that GBS are unable to invade human amniotic epithelial cells (hAECs), which represent the last barrier to the amniotic cavity and fetus. We show that GBS invades hAECs and strains lacking the hemolysin repressor CovR/S accelerate amniotic barrier failure and penetrate chorioamniotic membranes in a hemolysin-dependent manner. Clinical GBS isolates obtained from women in preterm labor are hyperhemolytic and some are associated with covR/S mutations. We demonstrate for the first time that hemolytic and cytolytic activity of GBS is due to the ornithine rhamnolipid pigment and not due to a pore-forming protein toxin. Our studies emphasize the importance of the hemolytic GBS pigment in ascending infection and fetal injury.

Clinical and genetic determinants of plasma nevirapine exposure following an intrapartum dose to prevent mother-to-child HIV transmission.

OBJECTIVE: Nevirapine is metabolized by cytochrome P450 (CYP) 2B6 and CYP3A4. We characterized relationships between clinical parameters, human genetics, pharmacokinetics, and human immunodeficiency virus type 1 (HIV-1) drug resistance mutations in pregnant women following single-dose intrapartum nevirapine. METHODS: In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor and were randomly assigned to receive lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir for 7 or 21 days. Plasma nevirapine level was quantified on postpartum day 1 and on weeks 1, 3, and 5. We assayed 214 polymorphisms in CYP2B6 and other genes and evaluated associations with pharmacokinetic parameters, including elimination constant, time to protein-adjusted 50% inhibitory concentration (IC50), and week 5 nevirapine level below the quantification limit. RESULTS: Among 301 women with evaluable pharmacokinetic and genotype data, lower body mass index and random assignment to receive lopinavir/ritonavir were associated with more rapid nevirapine elimination. Among those of African ancestry, longer time to IC50 was associated with CYP2B6 983T → C (P = .004) but not with CYP2B6 516G → T (P = .8). Among Indians, slower nevirapine elimination was associated with CYP2B6 516G → T (P = .04). Emergent resistance was infrequent and not associated with pharmacokinetics or CYP2B6 genotype. CONCLUSIONS: The effects on plasma drug exposure following single-dose nevirapine may be greater for CYP2B6 983T → C than for 516G → T and are less pronounced than at steady state.