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Objective: To study maternal and neonatal effects of combination nucleoside analog therapy administered to human immunodeficiency virus (HIV)-infected pregnant women for maternal indications.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing—a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies.Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases.Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.

Seven Northern Inuit Dogs (NID) were diagnosed by pedigree analysis with an autosomal recessive inherited oculoskeletal dysplasia (OSD). Short-limbed dwarfism, angular limb deformities and a variable combination of macroglobus, cataracts, lens coloboma, microphakia and vitreopathy were present in all seven dogs, while retinal detachment was diagnosed in five dogs. Autosomal recessive OSD caused by COL9A3 and COL9A2 mutations have previously been identified in the Labrador Retriever (dwarfism with retinal dysplasia 1-drd1) and Samoyed dog (dwarfism with retinal dysplasia 2-drd2) respectively; both of those mutations were excluded in all affected NID. Nine candidate genes were screened in whole genome sequence data; only one variant was identified that was homozygous in two affected NID but absent in controls. This variant was a nonsense single nucleotide polymorphism in COL9A3 predicted to result in a premature termination codon and a truncated protein product. This variant was genotyped in a total of 1,232 dogs. All seven affected NID were homozygous for the variant allele (T/T), while 31/116 OSD-unaffected NID were heterozygous for the variant (C/T) and 85/116 were homozygous for the wildtype allele (C/C); indicating a significant association with OSD (p = 1.41x10-11). A subset of 56 NID unrelated at the parent level were analysed to determine an allele frequency of 0.08, estimating carrier and affected rates to be 15% and 0.6% respectively in NID. All 1,109 non-NID were C/C, suggesting the variant is rare or absent in other breeds. Expression of retinal mRNA was similar between an OSD-affected NID and OSD-unaffected non-NID. In conclusion, a nonsense variant in COL9A3 is strongly associated with OSD in NID, and appears to be widespread in this breed.

Sensory neuropathy in the Border Collie is a severe neurological disorder caused by the degeneration of sensory and, to a lesser extent, motor nerve cells with clinical signs starting between 2 and 7 months of age. Using a genome-wide association study approach with three cases and 170 breed matched controls, a suggestive locus for sensory neuropathy was identified that was followed up using a genome sequencing approach. An inversion disrupting the candidate gene FAM134B was identified. Genotyping of additional cases and controls and RNAseq analysis provided strong evidence that the inversion is causal. Evidence of cryptic splicing resulting in novel exon transcription for FAM134B was identified by RNAseq experiments. This investigation demonstrates the identification of a novel sensory neuropathy associated mutation, by mapping using a minimal set of cases and subsequent genome sequencing. Through mutation screening, it should be possible to reduce the frequency of or completely eliminate this debilitating condition from the Border Collie breed population.

Abstract Background Canine progressive retinal atrophies are a group of hereditary retinal degenerations in dogs characterised by depletion of photoreceptor cells in the retina, which ultimately leads to blindness. PRA in the Lhasa Apso (LA) dog has not previously been clinically characterised or described in the literature, but owners in the UK are advised to have their dog examined through the British Veterinary Association/ Kennel Club/ International Sheep Dog Society (BVA/KC/ISDS) eye scheme annually, and similar schemes that are in operation in other countries. After the exclusion of 25 previously reported canine retinal mutations in LA PRA-affected dogs, we sought to identify the genetic cause of PRA in this breed. Results Analysis of whole-exome sequencing data of three PRA-affected LA and three LA without signs of PRA did not identify any exonic or splice site variants, suggesting the causal variant was non-exonic. We subsequently undertook a genome-wide association study (GWAS), which identified a 1.3 Mb disease-associated region on canine chromosome 33, followed by whole-genome sequencing analysis that revealed a long interspersed element-1 (LINE-1) insertion upstream of the IMPG2 gene. IMPG2 has previously been implicated in human retinal disease; however, until now no canine PRAs have been associated with this gene. The identification of this PRA-associated variant has enabled the development of a DNA test for this form of PRA in the breed, here termed PRA4 to distinguish it from other forms of PRA described in other breeds. This test has been used to determine the genotypes of over 900 LA dogs. A large cohort of genotyped dogs was used to estimate the allele frequency as between 0.07–0.1 in the UK LA population. Conclusions Through the use of GWAS and subsequent sequencing of a PRA case, we have identified a LINE-1 insertion in the retinal candidate gene IMPG2 that is associated with a form of PRA in the LA dog. Validation of this variant in 447 dogs of 123 breeds determined it was private to LA dogs. We envisage that, over time, the developed DNA test will offer breeders the opportunity to avoid producing dogs affected with this form of PRA.

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., Competing Interests: Potential conflicts of interest. A. W. reports research funding from NIH and GlaxoSmithKline; consulting fees for advisory board roles with GlaxoSmithKline, Seqirus, and Merck; and payment or honoraria from GlaxoSmithKline (for a podcast) and Merck (meeting presentation). I. B. reports grants or contracts with the Canadian Institutes for Health Research, NIH, Altona, Moderna, and Ferring; consulting fees from Pfizer; and a role with the Society of Obstetricians and Gynecologists of Canada. J. D. reports travel support from the American College of Obstetricians and Gynecologists for the national conference. A. P. reports support from NIAID (grant number K23AI155296) and royalties from UpToDate. K. K. reports meeting honoraria from Takeda Canada. L. A. reports grants or contracts from NIH and the Colorado Department of Public Health and Environment. L. R. reports consulting fees from the University of California, San Francisco Clinicians Consultation Center National Perinatal HIV Hotline. F. K. reports salary support from FRQS and research infrastructure support from the Quebec government (Ministère de la Santé et des Services Sociaux/Service de lutte contre infections transmissibles sexuellement et par le sang). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: None of our authors has any conflict of interest related to this publication. Outside of this work, Dr. Kachikis reported being a coinvestigator on studies funded by Pfizer and Merck outside the submitted work. Dr. Kachikis reported serving as an unpaid research consultant for Pfizer and GlaxoSmithKline on maternal immunization-related projects outside the submitted work., (Copyright © 2023 Alisa Kachikis et al.)

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., Competing Interests: The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication.

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., (© 2022 International Federation of Gynecology and Obstetrics.)

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.., Competing Interests: None declared., (Thieme. All rights reserved.)

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., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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 log 10 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 log 10 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.

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 χ 2 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., (Copyright © 2018. Published by Elsevier Inc.)

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., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

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 (R 2 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., (Copyright © 2017. Published by Elsevier Inc.)

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.

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., (© The Author(s) 2015.)

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)-1β, IL-6, IL-8, secretory leukocyte protease inhibitor, and human β-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-1β was lower in the H2O2+ groups. Human β-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-1β. 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.

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.

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.

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.

The effect of the levonorgestrel-releasing intrauterine device (LNG-IUD) on genital HIV-1 RNA shedding and inflammation among 25 HIV-infected women was evaluated. Blood, endocervical, and cervicovaginal lavage samples were collected from HIV-infected women not taking antiretrovirals before LNG-IUD insertion and 1 month, 3 month, and 6 months thereafter. HIV-1 RNA was quantitated by real-time reverse transcriptase-polymerase chain reaction. Inflammatory markers were measured by enzyme immunoassay. Genital HIV-1 RNA shedding and inflammatory markers did not differ between LNG-IUD placement and month 6, with the exception of interleukin 1β that increased (0.42 log10; 95% confidence interval: 0.10 to 0.75). The LNG-IUD did not increase genital HIV-1 RNA shedding after 6 months of use.

Background: Nevirapine (NVP) resistance emerges in up to 70% of women exposed to single-dose (sd) NVP for prevention of mother-to-child transmission of human immunodeficiency virus (HIV)., Methods: HIV-infected pregnant women were randomized to receive sdNVP and either zidovudine/lamivudine (3TC), tenofovir/emtricitabine (FTC), or lopinavir/ritonavir for either 7 or 21 days. The primary endpoint was the emergence of new NVP resistance mutations as detected by standard population genotype at 2 and 6 weeks after treatment. Low-frequency NVP- or 3TC/FTC-resistant mutants at codons 103, 181, and 184 were sought using allele-specific polymerase chain reaction (ASP)., Results: Among 484 women randomized, 422 (87%) received study treatment. Four hundred twelve (98%) women had primary endpoint results available; of these, 5 (1.2%) had new NVP resistance detected by population genotype: 4 of 215 in the 7-day arms (1.9%; K103N in 4 women with Y181C, Y188C, or G190A in 3 of 4) and 1 of 197 (0.5%; V108I) in the 21-day arms (P = .37). Among women with ASP results, new NVP resistance mutations emerged significantly more often in the 7-day arms (13/74 [18%]) than in the 21-day arms (3/66 [5%], P = .019). 3TC/FTC-resistant mutants (M184V/I) emerged infrequently (7/134 [5%]), and their occurrence did not differ by arm., Conclusions: Three short-term antiretroviral strategies, begun simultaneously with the administration of sdNVP, resulted in a low rate (1.2%) of new NVP-resistance mutations when assessed at 2 and 6 weeks following completion of study treatment by standard genotype. ASP revealed that 21-day regimens were significantly better than 7-day regimens at preventing the emergence of minor NVP resistance variants. Clinical Trials Registration.NCT00099632.

Cervical shedding of HIV-1 DNA may influence HIV-1 sexual transmission. HIV-1 DNA was detected in 250 (80%) of 316 and 207 (79%) of 259 cervical cytobrush specimens from 56 US and 80 Kenyan women, respectively. Plasma HIV-1 RNA concentration was associated with increased HIV-1 DNA shedding among US and Kenyan women. Kenyan women had higher cervicovaginal concentrations of proinflammatory interleukins (IL)-1β, IL-6, IL-8, and anti-inflammatory secretory leukocyte protease inhibitor compared with US women (all P < 0.01). HIV-1 DNA shedding was associated with increased concentrations of IL-1β and IL-6 and lower secretory leukocyte protease inhibitor among US women but not Kenyan women.

Bacterial vaginosis has been associated with genital HIV-1 shedding; however, the effect of specific vaginal bacterial species has not been assessed. We tested cervicovaginal lavage from HIV-1-seropositive women for common Lactobacillus species: L. crispatus, L. jensenii, and seven BV-associated species: BVAB1, BVAB2, BVAB3, Leptotrichia, Sneathia, Megasphaera, and Atopobium spp. using quantitative PCR. We used linear and Poisson regression to evaluate associations between vaginal bacteria and genital HIV-1 RNA and DNA. Specimens from 54 U.S. (310 visits) and 50 Kenyan women (137 visits) were evaluated. Controlling for plasma viral load, U.S. and Kenyan women had similar rates of HIV-1 RNA (19% of visits vs. 24%; IRR=0.95; 95% CI 0.61, 1.49) and DNA shedding (79% vs. 76%; IRR=0.90; 0.78, 1.05). At visits during antiretroviral therapy (ART), the likelihood of detection of HIV-1 RNA shedding was greater with BVAB3 (IRR=3.16; 95% CI 1.36, 7.32), Leptotrichia, or Sneathia (IRR=2.13; 1.02, 4.72), and less with L. jensenii (IRR=0.39; 0.18, 0.84). At visits without ART, only L. crispatus was associated with a lower likelihood of HIV-1 RNA detection (IRR=0.6; 0.40, 0.91). Vaginal Lactobacillus species were associated with lower risk of genital HIV-1 shedding, while the presence of certain BV-associated species may increase that risk.

Background: The presence of hydrogen peroxide (H(2)O(2)) producing Lactobacillus in the vagina may play a role in controlling genital HIV-1 shedding. Sensitive molecular methods improve our ability to characterize the vaginal microbiota; however, they cannot characterize phenotype. We assessed the concordance of H(2)O(2)-producing Lactobacillus detected by culture with quantitative PCR (qPCR) detection of Lactobacillus species commonly assumed to be H(2)O(2)-producers., Methods: Samples were collected as part of a prospective cohort study of HIV-1 seropositive US women. Cervicovaginal lavage specimens were tested for L. crispatus and L. jensenii using 16S rRNA gene qPCR assays. Vaginal swabs were cultured for Lactobacillus and tested for H(2)O(2)-production. We calculated a kappa statistic to assess concordance between culture and qPCR., Results: Culture and qPCR results were available for 376 visits from 57 women. Lactobacilli were detected by culture at 308 (82%) visits, of which 233 of 308 (76%) produced H(2)O(2). L. crispatus and/or L. jensenii were detected at 215 (57%) visits. Concordance between detection of L. crispatus and/or L. jensenii by qPCR and H(2)O(2)-producing Lactobacillus by culture was 75% (kappa = 0.45)., Conclusions: Among HIV-1 seropositive women, there was a moderate level of concordance between H(2)O(2)-producing Lactobacillus detected by culture and the presence of L. crispatus and/or L. jensenii by qPCR. However, one-quarter of samples with growth of H(2)O(2)-producing lactobacilli did not have L. crispatus or L. jensenii detected by qPCR. This discordance may be due to the presence of other H(2)O(2)-producing Lactobacillus species.

Background and Objective: The impact of maternal antiretrovirals (ARVs) during pregnancy, labor, and postpartum on infant outcomes is unclear., Methods: Infants born to HIV-infected mothers in ARV studies were followed for 18 months., Results: Between June 2006 and December 2008, 236 infants enrolled from Africa (n = 36), India (n = 47), Thailand (n = 152), and Brazil (n = 1). Exposure to ARVs in pregnancy included ≥ 3 ARVs (10%), zidovudine/intrapartum ARV (81%), and intrapartum ARV (9%). There were 4 infant infections (1 in utero, 3 late postpartum) and 4 deaths with 1.8% mortality (95% confidence interval [CI], 0.1%-3.5%) and 96.4% HIV-1-free survival (95% CI, 94.0%-98.9%). Birth weight was ≥ 2.5 kg in 86%. In the first 6 months, Indian infants (nonbreastfed) had lowest median weights and lengths and smallest increases in growth. After 6 months, African infants had the lowest median weight and weight-for-age z scores. Infants exposed to highest maternal viral load had the lowest height and height-for-age z scores. Serious adverse events occurred in 38% of infants, did not differ by country, and correlated with less maternal ARV exposure. Clinical diagnoses were seen in 84% of Thai, 31% of African, and 9% of Indian infants. Congenital defects/inborn errors of metabolism were seen in 18 (7.6%) infants, of which 17 were Thai (11%: 95% CI, 6.7%-17.0%); none had first trimester ARV exposure., Conclusions: Infant follow-up in large international cohorts is feasible and provides important safety and HIV transmission data following maternal ARV exposure. Increased surveillance increases identification of congenital/inborn errors.

Background: The effect of herpes simplex virus type 2 (HSV-2) suppression on human immunodeficiency virus type 1 (HIV-1) RNA in the context of prevention of mother-to-child transmission (PMTCT) interventions is unknown., Methods: Between April 2008 and August 2010, we conducted a randomized, double-blind trial of twice daily 500 mg valacyclovir or placebo beginning at 34 weeks gestation in 148 HIV-1/HSV-2 coinfected pregnant Kenyan women ineligible for highly active antiretroviral therapy (CD4 > 250 cells/mm(3)). Women received zidovudine and single dose nevirapine for PMTCT and were followed until 12 months postpartum., Results: Mean baseline plasma HIV-1 RNA was 3.88 log(10) copies/mL. Mean plasma HIV-1 was lower during pregnancy (-.56 log(10) copies/mL; 95% confidence interval [CI], -.77 to -.34) and after 6 weeks postpartum (-.51 log(10) copies/mL; 95% CI, -.73 to -.30) in the valacyclovir arm than the placebo arm. Valacyclovir reduced breast milk HIV-1 RNA detection at 6 and 14 weeks postpartum compared with placebo (30% lower, P = .04; 46% lower, P = .01, respectively), but not after 14 weeks. Cervical HIV-1 RNA detection was similar between arms (P = .91)., Conclusions: Valacyclovir significantly decreased early breast milk and plasma HIV-1 RNA among women receiving PMTCT., Clinical Trials Registration: NCT00530777.