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The U.S. Food and Drug Administration and European Commission have developed successful orphan drug legislation to promote the research, development, and marketing approval of drugs to treat rare diseases. Central to these regulations are the concepts of structural similarity and clinical superiority/significant benefit to achieve orphan drug exclusivity. However, differences in health authority expectations remain regarding the qualification for an orphan drug designation, defining structural similarity, and demonstrating clinical superiority/significant benefit. These differences can create sponsor company uncertainty regarding the approvability of products (e.g., blocking risk by an existing orphan product) and divergent orphan drug decisions among health authorities. A comprehensive assessment of current regulations, case studies in exclusivities, and recommendations for improvement are presented.

Epoxyketone 4 is an isolated intermediate in the manufacturing route to the commercial proteasome inhibitor carfilzomib (Kyprolis). Commercial process development and optimization efforts toward th...

A discussion on the regulatory chemistry, manufacturing, and control (CMC) strategy and the dialogue and response from global health authorities regarding the proposed impurity/degradant control st...

To evaluate the efficacy of incisional negative pressure wound therapy in the prevention of postoperative wound morbidity in women with class III obesity undergoing cesarean delivery.In an open label randomized controlled trial, women admitted for delivery with class III obesity (body mass index 40 or higher) measured within 2 weeks of admission for delivery were offered participation in the study. They were consented either in the outpatient maternal-fetal medicine specialty clinic, during admission to labor and delivery and before a decision to perform cesarean delivery, or in the preoperative area of the hospital before scheduled cesarean delivery. Exclusion criteria included anticoagulation therapy, human immunodeficiency virus infection, and silver or acrylic allergy. Those who ultimately underwent cesarean delivery were randomized to standard surgical dressing or incisional negative pressure wound therapy dressing. The primary outcome was wound morbidity. Preplanned secondary outcomes included characteristics of composite wound morbidity, and hospital, emergency room, and clinic utilization. The sample size estimate required randomization of 440 women to detect a 50% decrease in composite outcome.Between January 1, 2015, and July 31, 2016, 850 women were screened and 677 women with class III obesity were enrolled. Of these, 441 underwent cesarean delivery and were subsequently randomized (219 to standard dressing and 222 to incisional negative pressure wound therapy). The primary outcome, overall composite wound morbidity rate, was 18%. This was not different between the two cohorts (incisional negative pressure wound therapy 17% vs standard dressing 19%, relative risk 0.9 [95% CI 0.5-1.4]).Prophylactic incisional negative pressure wound therapy use did not reduce postoperative wound morbidity when compared with a standard surgical dressing in women with class III obesity.ClinicalTrials.gov, NCT02289157.

The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Control (CMC) Community hosted a virtual panel discussion on December 9, 2020, to provide a forum to discuss N-nitrosamine control strategies in the pharmaceutical and biotechnology industries. The panel included staff from the US Food and Drug Administration (FDA) and industry subject matter experts. Meeting topics included acceptable intake levels for nitrosamine impurities, definitions of "acceptable level of risk," water as a contributor in nitrosamine risk assessments, nitrosamine impurity control strategies based upon fate/purge data, early vs. late development assessment expectations, application to oncology programs developed under ICH S9, and Drug Master File (DMF) regulatory expectations. During the meeting, divergence in global health authority expectations was additionally discussed. One of the most important outputs from this AAPS panel discussion was the criticality of continued dialog between industry and health authorities to help understand actual versus perceived risks and provide pragmatic, scientifically justified solutions to ensure patients are provided with an uninterrupted supply of safe medicines based on globally harmonized requirements.

Background The definition for anemia in pregnancy is outdated, derived from Scandinavian studies in the 1970’s to 1980’s. To identity women at risk of blood transfusion, a common cause of Severe Maternal Morbidity, a standard definition of anemia in pregnancy in a modern, healthy United States cohort is needed. Objective To define anemia in pregnancy in a United States population including a large county vs. private hospital population using uncomplicated patients. Materials and methods Inclusion criteria were healthy women with the first prenatal visit before 20 weeks. Exclusion criteria included preterm birth, preeclampsia, hypertension, diabetes, short interval pregnancy ( Results In the public and private populations, 777 and 785 women presented in the first trimester while 223 and 215 presented in the second. The women at the private hospital were more likely to be older, Caucasian race, nulliparous, and present earlier to care. The fifth percentile was compared between the women in the private and public hospitals and were clinically indistinguishable. When combining the cohorts, the fifth percentile for hemoglobin/hematocrit was 11 g/dL/32.8% in the first trimester, 10.3 g/dL/30.6% in the second trimester, and 10.0 g/dL/30.2% pre-delivery. Conclusions Fifth percentile determinations were made from a combined cohort of normal, uncomplicated pregnancies to define anemia in pregnancy. Comparison of two different cohorts confirms that the same definition for anemia is appropriate regardless of demographics or patient mix.

Background Expedited partner therapy for Chlamydia trachomatis has had mixed efficacy in different populations, but limited data exist on the efficacy of the therapy in a pregnant population. Objective This study aimed to evaluate the real-world effectiveness of establishing a prenatal expedited partner therapy program in eradicating chlamydia before delivery and to examine the maternal and neonatal outcomes between women who received expedited partner therapy for chlamydia and women who received standard partner referral testing and treatment during pregnancy. Study Design An expedited partner therapy program was implemented on August 21, 2019, at a public hospital in a county with high chlamydia prevalence. Pregnant women were provided with single-dose packets of azithromycin to treat partners following a diagnosis of chlamydia infection. We prospectively observed pregnant women treated in the expedited partner therapy program who delivered at our institution in the same year and compared the outcomes with a historic cohort from the previous year that had traditional partner referral testing and treatment. We excluded women with concurrent gonorrhea, HIV, syphilis, or current intimate partner violence. The primary outcome was chlamydia reinfection or no-cure rates at repeat testing in 4 to 6 weeks following treatment or at the 36-week prenatal care screening. Secondary outcomes included obstetrical, maternal, and neonatal outcomes, including premature rupture of membranes, chorioamnionitis, endometritis, neonatal intensive care unit admission, neonatal sepsis, pneumonia, and conjunctivitis. Results The rate of chlamydia infection was 3.6% over a 2-year period in our delivered population. In the year following the implementation of the expedited partner therapy, compared with 419 women (mean±standard deviation, 23.4±5.5 years) who were diagnosed with chlamydia infection in the previous year, 471 women (mean±standard deviation age, 23.8±5.3 years) who delivered at our institution were diagnosed with chlamydia infection. There was no difference in race, parity, prenatal care attendance, or concomitant sexually transmitted infections. Compared with the pre-expedited partner therapy group, the rate of reinfection in the post-expedited partner therapy group was not statistically different (60/471 [13%] vs 61/419 [15%]; odds ratio, 0.86 [95% confidence interval 0.58–1.26]). In a per-protocol analysis, 72 women (17%) in the pre-expedited partner therapy group and 389 women (83%) in post-expedited partner therapy group received expedited partner therapy; reinfection was not statistically different between groups (P=.47). There was no difference in secondary outcomes, although a trend toward improved rates of endometritis was noted in the post-expedited partner therapy group (odds ratio, 0.13; 95% confidence interval, 0.02–1.02). Conclusion The implementation of a prenatal expedited partner therapy program did not affect the rate of chlamydia reinfection before delivery. Treatment of chlamydia in an inner-city population has multiple factors that lead to successful treatment. Future efforts to reduce sexually transmitted infection and chlamydia reinfection rates in an at-risk population should include exploring patient education and safe sex practices beyond expedited partner therapy alone during pregnancy.

Objective This study aimed to evaluate the association of ARCHITECT chemiluminescent immunoassay (CIA) signal strength (signal-to-cutoff [S/CO] ratio), with maternal syphilis stage, rapid plasma reagin (RPR) reactivity, and congenital syphilis. Study Design A prospective observational study of reverse syphilis screening was conducted. Pregnant women were screened with CIA. Reactive CIA was reflexed to RPR; particle agglutination test (Treponema pallidum particle agglutination [TPPA]) was performed for CIA+/RPR− results. Clinical staging with history and physical was performed, and disease stage was determined. Prior treatment was confirmed. We compared S/CO ratio and neonatal outcomes among the following groups: Group 1: CIA+/RPR+/TPPA+ or CIA+/RPR−/TPPA+ with active syphilis; Group 2: CIA+/RPR−/TPPA+ or CIA+/serofast RPR/TPPA+, previously treated; Group 3: CIA+/RPR−/TPPA+, no history of treatment or active disease; Group 4: CIA+/RPR−/TPPA−, false-positive CIA. Results A total of 144 women delivered with reactive CIA: 38 (26%) in Group 1, 69 (48%) in Group 2, 20 (14%) in Group 3, and 17 (12%) in Group 4. Mean (±standard deviation) S/CO ratio was 18.3 ± 5.4, 12.1 ± 5.3, 9.1 ± 4.6, and 1.9 ± 0.8, respectively (p Conclusion Women with active syphilis based on treatment history, clinical staging, and laboratory indices have higher CIA S/CO ratio and are more likely to deliver neonates with overt evidence of congenital syphilis.

Objective To examine blood pressure patterns across pregnancy in women with treated chronic hypertension according to the occurrence of severe preeclampsia, growth restriction, and preterm birth34 weeks. Methods This retrospective descriptive case study included only pregnant women receiving antihypertensive therapy. Using a random effects model, mean arterial pressures were plotted across gestation for women with and without preeclampsia, fetal growth restriction, and preterm birth34 weeks with differences analyzed for each curve. Results Between January 2002 and December 2014, 447 women met inclusion criteria. Of these women, 65% developed severe preeclampsia, 24% delivered an infant weighing10th percentile, and 15% had a preterm birth34 weeks. Women diagnosed with either preeclampsia (23.3 vs 26.4 weeks; mean difference, 3.1 weeks; 95% confidence interval [CI], 2.3-4.3), fetal growth restriction (23.5 vs 24.9 weeks; mean difference, 1.4 weeks; 95% CI, 0.2-2.6), or preterm birth (19.8 vs 24.9 weeks; mean difference, 5.1 weeks; 95% CI, 3.7-6.9) reached a blood pressure nadir at a significantly earlier gestational age than those who did not. Conclusion For pregnant women with treated chronic hypertension, blood pressure patterns differ significantly in those who develop severe preeclampsia, fetal growth restriction, and preterm birth34 weeks.

Pregnant women living with HIV are at risk for loss to follow-up and viral rebound after delivery. We conducted a retrospective cohort study of women with HIV who delivered at Parkland Hospital, Dallas, to identify factors associated with postpartum loss to HIV care 1 year after delivery. Logistic regression was used to identify factors predicting loss to follow-up. For a subset of women, we compared odds of viremia detectable at delivery and postpartum among women with higher versus lower pill burden regimens. We included 604 women with HIV who delivered between 2005 and 2015. Three hundred ninety-one (65%) women completed at least one visit with an HIV provider within 1 year of delivery. The follow-up rate among black, non-Hispanic women was 65%; 57% for white, non-Hispanic women; and 78% for Hispanic women. Women without follow-up presented for prenatal care later (17 vs. 11 weeks, p 0.001), and were less likely to be on antiretroviral therapy at initial prenatal visit (29% vs. 49%, p 0.001). Factors predicting loss to follow-up in multivariate analysis included low-level viremia at delivery [adjusted odds ratio (aOR) = 2.85, 95% confidence interval (CI) = 1.73-4.71] and failure to return for a postpartum visit (aOR = 3.19, 95% CI = 2.07-4.94). High antiretroviral pill burden (≥6 pills daily) was associated with viremia (1000 copies/mL) at the first prenatal visit (OR = 8.7, 95% CI = 4.6-16.6) through 1 year postpartum (OR = 2.3, 95% CI = 1.2-4.4). Viremia at delivery, failure to return for a postpartum visit, and high pill burden during pregnancy are predictors of postpartum loss to HIV care.

An operationally efficient CDI mediated tandem coupling and cyclization reaction to generate [1,2,4]triazolo[4,3-a]pyridines has been reported. The reaction conditions and scope were investigated, and the methodology was demonstrated in batch mode as well as in a continuous process.

Adverse maternal outcomes associated with chronic hypertension include accelerated hypertension and resultant target organ damage. One example is long-standing hypertension leading to maternal cardiac dysfunction. Our group has previously identified that features of such injury manifest as cardiac remodeling with left ventricular hypertrophy. Moreover, these features of cardiac remodeling identified in women with chronic hypertension during pregnancy were associated with adverse perinatal outcomes. Recent definitions of maternal cardiac remodeling using echocardiography have been expanded to include measurements of wall thickness. We hypothesized that these new features characterizing cardiac remodeling in women with chronic hypertension may also be associated with adverse perinatal outcomes.There were 3 aims in this study of women with treated chronic hypertension during pregnancy: to (1) apply the updated definitions of maternal cardiac remodeling; (2) elucidate whether these features of cardiac remodeling were associated with adverse perinatal outcomes; and (3) determine which, if any, of the newly defined cardiac remodeling strata were most damaging when compared to women with normal cardiac geometry.This was a retrospective study of women with treated chronic hypertension during pregnancy delivered from January 2009 through January 2016. Cardiac remodeling was categorized by left ventricular mass index and relative wall thickness into 4 groups determined using the 2015 American Society of Echocardiography guidelines: normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Perinatal outcomes were analyzed according to each category of cardiac remodeling compared with outcomes in women with normal geometry.A total of 314 women with treated chronic hypertension underwent echocardiography at a mean gestational age of 17.9 weeks. There were no differences between maternal age (P = .896), habitus (P = .36), or duration of chronic hypertension (P = .212) among the 4 groups. Abnormal cardiac remodeling was found in 51% and was significantly associated with increased rates of superimposed preeclampsia (P = .015), preterm birth (P.001), and neonatal intensive care admission (P = .003). These outcomes reached the greatest significance when comparisons were made between eccentric hypertrophy and normal geometry.Using current American Society of Echocardiography guidelines, 51% of women with treated chronic hypertension during pregnancy have some degree of abnormal cardiac remodeling. Any suggestion of maternal cardiac remodeling, regardless of subtype, was associated with increased risks for superimposed preeclampsia and preterm birth with its resultant perinatal sequelae. Eccentric ventricular hypertrophy, previously thought to mimic exercise physiology, appears to be the most associated with adverse perinatal outcomes. Despite evidence of cardiac remodeling, ejection fraction was preserved.

Amlodipine is rarely used in the treatment of pregnant hypertensive women due to limited pharmacokinetic data during pregnancy and the postpartum period.To evaluate the pharmacokinetics of amlodipine besylate in the peri-partum period including quantities of placental passage, breast milk excretion and infant exposure.This was a prospective study of pregnant women who were prescribed 5 mg of amlodipine daily for treatment of chronic hypertension and delivered at term. Cord and maternal blood samples were collected at delivery. On postpartum day 2, six paired maternal plasma and breast milk samples were obtained at 4, 6, 8, 12, 15 and 24 h following amlodipine dosing. Infant plasma samples were collected 24-48 h after delivery. All samples were analyzed for amlodipine concentration. A one compartment, first-order model was used to calculate pharmacokinetic estimates for maternal plasma.Of the 16 patients enrolled in the study, 11 had cord blood and maternal serum collected at delivery, of which only 6 produced sufficient breast milk for sampling. Amlodipine was detected in infant cord blood plasma with a mean concentration of 0.49 ± 0.29 ng/mL compared to mean maternal serum level of 1.27 ± 0.84 ng/mL. Amlodipine concentrations in both in breast milk and infant plasma were undetectable at the lower limit of assay detection (0.1 ng/mL). In the immediate postpartum period, the amlodipine elimination half-life was 13.7 ± 4.9 h, the area under the curve was 53.4 ± 19.8 ng*h/mL and the peak concentration was 2.0 ± 1.0 ng/mL.Amlodipine does cross the placenta in measurable quantities, but is not detected in breast milk or infant plasma at 24-48 h of life indicating that it is likely safe to use during the peripartum period.

Background Ventricular hypertrophy is a known sequela of long-standing chronic hypertension with associated morbidity and mortality. Objective We sought to assess the frequency and importance of left ventricular hypertrophy in gravidas treated for chronic hypertension during pregnancy. Study Design This was a retrospective study of pregnant women with chronic hypertension who were delivered at our hospital from January 2009 through February 2015. All women who were given antihypertensive therapy underwent maternal echocardiography and were managed in a dedicated, high-risk prenatal clinic. Left ventricular hypertrophy was defined using the criteria of the American Society of Echocardiography as left ventricular mass indexed to maternal body surface area with a value of >95 g/m 2 . Maternal and infant outcomes were then analyzed according to the presence or absence of left ventricular hypertrophy. Results Of 253 women who underwent echocardiography, 48 (19%) met criteria for left ventricular hypertrophy. Women in this latter cohort were significantly more likely to be African American ( P = .031), but there were no other demographic differences. More than 85% of the entire cohort had a body mass index >30 kg/m 2 and a third of all women had class III obesity with a body mass index of >40 kg/m 2 . Importantly, duration of chronic hypertension ( P = .248) and gestational age at time of echocardiography ( P = .316) did not differ significantly between the groups. Left ventricular function was preserved in both groups as measured by left ventricular ejection fraction ( P = .303). Those with ventricular hypertrophy were at greater risk to be delivered preterm ( P = .001), to develop superimposed preeclampsia ( P = .028), and to have an infant requiring intensive care ( P = .023) when compared with women without ventricular hypertrophy. These findings persisted after adjustment for age, race, and parity. The gestational age at delivery according to measured left ventricular size was also examined and with increasing ventricular mass there was a significant association with the severity of preterm birth ( P Conclusion Left ventricular hypertrophy was identified in 1 in 5 women given antepartum treatment for chronic hypertension. Further analysis showed that these women were at significantly greater risk for superimposed preeclampsia and its attendant perinatal sequelae of preterm birth.

Walker Lake, Nevada, a saline desert lake, has been undergoing loss of stream inflows, lowering of lake level, and concentration of dissolved salts for over a century due to agricultural diversions of water. This lake is or has been inhabited by native fish and visited by many species of waterbirds that depend on productive invertebrate life for food resources. The extent to which salinity limits the present and future viability of resident invertebrate fauna was evaluated using salt-tolerance bioassays and studies of salinity effects on growth and behavior in larval stages of the midges Cricotopus ornatus and Tanypus grodhausi, and nymphs of the damselfly Enallagma clausum. We found that salinities into and above a range of 20–25 g/L present either lethal limits or sublethal inhibitions to survival and growth that will eliminate or substantially reduce the current community of common benthic invertebrates. All species survived best at salinities below the current ambient level, suggesting these populations are already under stress. The 72-h LC-50 for Cricotopus was 25 g/L, and while mature damselfly nymphs were somewhat more tolerant, early instars survived for only short times in increased salinity. Damselflies also grew more slowly and fed less when salinity increased from 20 to 30 g/L. A conservation level for the lake that incorporates survival of native fish and recovers diversity and viability of invertebrate life should be within the range of 10–15 g/L salinity of Walker Lake water.

To assess the importance of baseline proteinuria in women treated for chronic hypertension during pregnancy.This retrospective cohort study included women with chronic hypertension who received antihypertensive therapy in the first half of pregnancy and completed urine protein quantification before 20 weeks of gestation. Maternal and neonatal outcomes were analyzed according to the presence or absence of baseline proteinuria, defined as 300 mg or greater per 24 hours identified before 20 weeks of gestation. Frequencies of superimposed preeclampsia, preterm birth, and small-for-gestational-age neonates were further evaluated according to stratified urine protein excretion levels from less than 50 mg to greater than 1,000 mg/24 hours.Between January 2002 and December 2014, a total of 447 women met inclusion criteria. Of these, 56 (13%) had baseline proteinuria. Women with baseline proteinuria were statistically significantly more likely to develop superimposed preeclampsia (79% compared with 49%), deliver preterm (18% compared with 6% 30 weeks of gestation or less, 34% compared with 17% 34 weeks of gestation or less, and 48% compared with 26% less than 37 weeks of gestation), and deliver an small-for-gestational-age neonate (41% compared with 22% less than the 10th percentile, 20% compared with 9% less than the third percentile) when compared with women who did not have proteinuria (all P.05). Furthermore, the rates of superimposed preeclampsia and small for gestational age were significantly increased as 24-hour protein excretion levels increased across stratified levels (P for trend .002 and .015, respectively). When proteinuria levels less than 300 mg/d were analyzed separately, a significant association was observed for rates of superimposed preeclampsia and preterm birth.In pregnant women with treated chronic hypertension, baseline proteinuria was significantly associated with increased rates of preeclampsia, preterm birth, and growth restriction-even at proteinuria values previously considered to be within normal range (less than 300 mg/d).

An operationally efficient CDI mediated tandem coupling and cyclization reaction to generate [1,2,4]triazolo[4,3-a]pyridines has been reported. The reaction conditions and scope were investigated, and the methodology was demonstrated in batch mode as well as in a continuous process.

To estimate the rate of early-onset group B streptococcal (GBS) neonatal sepsis with combined maternal and neonatal chemoprophylaxis.Since 1995, GBS chemoprophylaxis at our institution has consisted of intrapartum antibiotic prophylaxis to all women with identified risk factors. In addition, a single dose of penicillin G was administered within 1 hour of birth to all newborns without clinical signs or symptoms of infection. All neonates born between January 1, 2000, and December 31, 2008, and who developed early-onset (occurring at 72 hours of age or younger) invasive bacterial disease were identified. Incidence rates for sepsis resulting from GBS and other organisms were estimated. Compliance with risk factor identification and appropriate treatment was also ascertained. Rates of β-lactam resistance among cases of neonatal disease caused by Gram-negative organisms were calculated.Ninety-four cases of early-onset GBS sepsis were identified among 143,467 live births with a rate of 0.66 per 1,000 births (0.53-0.80 per 1,000). Of available GBS sensitivities, 8.8% demonstrated clindamycin resistance, and 26.6% were resistant to erythromycin. Thirty-four cases of non-GBS early-onset sepsis were identified for a rate of 0.24 per 1,000 live births. Of available sensitivity reports, 42.1% of Gram-negative isolates were sensitive to β-lactams. No significant difference in rates of early-onset GBS disease was found between the years 1995 and 2008.The sustained rates in early-onset GBS sepsis from 1995 to 2008, along with the low rates of neonatal disease caused by other pathogens, confirms the continued feasibility and efficacy of a combined maternal and neonatal GBS chemoprophylaxis.

Walker Lake, a terminal salt lake in western Nevada, is undergoing rapid changes because of falling lake level and rising salinity, affecting the potential habitat of benthic invertebrates that supply food to native fish and birds. Benthic invertebrate surveys were conducted within different substratum size classes and macrophyte beds in the nearshore littoral shallows ( 10 m) zones of the lake. Samples were dominated by the chironomid midges Cricotopus ornatus and Tanypus grodhausi; the damselfly Enallagma clausum; and an oligochaete worm of the genus Monopylephorus. Midges showed distinct depth preferences, with Cricotopus found primarily in the shallow littoral, and Tanypus found in the lower littoral and profundal regions. Enallagma occurred throughout the littoral region but was reduced in abundance below 10 m. Cricotopus and Enallagma were most abundant on cobble rock substratum and macrophytes. Sand and small gravel substrata supported few invertebrates except oligochaetes, which were most common in shallow littoral areas. The extent of Ruppia beds was determined using hydroacoustic sounding and showed that these beds were most well-developed in a zone from 1.25 to 5 m depth. The estimated area of productive shallow littoral zone habitat at different lake levels showed that coverage was lowest near the current surface elevation. Rising lake levels would result in expansion of suitable habitat area, and while falling levels could also expand nearshore habitat, this would likely occur on areas of poorer substratum quality and under high salinities that may inhibit growth.

The Ritter reaction utilizing tert-butyl acetate as the tert-butyl cation source was investigated by in situ FTIR and calorimetry under various reaction conditions. It was established that, when a batch mode reaction in acetic acid was performed, minimal isobutylene was evolved into the headspace, thereby avoiding pressurization of the reaction vessel. The safety of these conditions is due to the equilibrium of isobutylene and acetic acid with tert-butyl acetate. In addition, the observation of acetic anhydride provided insight into the role of acetic acid in the mechanistic pathway.

To estimate if neonates with early-onset group B streptococcus (GBS) sepsis have clinical evidence of fetal infection during labor or at delivery.Retrospective cohort study of all neonates diagnosed with GBS sepsis by culture and clinical findings within the first 72 hours of life from January 1, 2000, through December 31, 2008, at Parkland Health and Hospital System. Medical records were reviewed and maternal, neonatal, and delivery data were ascertained. These neonates then were compared with all neonates delivered during the same time period.During the study period, 143,384 live-born neonates were delivered at our institution; 94 were diagnosed with early-onset GBS sepsis. The majority of these neonates (n=93) were diagnosed with early-onset GBS within the first hour of life. Neonates with early-onset GBS sepsis had a significant increase in preterm delivery, cesarean delivery (total and for fetal distress), 1- and 5-minute Apgar scores of 3 or lower, umbilical cord pH less than 7.0, and a base deficit of 12 mmol/L or higher. In addition, nulliparity differed between those with early-onset GBS and those without (74% compared with 33%, P.001) as did chorioamnionitis rates (62% compared with 8%, P.001).We believe that these findings are compelling evidence that fetuses with early-onset GBS may have signs of sepsis peripartum. We hypothesize that these data support the concept that early-onset GBS represents a spectrum of infection that often precedes birth.

Objective. To examine risk factors for false positive HIV enzyme immunoassay (EIA) testing at delivery. Study Design. A review of pregnant women who delivered at Parkland Hospital between 2005 and 2008 was performed. Patients routinely received serum HIV EIA testing at delivery, with positive results confirmed through immunofluorescent testing. Demographics, HIV, hepatitis B surface antigen (HBsAg), and rapid plasma reagin (RPR) results were obtained. Statistical analyses included Pearson's chi-square and Student's t-test. Results. Of 47,794 patients, 47,391 (99%) tested negative, 145 (0.3%) falsely positive, 172 (0.4%) positive, and 86 (0.2%) equivocal or missing HIV results. The positive predictive value of EIA was 54.3%. Patients with false positive results were more likely nulliparous (43% versus 31%, 𝑃 0 . 0 0 1 ) and younger ( 2 3 . 9 ± 5 . 7 versus 2 6 . 2 ± 5 . 9 years, 𝑃 0 . 0 0 1 ). HIV positive patients were older than false positive patients and more likely positive for HBsAg and RPR. Conclusion. False positive HIV testing at delivery using EIA is associated with young maternal age and nulliparity in this population.

The purpose of this study was to determine pharmacokinetic parameters for oseltamivir in all trimesters of pregnancy. Thirty pregnant women, 10 per trimester, who were receiving oseltamivir phosphate (75 mg) were recruited to study first-dose pharmacokinetics. Plasma samples were obtained at 0, 0.5, 1, 2, 4, 8, and 12 hours after the first dose. Samples were analyzed for oseltamivir and oseltamivir carboxylate levels. With the use of a noncompartmental model, we estimated the area-under-the-curve, maximum concentration, time-to-maximum concentration, and half-life. There were no significant differences in the pharmacokinetics of oseltamivir by trimester, except for an increased half-life in the first trimester for oseltamivir phosphate and an increased maximum concentration in the third trimester for oseltamivir carboxylate. The levels of oseltamivir carboxylate that were observed were within the range that was needed to achieve inhibitory concentrations at 50% for pandemic H1N1. The pharmacokinetics of oseltamivir does not change significantly according to trimester of pregnancy.

False-positive HIV screening tests in pregnancy may lead to unnecessary interventions in labor. In 2014, the Centers for Disease Control and Prevention released a new algorithm for HIV diagnosis using a fourth-generation screening test, which detects antibodies to HIV as well as p24 antigen and has a shorter window period compared with prior generations. A reactive screen requires a differentiation assay, and supplemental qualitative RNA testing is necessary for nonreactive differentiation assay. One screening test, the ARCHITECT Ag/Ab Combo assay, is described to have 100% sensitivity and99% specificity in nonpregnant populations; however, its clinical performance in pregnancy has not been well described.The objective of the study was to determine the performance of the ARCHITECT assay among pregnant women at a large county hospital and to assess whether the relative signal-to-cutoff ratio can be used to differentiate between false-positive vs confirmed HIV infections in women with a nonreactive differentiation assay.This is a retrospective review of fourth-generation HIV testing in pregnant women at Parkland Hospital between June 1, 2015, and Jan. 31, 2017. We identified gravidas screened using the ARCHITECT Ag/Ab Combo assay (index test), with reflex to differentiation assay. Women with reactive ARCHITECT and nonreactive differentiation assay were evaluated with a qualitative RNA assay (reference standard). We calculated sensitivity, specificity, predictive value, and false-positive rate of the ARCHITECT screening assay in our population and described characteristics of women with false-positive HIV testing vs confirmed infection. Among women with a nonreactive differentiation assay, we compared interventions among women with and without a qualitative RNA assay result available at delivery and examined relative signal-to-cutoff ratios of the ARCHITECT assay in women with false-positive vs confirmed HIV infection.A total of 21,163 pregnant women were screened using the ARCHITECT assay, and 190 tested positive. Of these, 33 of 190 (17%) women had false-positive HIV screening tests (28 deliveries available for analysis), and 157 of 190 (83%) had confirmed HIV-1 infection (140 available for analysis). Diagnostic accuracy of the ARCHITECT HIV Ag/Ab Combo assay in our prenatal population (with 95% confidence interval) was as follows: sensitivity, 100% (97.7-100%); specificity, 99.8% (99.8-99.9%); positive likelihood ratio, 636 (453-895); negative likelihood ratio, 0.0 (NA); positive predictive value, 83% (77-88%); and false positive rate, 0.16% (0.11-0.22%), with a prevalence of 7 per 1000. Women with false-positive HIV testing were younger and more likely of Hispanic ethnicity. A qualitative RNA assay (reference standard) was performed prenatally in 24 (86%) and quantitative viral load in 22 (92%). Interventions occurred more frequently in women without a qualitative RNA assay result available at delivery, including intrapartum zidovudine (75% vs 4%, P = .002), breastfeeding delay (75% vs 8%, P = .001), and neonatal zidovudine initiation (75% vs 4%, P = .002). The ARCHITECT signal-to-cutoff ratio was significantly lower for women with false-positive HIV tests compared with those with established HIV infection (1.89 [1.27, 2.73] vs 533.65 [391.12, 737.22], respectively, P.001).While the performance of the fourth-generation ARCHITECT HIV Ag/Ab Combo assay among pregnant women is comparable with that reported in nonpregnant populations, clinical implications of using a screening test with a positive predictive value of 83% in pregnancy are significant. When the qualitative RNA assay result is unavailable, absence of risk factors in combination with an ARCHITECT HIV Ag/Ab assay S/Co ratio5 and nonreactive differentiation assay provide sufficient evidence to support deferral of unnecessary intrapartum interventions while awaiting qualitative RNA results.

Approaches physicians can use to encourage pregnant patients to stop smoking while preserving the patient-physician relationship. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.

Background. Previous studies examining protease inhibitor use in pregnancy and the rate of preterm and small-for-gestational-age infants have yielded conflicting results.Methods. This was a retrospective study of HIV-infected women who delivered singleton infants at our institution between 1984 and 2014. Women with protease inhibitor use were compared to women on regimens without a protease inhibitor as well as those who received no antepartum antiretroviral therapy. Infants were considered preterm if less than 37 completed weeks of gestation and small-for-gestational-age if less than 10th percentile.Results. During the study period 1,004 pregnancies met inclusion criteria. Of those, 597 received a protease inhibitor as part of their regimen, 230 ART without a protease inhibitor, and 177 no ART. There was no difference in the rate of preterm birth between groups who received ART with or without a protease inhibitor, 14% versus 13%. There was no difference in the rate of small-for-gestational-age infants between the three groups. Use of a protease inhibitor was associated with a greater fall in viral load during pregnancy,p<0.001.Conclusion. In this population with access to prenatal care and ART, treatment with protease inhibitors was associated with a greater fall in viral load, but not an increase in small or preterm infants.

To establish the role of clinical chorioamnionitis as an independent risk factor for recurrence in a subsequent pregnancy.This was a historical cohort study of pregnant women who had their first and second deliveries at our institution between January 1988 and May 2005. The index pregnancy was restricted to those who delivered vaginally. Data were collected from a continuously updated obstetric database and included demographic and labor characteristics and neonatal outcomes. Chorioamnionitis was diagnosed clinically.The study population consisted of 23,397 women. During the index pregnancy, 10% of women developed chorioamnionitis. This group was significantly different from the rest of the cohort in terms of age, ethnicity, length of labor, epidural analgesia, use of internal monitors, and incidence of prolonged rupture of membranes. In the second pregnancy, 6% of those women again developed chorioamnionitis compared with 2% of women who did not have chorioamnionitis in the first pregnancy (odds ratio 2.93, 95% confidence interval 2.40-3.57). After adjusting for the above confounders, the increased risk of recurrence persisted (odds ratio 1.85, 95% confidence interval 1.49-2.30).Women delivering vaginally who were diagnosed with chorioamnionitis during their first pregnancy are at increased risk for chorioamnionitis in a subsequent pregnancy. This supports the concept that there may be a predisposition to chorioamnionitis that should be further investigated.II-2.