Natali Aziz

Antibody Treatment Promotes Compensation for Human Cytomegalovirus-Induced Pathogenesis and a Hypoxia-Like Condition in Placentas with Congenital Infection

Human cytomegalovirus (HCMV) is the major viral cause of birth defects worldwide. Affected infants can have temporary symptoms that resolve soon after birth, such as growth restriction, and permanent disabilities, including neurological impairment. Passive immunization of pregnant women with primary HCMV infection is a promising treatment to prevent congenital disease. To understand the effects of sustained viral replication on the placenta and passive transfer of protective antibodies, we performed immunohistological analysis of placental specimens from women with untreated congenital infection, HCMV-specific hyperimmune globulin treatment, and uninfected controls. In untreated infection, viral replication proteins were found in trophoblasts and endothelial cells of chorionic villi and uterine arteries. Associated damage included extensive fibrinoid deposits, fibrosis, avascular villi, and edema, which could impair placental functions. Vascular endothelial growth factor and its receptor fms-like tyrosine kinase 1 (Flt1) were up-regulated, and amniotic fluid contained elevated levels of soluble Flt1 (sFlt1), an antiangiogenic protein, relative to placental growth factor. With hyperimmune globulin treatment, placentas appeared uninfected, vascular endothelial growth factor and Flt1 expression was reduced, and sFlt1 levels in amniotic fluid were lower. An increase in the number of chorionic villi and blood vessels over that in controls suggested compensatory development for a hypoxia-like condition. Taken together the results indicate that antibody treatment can suppress HCMV replication and prevent placental dysfunction, thus improving fetal outcome.

Neonatal outcomes in the setting of preterm premature rupture of membranes complicated by chorioamnionitis.

Objective. To examine the outcomes of neonates born to women with chorioamnionitis in the setting of preterm premature rupture of membranes (PPROM). Methods. A retrospective cohort study was conducted of deliveries with diagnosis of PPROM between 24 and 34 weeks of gestation at an academic medical center. Patients who delivered with the diagnosis of clinical chorioamnionitis were compared with patients who delivered without this diagnosis. Neonatal outcomes including Apgar scores, intracranial hemorrhage (ICH), sepsis, pneumonia, respiratory distress syndrome (RDS), and necrotizing enterocolitis (NEC) were assessed. Dichotomous outcomes were compared using chi-square test. Multivariable regression analyses were performed to control for potential confounding variables. Results. Of the 1153 patients diagnosed with PPROM, 29.0% were diagnosed with chorioamnionitis prior to delivery. Neonates born to mothers with a diagnosis of chorioamnionitis in the setting of PPROM had higher incidences (34.8%) of low 5-min Apgar scores, RDS, NEC, ICH, and pneumonia compared with 22.9% in neonates born to mothers without chorioamnionitis (p < 0.001). Conclusions. Patients who develop chorioamnionitis in the setting of PPROM are at higher risk for adverse neonatal outcomes compared with patients without chorioamnionitis in the setting of PPROM.

Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy

Significance Pregnant women are subject to increased morbidity and mortality after influenza-virus infection. Pregnancy-induced suppression of the cellular immune system to promote fetal tolerance has been suggested as a potential mechanism. Here, we report that, whereas pregnant women indeed have decreased natural killer (NK)- and T-cell functional responses after nonspecific stimulation with phorbol 12-myristate 13-acetate and ionomycin, they have significantly increased NK- and T-cell responses to influenza virus compared with nonpregnant women. Intriguingly, these differences were present prior to influenza vaccination and were further enhanced after vaccination. Collectively, our data suggest a model in which an enhanced inflammatory response to influenza during pregnancy results in additional pathology in pregnant women, providing a potential explanation for their disproportionate morbidity and mortality. Pregnant women experience increased morbidity and mortality after influenza infection, for reasons that are not understood. Although some data suggest that natural killer (NK)- and T-cell responses are suppressed during pregnancy, influenza-specific responses have not been previously evaluated. Thus, we analyzed the responses of women that were pregnant (n = 21) versus those that were not (n = 29) immediately before inactivated influenza vaccination (IIV), 7 d after vaccination, and 6 wk postpartum. Expression of CD107a (a marker of cytolysis) and production of IFN-γ and macrophage inflammatory protein (MIP) 1β were assessed by flow cytometry. Pregnant women had a significantly increased percentage of NK cells producing a MIP-1β response to pH1N1 virus compared with nonpregnant women pre-IIV [median, 6.66 vs. 0.90% (P = 0.0149)] and 7 d post-IIV [median, 11.23 vs. 2.81% (P = 0.004)], indicating a heightened chemokine response in pregnant women that was further enhanced by the vaccination. Pregnant women also exhibited significantly increased T-cell production of MIP-1β and polyfunctionality in NK and T cells to pH1N1 virus pre- and post-IIV. NK- and T-cell polyfunctionality was also enhanced in pregnant women in response to the H3N2 viral strain. In contrast, pregnant women had significantly reduced NK- and T-cell responses to phorbol 12-myristate 13-acetate and ionomycin. This type of stimulation led to the conclusion that NK- and T-cell responses during pregnancy are suppressed, but clearly this conclusion is not correct relative to the more biologically relevant assays described here. Robust cellular immune responses to influenza during pregnancy could drive pulmonary inflammation, explaining increased morbidity and mortality.

A First Look at Chorioamnionitis Management Practice Variation among US Obstetricians

Objective. To examine practice patterns for diagnosis and treatment of chorioamnionitis among US obstetricians. Study Design. We distributed a mail-based survey to members of the American College of Obstetricians and Gynecologists, querying demographics, practice setting, and chorioamnionitis management strategies. We performed univariable and multivariable analyses. Results. Of 500 surveys distributed, 53.8% were returned, and 212 met study criteria and were analyzed. Most respondents work in group practice (66.0%), perform >100 deliveries per year (60.0%), have been in practice >10 years (77.3%), and work in a nonuniversity setting (85.1%). Temperature plus one additional criterion (61.3%) was the most common diagnostic strategy. Over 25 different primary antibiotic regimens were reported, including use of a single agent by 30.0% of respondents. A wide range of postpartum antibiotic duration was reported from no postpartum treatment (34.5% after vaginal delivery, 11.3% after cesarean delivery) to 48 hours of postpartum treatment (24.7% after vaginal delivery, 32.1% after cesarean delivery). No practitioner characteristic was independently associated with diagnostic or therapeutic strategies in multivariable analysis. Conclusion. There is a wide variation in contemporary clinical practices for the management of chorioamnionitis. This may represent a dearth of level I evidence. Future prospective clinical trials may provide more evidence-based practice recommendations for diagnosis and treatment of chorioamnionitis.

Factors and outcomes associated with longer latency in preterm premature rupture of membranes

Objective. To examine factors and outcomes associated with latency in preterm premature rupture of membranes (PPROM). Methods. A retrospective cohort study was conducted of all deliveries with a diagnosis of PPROM at 24–34 weeks of gestation at an academic medical center for the period 1980–2001. Gestational age at PPROM was examined as the primary independent variable. Primary outcome was duration from rupture of membranes until delivery. The association with neonatal and maternal perinatal morbidity was examined with duration of latency. Dichotomous outcomes were compared using the Chi-square test. Multivariable regression analyses were performed to control for potential confounding variables. Results. One thousand one hundred and sixty-eight patients were identified. Latency duration was inversely associated with gestational age at time of PPROM (p < 0.001). These findings persisted when potential confounders were controlled for in multivariable models. Neonatal sepsis and chorioamnionitis were not associated with increased duration of latency. Conclusion. Earlier gestational age at time of PPROM is associated with longer latency duration, which, in turn, is not associated with increased neonatal sepsis or chorioamnionitis. These data can be used to counsel patients with PPROM about expected duration of latency and outcomes.

Comparison of rapid intrapartum screening methods for group B streptococcal vaginal colonization

Objective. To compare optical immunoassay (OIA) and rapid polymerase-chain reaction (PCR) with enrichment broth culture for intrapartum detection of vaginal group B streptococcal (GBS) colonization. Methods. Paired vaginal swabs from 315 consecutive term pregnant women at the time of presentation for delivery to a university medical center were tested for GBS by OIA, PCR, and culture. Sensitivity, specificity, and positive and negative predictive values were calculated. Results. Vaginal colonization was identified by culture in 56 subjects (17.8%). The sensitivity of OIA (7.1%, 95% confidence interval 5.1–9.5%) was significantly less than that of unenhanced rapid PCR (62.5%, 95% CI 48.5–74.8%). Conclusions. Neither PCR nor OIA is sufficiently sensitive for intrapartum detection of vaginal GBS colonization. Rapid PCR is more sensitive, but further improvements in technique to increase sensitivity will be necessary if PCR is to have a useful role in the management of women at time of presentation for delivery.

Postpartum uterine arteriovenous fistula.

BACKGROUND: Uterine arteriovenous communications are uncommon lesions that may be associated with life-threatening postpartum and postinstrumentation hemorrhage. CASE: A primigravida presented with infected retained products of conception. Excessive hemorrhage of unclear etiology occurred at dilation and curettage. After a second episode of bleeding, the patient received a diagnosis of uterine arteriovenous fistula. CONCLUSION: Uterine arteriovenous communications should be included in the differential diagnosis in patients with excessive postpartum or postinstrumentation bleeding. Color and spectral flow Doppler can aid diagnosis and clinical management.

Group B Streptococcus colonization by HIV status in pregnant women: prevalence and risk factors.

OBJECTIVES To examine the prevalence of and risk factors for group B Streptococcus (GBS) colonization in an HIV-infected and uninfected pregnant population. METHODS We conducted a retrospective double cohort study comparing the prevalence of GBS colonization between 90 HIV-infected and 1947 uninfected women attending prenatal care at San Francisco General Hospital, an urban public hospital affiliated with the University of California, San Francisco. We investigated risk factors for GBS colonization, including age, ethnicity, obesity, diabetes, alcohol or illicit drug use, tobacco use, degree of immunosuppression, and infectious comorbidities. RESULTS In the multivariable analysis, HIV serostatus was not independently associated with GBS colonization (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.62-1.62). Obesity (OR 1.53, 95% CI 1.13-2.07), white race (OR 1.89, 95% CI 1.30-2.75), and black race (OR 1.78, 95% CI 1.32-2.41) were independently associated with increased maternal GBS colonization. Among HIV-infected women, univariate analysis showed an association between GBS colonization and detectable HIV-1 plasma viral load at the time of rectovaginal culture (p<0.05). Mean CD4 lymphocyte count, infectious comorbidities, and HIV-1 plasma viral load at delivery were not associated with GBS colonization in HIV-infected pregnant women. CONCLUSIONS HIV-1 infection is not a risk factor for GBS colonization among an ethnically diverse pregnant population at San Francisco General Hospital, although our data suggest that among HIV-infected women, plasma HIV-1 viremia may be associated with GBS colonization. Interventions that diminish HIV-1 plasma viral load and, perhaps, genital tract shedding of HIV may be associated with a reduced risk of GBS colonization in future studies.

Pregnancy Does Not Attenuate the Antibody or Plasmablast Response to Inactivated Influenza Vaccine

BACKGROUND Inactivated influenza vaccine (IIV) is recommended during pregnancy to prevent influenza infection and its complications in pregnant women and their infants. However, the extent to which pregnancy modifies the antibody response to vaccination remains unclear, and prior studies have focused primarily on hemagglutinin inhibition (HI) titers. A more comprehensive understanding of how pregnancy modifies the humoral immune response to influenza vaccination will aid in maximizing vaccine efficacy. METHODS Healthy pregnant women and control women were studied prior to, 7 days after, and 28 days after vaccination with IIV. HI titers, microneutralization (MN) titers, and the frequency of circulating plasmablasts were evaluated in pregnant versus control women. RESULTS Pregnant women and control women mount similarly robust serologic immune responses to IIV, with no significant differences for any influenza strain in postvaccination geometric mean HI or MN titers. HI and MN titers correlate, though MN titers demonstrate more robust changes pre- versus postvaccination. The induction of circulating plasmablasts is increased in pregnant women versus controls (median fold-change 2.60 vs 1.49 [interquartile range, 0.94-7.53 vs 0.63-2.67]; P = .03). CONCLUSIONS Pregnant women do not have impaired humoral immune responses to IIV and may have increased circulating plasmablast production compared to control women.

Interferon gamma release assay compared with the tuberculin skin test for latent tuberculosis detection in pregnancy.

OBJECTIVE: To estimate agreement and correlation between the tuberculin skin test and an interferon gamma release assay for detecting latent tuberculosis (TB) infection in pregnant women. METHODS: We conducted a cross-sectional study of pregnant women initiating prenatal care at a university-affiliated public hospital between January 5, 2009, and March 15, 2010. Eligible women received a questionnaire about TB history and risk factors as well as the tuberculin skin test and phlebotomy for the interferon gamma release assay. Agreement and correlation between tests were estimated, and different cutoffs for interferon gamma release assay positivity were used to assess effect on agreement. Furthermore, predictors of test positivity and test discordance were evaluated using multivariable analysis. RESULTS: Of the 220 enrolled women, 199 (90.5%) returned for tuberculin skin test evaluation. Over 70% were Hispanic and 65% were born in a country with high TB prevalence. Agreement between the tuberculin skin test and interferon gamma release assay was 77.39 (&kgr;=0.26). This agreement was not significantly changed using different cutoffs for the assay. Birth bacille Calmette-Guérin vaccination was associated with tuberculin skin test positivity (odds ratio [OR] 4.33, 95% confidence interval [CI] 1.4–13.48, P=.01), but not interferon gamma release assay positivity. There were no statistically significant predictors of the tuberculin skin test and interferon gamma release assay result discordance; however, birth in a high-prevalence country was marginally associated with tuberculin skin test-positive and interferon gamma release assay-negative results (OR 2.94, 95% CI 0.86–9.97 P=.08). CONCLUSION: Comparing the tuberculin skin test and interferon gamma release assay results in pregnancy, concordance and agreement were poor. Given that much is still unknown about the performance of interferon gamma release assays in pregnancy, further research is necessary before the tuberculin skin test is abandoned for screening of latent TB infection in pregnancy. LEVEL OF EVIDENCE: III