William W. Andrews

Vaccine Prevention of Maternal Cytomegalovirus Infection

BACKGROUND Congenital infection with cytomegalovirus (CMV) is an important cause of hearing, cognitive, and motor impairments in newborns. METHODS In this phase 2, placebo-controlled, randomized, double-blind trial, we evaluated a vaccine consisting of recombinant CMV envelope glycoprotein B with MF59 adjuvant, as compared with placebo. Three doses of the CMV vaccine or placebo were given at 0, 1, and 6 months to CMV-seronegative women within 1 year after they had given birth. We tested for CMV infection in the women in quarterly tests during a 42-month period, using an assay for IgG antibodies against CMV proteins other than glycoprotein B. Infection was confirmed by virus culture or immunoblotting. The primary end point was the time until the detection of CMV infection. RESULTS We randomly assigned 234 subjects to receive the CMV vaccine and 230 subjects to receive placebo. A scheduled interim analysis led to a stopping recommendation because of vaccine efficacy. After a minimum of 1 year of follow-up, there were 49 confirmed infections, 18 in the vaccine group and 31 in the placebo group. Kaplan-Meier analysis showed that the vaccine group was more likely to remain uninfected during a 42-month period than the placebo group (P=0.02). Vaccine efficacy was 50% (95% confidence interval, 7 to 73) on the basis of infection rates per 100 person-years. One congenital infection among infants of the subjects occurred in the vaccine group, and three infections occurred in the placebo group. There were more local reactions (pain, erythema, induration, and warmth) and systemic reactions (chills, arthralgias, and myalgias) in the vaccine group than in the placebo group. CONCLUSIONS CMV glycoprotein B vaccine has the potential to decrease incident cases of maternal and congenital CMV infection. (ClinicalTrials.gov number, NCT00125502.)

Diagnosis and Management of Clinical Chorioamnionitis

Chorioamnionitis is a common complication of pregnancy associated with significant maternal, perinatal, and long-term adverse outcomes. Adverse maternal outcomes include postpartum infections and sepsis whereas adverse infant outcomes include stillbirth, premature birth, neonatal sepsis, chronic lung disease, and brain injury leading to cerebral palsy and other neurodevelopmental disabilities. Research in the past 2 decades has expanded understanding of the mechanistic links between intra-amniotic infection and preterm delivery as well as morbidities of preterm and term infants. Recent and ongoing clinical research into better methods for diagnosing, treating, and preventing chorioamnionitis is likely to have a substantial impact on short and long-term outcomes in the neonate.

Amniotic fluid interleukin-6: correlation with upper genital tract microbial colonization and gestational age in women delivered after spontaneous labor versus indicated delivery.

OBJECTIVE Our purpose was to determine whether amniotic fluid interleukin-6 is increased and inversely proportional to gestational age in women with chorioamnion colonization and spontaneous labor versus women delivered for medical or obstetric indications. STUDY DESIGN The chorioamnion and amniotic fluid were cultured at cesarean delivery for aerobic and anaerobic bacteria, fungi, mycoplasmas, Chlamydia trachomatis and Trichomonas vaginalis in 269 women with singleton gestations with intact membranes. The amniotic fluid interleukin-6 concentration was also determined. RESULTS Amniotic fluid interleukin-6 levels were (1) higher in women with spontaneous labor versus those with indicated deliveries (15.8 +/- 5.0 vs 2.2 +/- 0.2 ng/ml, p = 0.01), (2) inversely proportional to gestational age in women with spontaneous labor (< 34 weeks: 47.4 +/- 18.0 ng/ml vs > or = 34 weeks: 8.7 +/- 4.1 ng/ml, p = 0.001) but not in women with indicated deliveries (1.5 +/- 0.4 vs 2.4 +/- 0.3 ng/ml), (3) higher in women with a positive versus a negative chorioamnion (15.1 +/- 4.8 vs 3.0 +/- 0.8 ng/ml, p < 0.001) or amniotic fluid (17.4 +/- 7.7 vs 3.8 +/- 0.9 ng/ml, p < 0.001) culture, and (4) higher in women with a negative amniotic fluid but positive chorioamnion culture compared with women in whom both cultures were negative (10.0 +/- 4.4 vs 3.0 +/- 0.9 ng/ml, p = 0.002). CONCLUSIONS Amniotic fluid interleukin-6 levels are (1) higher and inversely proportional to gestational age in women with intact membranes and spontaneous labor versus indicated deliveries, (2) higher in women with one or more microorganisms in the chorioamnion or amniotic fluid, and (3) reflective of chorioamnion microbial colonization, even when the amniotic fluid culture is negative, and may be a useful clinical marker for infection-mediated preterm labor.

Periodontal disease and upper genital tract inflammation in early spontaneous preterm birth.

OBJECTIVE: To estimate the relationship between maternal periodontal disease and both early spontaneous preterm birth and selected markers of upper genital tract inflammation. METHODS: In this case-control study, periodontal assessment was performed in 59 women who experienced an early spontaneous preterm birth at less than 32 weeks of gestation, in a control population of 36 women who experienced an early indicated preterm birth at less than 32 weeks of gestation, and in 44 women with an uncomplicated birth at term (≥ 37 weeks). Periodontal disease was defined by the degree of attachment loss. Cultures of the placenta and umbilical cord blood, cord interleukin-6 levels, and histopathologic examination of the placenta were performed for all women. RESULTS: Severe periodontal disease was more common in the spontaneous preterm birth group (49%) than in the indicated preterm (25%, P = .02) and term control groups (30%, P = .045). Multivariable analyses, controlling for possible confounders, supported the association between severe periodontal disease and spontaneous preterm birth (odds ratio 3.4, 95% confidence interval 1.5–7.7). Neither histologic chorioamnionitis, a positive placental culture, nor an elevated cord plasma interleukin-6 level was significantly associated with periodontal disease (80% power to detect a 50% difference in rate of histological chorioamnionitis, α = 0.05). CONCLUSION: Women with early spontaneous preterm birth were more likely to have severe periodontal disease than women with indicated preterm birth or term birth. Periodontal disease was not associated with selected markers of upper genital tract inflammation. LEVEL OF EVIDENCE: II-2

Bacterial Vaginosis Assessed by Gram Stain and Diminished Colonization Resistance to Incident Gonococcal, Chlamydial, and Trichomonal Genital Infection

BACKGROUND We sought to assess the relationship between bacterial vaginosis (BV) assessed by Gram stain and incident trichomonal, gonococcal, and/or chlamydial genital infection. METHODS This longitudinal study included 3620 nonpregnant women aged 15-44 years who presented for routine care at 12 clinics in Birmingham, Alabama. Participants were assessed quarterly for 1 year. Vaginal smears were categorized by the Nugent Gram stain score (0-3, normal; 4-6, intermediate state; 7-10, BV). Pooled logistic regression was used to estimate the hazard ratios for the comparison of trichomonal, gonococcal, and chlamydial infection incidence in participants by Nugent score at the prior visit. Participants were censored at their first visit with a positive test result for trichomonal, gonococcal, and/or chlamydial infection. RESULTS Of the 10,606 eligible visits, 37.96% were classified by BV and 13.3% by positive detection of trichomonal, gonococcal, and/or chlamydial infection. An intermediate state or BV at the prior visit was associated with a 1.5-2-fold increased risk for incident trichomonal, gonococcal, and/or chlamydial infection (adjusted hazard ratio [AHR] for intermediate state, 1.41 [95% confidence interval {CI}, 1.12-1.76]; AHR for BV, 1.73 [95% CI, 1.42-2.11]; P= .058 for trend). Estimates were similar for trichomonal-only, gonococcal-only, and chlamydial-only infection outcomes. CONCLUSION BV microbiota as gauged by Gram stain is associated with a significantly elevated risk for acquisition of trichomonal, gonococcal, and/or chlamydial genital infection.

Vulvovaginal symptoms in women with bacterial vaginosis.

OBJECTIVE: A substantial, but highly variable, percentage of women with bacterial vaginosis are said to be asymptomatic. The purpose of this study was to estimate the prevalence of symptoms among women with bacterial vaginosis compared with women without bacterial vaginosis by direct, explicit, and detailed questioning of these women. METHODS: Women presenting for a routine health care visit at 12 health department clinics in Birmingham, Alabama, were recruited to participate in a longitudinal study of vaginal flora. At the first visit, they underwent a pelvic examination, lower genital tract microbiological evaluation, and an interview that included detailed questions regarding lower genital tract symptoms. The prevalence of symptoms among women with and without bacterial vaginosis (Gram stain score 7 or higher) was compared. RESULTS: Among 2,888 women without gonorrhea, Chlamydia, or trichomonas, 75% of women with and 82% of women without bacterial vaginosis never noted any vaginal odor in the past 6 months (P < .001). The corresponding values were 63% and 65% for never noting vaginal “wetness” (P = .02); 58% and 57% for vaginal discharge (P = .65); 91% and 86% for irritation (P = .004); 88% and 85% for itching (P = .64); and 96% and 94% for dysuria (P = .002), respectively. Cumulatively, 58% of women with bacterial vaginosis noted odor, discharge, and/or wetness in the past 6 months compared with 57% of women without bacterial vaginosis (P = .70). CONCLUSION: The 2 classic symptoms of bacterial vaginosis discharge and odor are each reported by a minority of women with bacterial vaginosis and are only slightly more prevalent than among women without bacterial vaginosis. LEVEL OF EVIDENCE: II-3

Choriodecidual Infection and Preterm Birth

Of all U.S. births, 11% occur preterm. These infants are responsible for the majority of perinatal mortality and morbidity. Infants at highest risk are those born weighing < 1000 g and those born at <28 weeks gestation. Recent evidence suggests that the majority of these preterm births are caused by bacterial infections of the chorioamnion, with the organisms originating in the vagina. The mechanisms leading to preterm labor and rupture of membranes involve an inflammatory response involving increased production of cytokines, prostaglandins, and metalloproteases. Results of treatment trials to eradicate the infection and reduce preterm birth have been mixed.

A Longitudinal Study of Vaginal Douching and Bacterial Vaginosis—A Marginal Structural Modeling Analysis

The etiology of bacterial vaginosis is unknown, and there are no long-term therapies for preventing this frequently recurring condition. Vaginal douching has been reported to be associated with bacterial vaginosis in observational studies. However, this association may be due to confounding by indication--that is, confounding by women douching in response to vaginal symptoms associated with bacterial vaginosis. The authors used marginal structural modeling to estimate the causal effect of douching on bacterial vaginosis risk while controlling for this confounding effect. In 1999-2002, nonpregnant women (n = 3,620) were recruited into a prospective study when they visited one of 12 public health clinics in Birmingham, Alabama, for routine care. Participants were assessed quarterly for 1 year. Bacterial vaginosis was based on a Nugents Gram stain score of 7 or higher. Thirty-two percent of participants douched in every study interval, and 43.0% never douched. Of the 12,349 study visits, 40.2% were classified as involving bacterial vaginosis. The relative risk for regular douching as compared with no douching was 1.21 (95% confidence interval: 1.08, 1.38). These findings indicate that douching confers increased risk of disruption of vaginal flora. In the absence of a large randomized trial, these findings provide the best evidence to date for a risk of bacterial vaginosis associated with douching.

Genital tract methicillin-resistant Staphylococcus aureus: risk of vertical transmission in pregnant women.

OBJECTIVE: To estimate the frequency of genital tract colonization by methicillin-resistant Staphylococcus aureus (MRSA) among pregnant women and evaluate the association of such colonization with infant outcome. METHODS: Between July 2003 and July 2006, anovaginal screening cultures for group B Streptococcus (GBS) were prospectively obtained in the third trimester (35 to less than 37 weeks of gestation) and were also processed for identification of Staphylococcus aureus including methicillin-resistant strains. Maternal colonization by MRSA was linked to a computerized database of invasive neonatal infections that occurred at our center during the study period. RESULTS: Among 5,732 mothers (who delivered 5,804 infants) with GBS screening cultures and infant infection data available, 22.9% were GBS-positive and 14.5% were positive for Staphylococcus aureus. A total of 24.3% of the Staphylococcus aureus isolates were MRSA. The overall MRSA colonization rate was 3.5%. Colonization by any Staphylococcus aureus (relative risk 1.6, 95% confidence interval 1.4–1.9) as well as MRSA (relative risk 2.2, 95% confidence interval 1.6–2.8) was significantly more common among GBS-positive than among GBS-negative women. No cases of early-onset invasive neonatal infection by MRSA occurred among infants in the study. CONCLUSION: Genital tract colonization with MRSA affected 3.5% of pregnant women. Such MRSA colonization is associated with colonization by GBS but does not predispose to a high risk of early-onset neonatal MRSA infection. LEVEL OF EVIDENCE: III

Emerging concepts in antibiotic prophylaxis for cesarean delivery: a systematic review.

OBJECTIVE: To review the current status of antibiotic prophylaxis for cesarean delivery, emerging strategies to enhance the effectiveness of antibiotic prophylaxis in reducing postcesarean infection, and the implications of the emerging practices. DATA SOURCES: We conducted a full PubMed (January 1966 to July 2008) search using the key words “cesarean” and “antibiotic prophylaxis.” A total of 277 articles were identified and supplemented by a bibliographic search. METHODS OF STUDY SELECTION: We selected a total of 15 studies, which included all published clinical trials, meta-analyses of clinical trials, and observational studies evaluating either the timing of antibiotics or the use of extended-spectrum prophylaxis. We also reviewed nine reports involving national recommendations or technical reviews supporting current standards for antibiotic prophylaxis. TABULATION, INTEGRATION, AND RESULTS: We conducted an analytic review and tabulation of selected studies without further meta-analysis. Although current guidelines for antibiotic prophylaxis recommend the administration of narrow-spectrum antibiotics (cefazolin) after clamping of the umbilical cord, the data suggest that antibiotic administration before surgical incision or the use of extended-spectrum regimens (involving azithromycin or metronidazole) after cord clamp may reduce postcesarean maternal infection by up to 50%. However, these two strategies have not been compared with each other. In addition, their effect on neonatal infection or infection with resistant organisms warrants further study. CONCLUSION: The use of either cefazolin alone before surgical incision or an extended-spectrum regimen after cord clamp seems to be associated with a reduction in postcesarean maternal infection. Confirmatory studies focusing additionally on neonatal outcomes and the effect on resistant organisms, as well as studies comparing both strategies, are needed.