Preventing neonatal herpes--current strategies.
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Biomedical subjects
Publications and source records attributed to R S Gibbs.
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This study was undertaken to define the characteristics and persistence of vaginal flora in 7918 pregnant women at 23 to 26 weeks' gestation. Vaginal smears were categorized as normal (predominant lactobacilli), intermediate (reduced lactobacilli), or positive for bacterial vaginosis. The women with normal flora were least likely to have elevated vaginal pH, amine odor, milky discharge, or colonization by Gardnerella, Bacteroides, or genital mycoplasmas. Women with intermediate vaginal flora had intermediate frequencies of these clinical signs and microorganisms. Group B streptococci and yeast were associated with normal or intermediate flora, whereas Neisseria gonorrhoeae and Chlamydia trachomatis were recovered more frequently from women with intermediate flora or bacterial vaginosis. Trichomonas vaginalis was most associated with intermediate flora. At follow-up, 81% of the women with normal flora had remained normal. Of the women with intermediate flora, 32% acquired bacterial vaginosis and 30% shifted to normal flora. Only 12% of the women with bacterial vaginosis had shifted to normal flora. We conclude that there are two primary stable vaginal flora patterns (normal flora or bacterial vaginosis) and a third less distinct transitional flora pattern between these two.
Premature birth causes high rates of neonatal morbidity and mortality. There are multiple causes of preterm birth. This article reviews the evidence linking subclinical infection and premature birth. Although maternal genital tract colonization with specific organisms has been inconsistently associated with preterm birth and/or premature rupture of membranes, some infections have been consistently associated with preterm delivery. The association of histologic chorioamnionitis with prematurity is a consistent finding, but the mechanisms require further study. The relationship between histologic chorioamnionitis infection and the chorioamnionitis of prematurity requires additional research. A varying number of patients in "idiopathic" preterm labor have positive amniotic fluid cultures (0% to 30%), but it is not clear whether infection preceded labor or occurred as a result of labor. Evidence of subclinical infection as a cause of preterm labor is raised by finding elevated maternal serum C-reactive protein and abnormal amniotic fluid organic acid levels in some patients in preterm labor. Biochemical mechanisms for preterm labor in the setting of infection are suggested by both in vitro and in vivo studies of prostaglandins and their metabolites, endotoxin and cytokines. Some, but by no means all, antibiotic trials conducted to date have reported decreases in prematurity. These results support the hypothesis that premature birth results in part from infection caused by genital tract bacteria. In the next few years, research efforts must be prioritized to determine the role of infection and the appropriate prevention of this cause of prematurity.
OBJECTIVE: The objective of this study was to determine whether the cytokines tumor necrosis factor-alpha, interleukin-1 alpha, and interleukin-1 beta were produced in the amniotic fluid of the rabbit after intracervical inoculation with Escherichia coli. STUDY DESIGN: Timed pregnant rabbits on day 21 (70% of gestation) were inoculated with a hysteroscope intracervically with 10(4) to 10(5) colony-forming units Escherichia coli or sterile saline solution. Escherichia coli-inoculated animals (N = 16) were put to death at 4, 8, 12, and 16 hours after inoculation. Control animals (N = 6) were put to death at similar intervals. At death, cultures were taken from endometrium, amniotic fluid, peritoneum, and blood. Amniotic fluid was collected and assayed for tumor necrosis factor bioactivity by a modified fibroblast cytotoxic assay in L929 cells, for interleukin-1 alpha, and interleukin-1 beta with a specific radioimmunoassay, and for prostaglandin E2 and prostaglandin F2 alpha by radioimmunoassay. RESULTS: Levels of amniotic fluid tumor necrosis factor-alpha, interleukin-1 alpha, and interleukin-1 beta were elevated as early as 4 hours after inoculation in some animals and by 12 to 16 hours after inoculation in all. Levels of all three cytokines correlated significantly with time from intracervical inoculation with Escherichia coli (p < 0.05). Levels of amniotic fluid prostaglandin E2 and prostaglandin F2 alpha correlated significantly with time from intracervical inoculation with Escherichia coli (p < 0.05). CONCLUSIONS: Levels of tumor necrosis factor-alpha, interleukin-1 alpha, interleukin-1 beta, prostaglandin E2 and prostaglandin F2 alpha are elevated in the amniotic fluid of rabbits after intracervical inoculation with Escherichia coli. Similarity exists between elevations of amniotic fluid cytokines in this model and in cases of intraamniotic infection and preterm labor unresponsive to tocolytics in humans. Modulation of cytokines may offer a strategy for improvement of outcome in this experimental model of infection-induced pregnancy loss.
Allotypic markers of immunoglobulin kappa (Km) may be determined using a novel method of amplification of the constant segment (C kappa) (IGKC) by polymerase chain reaction (PCR) followed by restriction enzyme digestion. Restriction sites in the C kappa PCR product correlate with allotypic differences among Km(1), Km(1,2), and Km(3) alleles. An AccI site in the PCR product correlates with Km(3); and presence or absence of a MaeII site correlates with the Km(1) or Km(1,2) allele, respectively. Km allelic frequencies were determined in a Caucasian population and compared to genotypic frequencies of nearby polymorphic markers. Among unrelated individuals with rheumatoid arthritis (RA) and controls, there is no evidence of allelic association between CD8A and polymorphic markers of the immunoglobulin kappa region [a V kappa (IGKV) BglII polymorphism about 24 kb centromeric to C kappa, Km allotype, and a SacI polymorphism 3.5 kb telomeric to the C kappa segment]. Similarly, there is no allelic association of the SacI C kappa polymorphism with Km or with the BglII V kappa polymorphism. However, there is evidence of allelic association of V kappa B3 and Km, specifically between the V kappa BglII 2.2-kb allele and Km(3) and also between the V kappa 3.5-kb allele and Km(1,2). Therefore, Km typing by PCR-based methods suggests the presence of allelic association between polymorphisms within the coding region of the C kappa segment and the nearest V kappa segment.
In studying the effects of amniotic fluid on bacterial growth in a laboratory model, we noted that the pH of the fluid appeared to exert an independent effect. This study was designed to test the ability to control the growth of Escherichia coli in amniotic fluid simply by controlling two important growth conditions, pH and osmolality. The effects of pH and osmolality on growth of E. coli were systematically studied in a standard media and in amniotic fluid. Optimal ranges in standard media were pH of 5.6 to 6.6 and osmolality of 150 to 215 mOsm. When the results of growth at 24 hours were corrected for pH by analysis of covariance, the presence of amniotic fluid or phosphate had no effect. We found pH to be the only variable predictive of bacterial growth in amniotic fluid in this laboratory model.
We describe two patients with life-threatening puerperal infection due to group A beta-hemolytic streptococcus. Each patient had bacteremia, shock, and multi-organ involvement. Both cases were compatible with a recently described streptococcal toxic shock-like illness. Both women failed to improve despite vigorous medical and antibiotic therapies, and each required hysterectomy. Obstetricians should be alert to the importance of early diagnosis and treatment of this potentially lethal infection.
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OBJECTIVE: The purpose of this study was to assess rates of endometritis, clinical chorioamnionitis, cesarean delivery, and neonatal sepsis from the records of patients with premature rupture of the membranes (PROM) and an unfavorable cervix treated with vaginal prostaglandin (PG) E2 in comparison with those in the literature. METHODS: Using a computer data base at Denver General Hospital, we identified 146 women with PROM and cervical dilatation of 2 cm or less at term who were treated with PGE2 gel or suppositories. The records were reviewed to identify rates of maternal and neonatal infection and complications, as well as cesarean delivery. RESULTS: The cesarean rate was 12%. Chorioamnionitis developed in 6.8% of the study group and endometritis in 2%. Neonatal complications were limited to two with low Apgar scores (less than 7 at 5 minutes), one with microbiologically confirmed sepsis, and two with positive urine counterimmunoelectrophoresis for group B streptococcus. The only instance of neonatal sepsis occurred in a patient with rupture of membranes longer than 24 hours. CONCLUSIONS: The use of vaginal PGE2 suppositories for induction of labor and cervical ripening in term patients with PROM was accompanied by a high rate of vaginal delivery and a low rate of maternal and neonatal complications in a city hospital setting.
We conducted experiments with a previously described rabbit model of Escherichia coli-induced preterm pregnancy loss. Does at 70% gestation were inoculated hysteroscopically with 0.2 ml of Escherichia coli (10(5) colony-forming units per milliliter) or saline solution. Animals were randomly assigned to either receive treatment with ampicillin-sulbactam (begun 1 to 2 hours before inoculation and continued for up to 7 days) or to receive no therapy. Animals were killed after delivery or after 7 days. Saline solution-inoculated animals had no pregnancy loss. Of the Escherichia coli-inoculated animals, those treated with ampicillin-sulbactam had significantly fewer deliveries, fewer positive cultures, and more live fetuses than the untreated animals (p less than or equal to 0.001). Cultures from multiple sites, amniotic fluid prostaglandin levels, and maternal progesterone levels were obtained, and the placenta, uterus, and fetal lung were histologically evaluated. In the second phase of the study, the Escherichia coli-inoculated animals were treated with ampicillin-sulbactam at one of three times: at inoculation or 2 or 4 hours after inoculation. The Escherichia coli-inoculated does treated with ampicillin-sulbactam at or before inoculation had significantly fewer deliveries, fewer positive cultures, and more live fetuses than the Escherichia coli-inoculated does in which treatment was delayed 4 hours (p less than or equal to 0.01).
Ureaplasma urealyticum has been associated with low birth weight and histologic chorioamnionitis and it is a frequent isolate from the chorioamnion of patients who are delivered prematurely. In prior clinical trials using antibiotics active against U. urealyticum, antibiotic treatment was associated with reduced prematurity and increased mean birth weight. In this multicenter, randomized, double-blind clinical trial, pregnant women with U. urealyticum were treated with 333 mg of erythromycin base or placebo three times daily, starting between 26 and 30 weeks' gestation and continuing through 35 completed weeks of pregnancy. Women with urinary tract infection or Neisseria gonorrhoeae infection were excluded from the trial, and women with Chlamydia trachomatis or group B streptococci were excluded from these analyses. Erythromycin did not eliminate U. urealyticum from the lower genital tract. There were no significant differences between erythromycin- and placebo-treated women in infant birth weight or gestational age at delivery, in frequency of premature rupture of membranes, or in neonatal outcome.
In the past decade, gratifying progress has been achieved in our understanding of clinical intraamniotic infection. With a usual incidence of 1% to 4%, clinical intraamniotic infection mainly develops as an ascending process after prolonged rupture of the membranes and labor, but other cases may be hematogenous in origin whereas still others complicate intrauterine procedures. The most common organisms isolated in amniotic fluid of cases of intraamniotic infections are anaerobes, genital mycoplasmas, group B streptococci, and Escherichia coli. The latter two are found most commonly in maternal or neonatal bacteremia complicating intraamniotic infection. Although the diagnosis remains largely a clinical one, laboratory tests have been suggested to confirm the diagnosis in women with symptoms. These include amniotic fluid Gram stain, gas-liquid chromatography, and leukocyte esterase measurement. Maternal treatment consists of antibiotic therapy and delivery. Studies to date have used a penicillin plus an aminoglycoside, with some authors advocating the addition of clindamycin after cesarean delivery. Other broad-spectrum regimens may be equally effective. Complications of clinical intraamniotic infections include an increase in cesarean section rate and in maternal and neonatal bacteremia. Poor neonatal outcomes in intraamniotic infection are more likely in the following cases: (1) when E. coli or group B streptococci are present in the amniotic fluid; (2) when the infant has a low birth weight; (3) when maternal antibiotic therapy is delayed until after delivery.
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One hundred thirty-six patients were enrolled in a randomized, double-blind, placebo-controlled trial of oral antibiotic therapy (amoxicillin) versus placebo following successful intravenous (IV) antibiotic therapy for postpartum endometritis. No subjects were readmitted to the hospital for recurrent endometritis and there were no wound infections or recurrent fevers. Minor side effects were seen in 10% of those taking amoxicillin and 14% of those taking placebo. Compliance was fair; only 52% of those taking amoxicillin and 65% of those taking placebo completed therapy. The lack of infectious complications in this high-risk population suggests that oral antibiotic therapy is unnecessary after successful IV antibiotic therapy for endometritis.
Bacterial infection has been implicated in premature labor in humans. To elucidate mechanisms and potential intervention strategies, we sought to develop a model of infection-induced pregnancy loss in rabbits. On day 21 (70% of gestation), each uterine horn was inoculated hysteroscopically with 0.2 ml containing saline solution of 10(6) cfu Escherichia coli or Bacteroides bivius or Fusobacterium necrophorum. Fetal viability was assessed. Animals were sacrificed at various times or as delivery occurred. Serum progesterone and amniotic fluid prostaglandins were measured. Cultures and histologic sections were prepared. Compared with the saline solution group, E coli and F. necrophorum-inoculated rabbits were significantly more likely to deliver (16 of 16 and six of seven with mean times of 31.9 +/- 10.7 and 28.3 +/- 11.5 hours, respectively for E. coli and F. necrophorum). Positive amniotic fluid cultures for the E. coli group were found in 11 of 12 (92%) and for the F. necrophorum group in three of three cases (100%). Histologic inflammation was seen heavily in both the E. coli and F. necrophorum groups, whereas it was absent in the saline solution group. Inoculation with B. bivius led to a much lower pregnancy loss rate (eight of 32) and less histologic inflammation despite positive uterine cultures in most animals. This model may provide an opportunity to determine mechanisms of clinical or subclinical intraamniotic infection and to test intervention strategies.
The division between "normal" and low Apgar scores is based largely on data obtained from term newborns and may not apply to the premature infant. Umbilical artery pH has been suggested as a better indicator of intrapartum asphyxia. We examined the charts of 558 infants with birth weights less than or equal to 2500 gm with respect to umbilical artery pH, 5-minute Apgar scores, and birth weight percentiles. A positive correlation between birth weight and 5-minute Apgar score was noted. No such relationship existed between birth weight and umbilical artery pH. Within birth weight groups, small-for-gestational-age infants have higher Apgar scores and lower umbilical artery pH values than their appropriate-for-gestational age counterparts.
A group of 1031 parturient women at high risk for intraamniotic infection were studied. Women in whom group B streptococci grew from cultures of the amniotic fluid did not differ in clinical risk factors when compared with similar parturient women without group B streptococcal colonization of amniotic fluid. Patients who had perinatal group B streptococcal disease (maternal or neonatal bacteremia) did not differ from those without disease, by maternal or neonatal acute antibody levels or antibody response, inoculum size, or serotype of the colonizing strain.
To assess the association between women with preterm premature rupture of membranes and 41 potential risk factors, we conducted a case-control study in six United States tertiary perinatal centers. The study involved completion of a comprehensive questionnaire for 341 women with preterm premature rupture of membranes in singleton pregnancies from 20 to 36 weeks' gestation and 253 control women matched for maternal age, gestational age, parity, clinic or private patient status, and previous vaginal or cesarean delivery. Univariate analysis revealed 11 variables associated with a significantly (p less than 0.05) increased risk of preterm premature rupture of membranes. After multiple logistic regression analysis, three variables remained in the model as independent risk factors: antepartum vaginal bleeding in more than one trimester (odds ratio 7.4; 95% confidence interval, 2.2, 25.6), current cigarette smoking (odds ratio, 2.1; 95% confidence interval, 1.4, 3.1), and previous preterm delivery (odds ratio, 2.5; 95% confidence interval, 1.4, 2.5). Cessation of cigarette smoking by pregnant women may reduce the risk of preterm premature rupture of membranes. Further study is necessary to determine the nature of the relationship between antepartum vaginal bleeding and preterm premature rupture of membranes.