Pharmacokinetics of tenofovir during pregnancy and postpartum.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum. METHODS: International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography-mass spectrometry (LC-MS). The target area under the concentration versus time curve from time 0 to 24 h post dose (AUC) was ≥ 1.99 µg h/mL (nonpregnant historical control 10th percentile). RESULTS: The median tenofovir AUC was decreased during the second (1.9 µg h/mL) and third (2.4 µg h/mL; P = 0.005) trimesters versus postpartum (3.0 µg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women [73%; 95% confidence interval (CI) 56%, 86%] in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P > 0.05). Median second/third-trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median third-trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2 kg, respectively; P = 0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected. CONCLUSIONS: This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90 kg) or inadequate HIV RNA response.

Predictors of adverse pregnancy outcomes in women infected with HIV in Latin America and the Caribbean: a cohort study.

OBJECTIVE: To examine maternal characteristics associated with adverse pregnancy outcomes among women infected with HIV. DESIGN: Prospective cohort study. SETTING: Multiple sites in Latin America and the Caribbean. POPULATION: Women infected with HIV enrolled in the Perinatal (2002-2007) and the Longitudinal Study in Latin American Countries (LILAC; 2008-2012) studies of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI). METHODS: Frequencies of adverse pregnancy outcomes assessed among pregnancies. Risk factors investigated by logistic regression analysis. MAIN OUTCOME MEASURES: Adverse pregnancy outcomes, including preterm delivery (PT), low birthweight (LBW), small for gestational age (SGA), stillbirth (SB), and neonatal death. RESULTS: Among 1512 women, 1.9% (95% confidence interval, 95% CI, 1.3-2.7) of singleton pregnancies resulted in a stillbirth and 32.9% (95% CI 30.6-35.4) had at least one adverse pregnancy outcome. Of 1483 singleton live births, 19.8% (95% CI 17.8-21.9) were PT, 14.2% (95% CI 12.5-16.1) were LBW, 12.6% (95% CI 10.9-14.4) were SGA, and 0.4% (95% CI 0.2-0.9) of infants died within 28 days of birth. Multivariable logistic regression modelling indicated that the following risk factors increased the probability of having one or more adverse pregnancy outcomes: lower maternal body mass index at delivery (odds ratio, OR, 2.2; 95% CI 1.4-3.5), hospitalisation during pregnancy (OR 3.3; 95% CI 2.0-5.3), hypertension during pregnancy (OR 2.7; 95% CI 1.5-4.8), antiretroviral use at conception (OR 1.4; 95% CI 1.0-1.9), and tobacco use during pregnancy (OR 1.7; 95% CI 1.3-2.2). The results of fitting multivariable logistic regression models for PT, LBW, SGA, and SB are also reported. CONCLUSIONS: Women infected with HIV had a relatively high occurrence of adverse pregnancy outcomes, and some maternal risk factors were associated with these adverse pregnancy outcomes. Interventions targeting modifiable risk factors should be evaluated further.

Treatment interruption after pregnancy: effects on disease progression and laboratory findings.

OBJECTIVE: To assess clinical progression and inflammatory markers among women stopping or continuing antiretroviral therapy (ART) after pregnancy. METHODS: ART-naïve women with CD4+ lymphocyte counts >350 cells/uL initiating ART during pregnancy had clinical events and laboratory markers compared over one year postpartum between those stopping (n = 59) or continuing (n = 147) ART. RESULTS: Slopes in CD4 count and HIV RNA did not differ between groups overall and in subsets of ZDV or combination therapy. The hazard ratio (HR) of a new class B event was 2.09 (95% CI 0.79-5.58) among women stopping ART, 1.24 (0.31-4.95) in those stopping ZDV, and 2.93 (0.64-13.36) among those stopping combination therapy. Women stopping ART had increased immune activation. No significant differences were seen in C-reactive protein, lipids, leptin, or interleukin-6. CONCLUSIONS: While changes in CD4 and HIV RNA levels over one year were similar between women stopping or continuing ART postpartum, higher immune activation among women stopping therapy requires further study.

Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353.

BACKGROUND: Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women. METHOD: HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC0-24 > 30 mug . h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity. RESULTS: Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median Cmax (3.90 microg/mL vs. 5.01 microg/mL, p < .05) and AUC0-24 (56.6 vs. 86.8 microg . h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum. CONCLUSION: NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and decrease in M8/NFV ratio suggest that CYP3A activity increases relative to CYP2C19 activity during pregnancy.

Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions.

We conducted an open-label, steady-state pharmacokinetic (PK) study of drug interactions among HIV-infected women treated with depo-medroxyprogesterone acetate (DMPA) while on nucleoside analogues plus nelfinavir (N=21), efavirenz (N=17), or nevirapine (N=16); or nucleosides only or no antiretroviral therapy as a control group (N=16). PK parameters were estimated using non-compartmental analysis, with between-group comparisons of medroxyprogesterone acetate (MPA) PKs and within-subject comparisons of ARV PKs before and 4 weeks after DMPA dosing. Plasma progesterone levels were measured at baseline and at 2, 4, 6, 8, 10, and 12 weeks after DMPA dosing. There were no significant changes in MPA area under the concentration curve, peak or trough concentrations, or apparent clearance in the nelfinavir, efavirenz, or nevirapine groups compared to the control group. Minor changes in nelfinavir and nevirapine drug exposure were seen after DMPA, but were not considered clinically significant. Suppression of ovulation was maintained.

The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women.

OBJECTIVE: Cervical intraepithelial neoplasia (CIN), a common condition among HIV-infected women, has been linked to HIV load and immune status. Highly active antiretroviral therapy (HAART) improves immunologic and virologic status. This study was undertaken to determine the relationship between HAART use and CIN. DESIGN: Cohort study. The Women's Interagency HIV Study (WIHS) in five cities in the USA (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois; Los Angeles, California; San Francisco Bay area, California; Washington, District of Columbia). METHODS: HIV-infected women were followed every 6 months with Papanicolaou smears and cervicovaginal lavage for human papillomavirus (HPV) DNA testing. To characterize exposures that changed over time and to capture the dynamic nature of cytologic changes, Papanicolaou smear findings from each participant's consecutive visits were defined as a pair. We determined the proportion of all pairs that exhibited either regression or progression, according to HAART exposure, HPV results and Papanicolaou smear status. As participants could contribute multiple pairs, inferences were based on robust methods to adjust for correlated observations. RESULTS: Women with persistent HPV infection were more likely to have progression of their lesions. After adjustment for CD4 cell count and Papanicolaou smear status, women on HAART were 40% (95% confidence interval, 4-81%) more likely to demonstrate regression and less likely (odds ratio, 0.68; 95% confidence interval, 0.52-0.88) to demonstrate progression CONCLUSIONS: HAART altered the course of HPV disease in HIV-infected women, reducing progression and increasing regression. As HPV disease is a common sex-specific manifestation of HIV disease this effect of HAART would be a major additional benefit from this modality of therapy.

Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. Pediatric AIDS Clinical Trials Group 185 Team.

OBJECTIVE: To evaluate independent contributions of maternal factors to adverse pregnancy outcomes (APO) in HIV-infected women receiving antiretroviral therapy (ART). DESIGN: Risk factors for preterm birth (< 37 weeks gestation), low birth weight (LBW) (< 2500 g), and intrauterine growth retardation (IUGR) (birth weight < 10th percentile for gestational age) examined in 497 HIV-infected pregnant women enrolled in PACTG 185, a perinatal clinical trial. METHODS: HIV RNA copy number, culture titer, and CD4 lymphocyte counts were measured during pregnancy. Information collected included antenatal use of cigarettes, alcohol, illicit drugs; ART; obstetric history and complications. RESULTS: Eighty-six percent were minority race/ethnicity; 86% received antenatal monotherapy, predominantly zidovudine (ZDV), and 14% received combination antiretrovirals. Preterm birth occurred in 17%, LBW in 13%, IUGR in 6%. Risk of preterm birth was independently associated with prior preterm birth [odds ratio (OR) 3.34; P < 0.001], multiple gestation (OR, 6.02; P = 0.011), antenatal alcohol use (OR, 1.91; P = 0.038), and antenatal diagnosis of genital herpes (OR, 0.24; P = 0.022) or pre-eclampsia (OR, 6.36; P = 0.025). LBW was associated with antenatal diagnosis of genital herpes (OR, 0.08; P = 0.014) and pre-eclampsia (OR, 5.25; P = 0.049), and baseline HIV culture titer (OR, 1.41; P = 0.037). IUGR was associated with multiple gestation (OR, 8.20; P = 0.010), antenatal cigarette use (OR, 3.60; P = 0.008), and pre-eclampsia (OR, 12.90; P = 0.007). Maternal immune status and HIV RNA copy number were not associated with APO. CONCLUSIONS: Risk factors for APO in antiretroviral treated HIV-infected women are similar to those reported for uninfected women. These data suggest that provision of prenatal care and ART may reduce APO.

Maternal physical activity in pregnancy and infant size for gestational age.

PURPOSE: To estimate the effect of several types of maternal physical activity in pregnancy on size for gestational age and length of gestation. METHODS: Telephone interviews, birth certificates, and medical records provided data on physical activity and other factors for a random sample of 291 Colorado residents. Backward polychotomous logistic regression modeling yielded estimates of the odds ratios for size for gestational age (appropriate versus small or large) and length of gestation (term versus pre-term or post-term) in relation to second and third trimester maternal physical activity. RESULTS: Performance of any moderate or vigorous physical activity for two hours per week or more in any month was associated with a decreased risk of large infant size for gestational age (LGA; odds ratio = 0.3, 95% confidence interval = 0.2, 0.7), but had no significant effect on risk of small infant size for gestational age (SGA; odds ratio (OR) = 0.8, 95% confidence interval (CI) = 0.3, 2.3). Length of gestation was not affected by prenatal physical activity. CONCLUSIONS: These results suggest that prenatal physical activity may decrease risk of LGA, as might be expected given its salutary effects on glucose tolerance.

Early postpartum endometritis: the role of bacteria, genital mycoplasmas, and Chlamydia trachomatis.

To characterize the flora of early postpartum endometritis and the clinical features of women with specific organisms, endometrial cultures for facultative and anaerobic bacteria, genital mycoplasmas, and Chlamydia trachomatis were taken with a triple-lumen sampling device. More than one organism was recovered from 80% of the women. Over 60% of the women had Gardnerella vaginalis and/or anaerobes associated with bacterial vaginosis isolated from the endometrium; these women were more likely to have severe illness and to develop a wound infection than were other women. Genital mycoplasmas were isolated frequently, but specific antibiotic therapy was not required for clinical cure in the 10% of patients who had Ureaplasma urealyticum only. Chlamydia trachomatis was infrequently isolated, but C trachomatis commonly remained after therapy.

Upper genital tract isolates at delivery as predictors of post-cesarean infections among women receiving antibiotic prophylaxis.

The introduction of antibiotic prophylaxis for cesarean delivery has decreased the risk of postpartum endometritis and wound infection, but factors that contribute to prophylaxis failure are not understood. To determine factors that might contribute to postpartum infections following antibiotic prophylaxis, we cultured amniotic fluid, decidua, and chorioamniotic membrane specimens for anaerobic and facultative bacteria and for genital mycoplasmas at cesarean delivery. Women were assessed daily for the development of infections, and if endometritis developed, a protected endometrial culture was obtained. Postpartum endometritis developed in 16 and wound infection in four of 102 women. Infection rates were similar for women receiving cefotetan (N = 50) or cefoxitin (N = 52) for prophylaxis. The isolation of group B streptococcus (P less than .001) or Enterococcus faecalis (P = .03) from the upper genital tract at delivery was significantly associated with postpartum endometritis. Antibiotic-resistant organisms (other than enterococci) were recovered uncommonly at delivery or with postpartum infections. Group B streptococcus was susceptible to the prophylactic agents used, suggesting that virulence factors other than antibiotic resistance are important for the development of postpartum endometritis. Group B streptococcus, E faecalis, and bacteria associated with bacterial vaginosis were recovered from the endometrium at the time of postpartum endometritis.

Bacterial vaginosis as a risk factor for post-cesarean endometritis.

Bacterial species associated with bacterial vaginosis have been isolated more frequently from endometrial cultures of patients with postpartum endometritis than expected from the prevalence of bacterial vaginosis among pregnant women. To further assess the association between bacterial vaginosis and postpartum endometritis, vaginal Gram smears were obtained from women admitted for delivery. Vaginal smears of women delivered by cesarean were scored as normal or as indicating bacterial vaginosis. Factors related independently to postpartum endometritis by multiple logistic regression analysis included maternal age less than 25 years, any duration of membrane rupture, and bacterial vaginosis. The unadjusted odds ratio for the development of postpartum endometritis associated with bacterial vaginosis (odds ratio = 6.1, 95% confidence interval 3.3-15.9) was not appreciably changed in the multivariable analysis (odds ratio = 5.8, 95% confidence interval 3.0-10.9) after adjusting for maternal age, duration of labor, and duration of membrane rupture. At the time of endometritis, Bacteroides sp, Peptostreptococcus sp, and Gardnerella vaginalis were isolated more frequently from the endometrium using a triple lumen endometrial sampling method among patients with bacterial vaginosis than among those with a normal Gram stain. Bacterial vaginosis appears to be an important risk factor for postpartum endometritis after cesarean delivery.

Microbiologic efficacy of intravaginal clindamycin cream for the treatment of bacterial vaginosis.

Bacterial vaginosis is characterized by replacement of the normal Lactobacillus-predominant vaginal flora with Gardnerella vaginalis, anaerobic bacteria, and Mycoplasma hominis. The present study evaluated the vaginal flora of women with bacterial vaginosis before and after treatment with intravaginal clindamycin cream. Sixty-seven nonpregnant women with symptoms and signs of bacterial vaginosis, and without other genital tract infections, were randomly assigned to receive placebo cream or 0.1, 1, or 2% clindamycin cream. Quantitative vaginal cultures for facultative and anaerobic bacteria and genital mycoplasmas were performed at enrollment and at 4-7 days and 4-5 weeks after completion of therapy. At enrollment, G vaginalis was recovered from 99%, Bacteroides sp from 94%, Peptostreptococcus sp from 81%, and M hominis from 58% of the 67 women with bacterial vaginosis. The vaginal cultures yielded a median of 12 isolates per specimen, with equal numbers of aerobic and anaerobic species. The mean log concentration was 1.2 X 10(9) cfu/mL for aerobic and 2.6 X 10(8) cfu/mL for anaerobic bacteria. After treatment, the frequency and concentration of bacteria per milliliter of vaginal fluid decreased for G vaginalis, Bacteroides sp, Peptostreptococcus sp, and M hominis. The 2% clindamycin cream had the greatest effect on the bacterial vaginosis-associated flora and resulted in clinical resolution of bacterial vaginosis in 15 (94%) of 16 women. Treatment with lower concentrations of clindamycin cream had less effect on the vaginal flora and resulted in clinical cure in 25 (71%) of 35 women. Therapy was associated with an increase in the frequency and concentration of Lactobacillus, and a probably transient increase in the frequency of Escherichia coli and Enterococcus.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of cardiac output during pregnancy: validation of Doppler technique and clinical observations in preeclampsia.

In 12 patients requiring pulmonary artery catheterization, cardiac output was measured using Doppler and thermodilution techniques. The Doppler technique accurately predicted measurements made by thermodilution (r = 0.91; P less than .001). Eighteen normal patients in the third trimester and 36 preeclamptics who had not been treated with medications other than magnesium sulfate were evaluated with Doppler alone. Of note was the heterogeneity among preeclamptics. Although their mean systemic vascular resistance was elevated, it ranged from 2256-648 dyne X sec X cm-5. Cardiac output ranged from 13.2-3.9 L/minute.

The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor.

To evaluate the relationships between gestational age, neonatal outcome, and amniotic fluid (AF) bacteria, we obtained AF from women with intact membranes in idiopathic preterm labor. Positive cultures were obtained from 20 (19%) of 105 women. The frequency of positive cultures was inversely related to gestational age: 23-26 weeks, nine of 20; 27-30 weeks, four of 24; and 31-34 weeks, seven of 61 (chi2 for trend, P less than .001). Fusobacterium nucleatum, Bacteroides ureolyticus, and Ureaplasma urealyticum were the most common isolates. Facultative and anaerobic bacteria were more commonly isolated from women at less than 30 weeks' gestation, and Ureaplasma urealyticum was commonly isolated at greater than 30 weeks' gestation. Forty percent of the patients identified as having positive AF facultative and anaerobic cultures by the research laboratory had negative cultures in the clinical laboratory. Clinical characteristics and maternal white blood cell count and differential did not differ between women with and without positive cultures. Elevated C-reactive protein levels and a positive AF Gram stain were the two most sensitive and specific methods to predict positive AF cultures. Women with positive cultures delivered a median of 1.0 day after enrollment, compared with 28.5 days for women with negative cultures. The median gestational age at delivery for women with positive cultures was 27.5 weeks, and the median birth weight was 866 g. Positive AF cultures were associated with respiratory distress syndrome, bronchopulmonary dysplasia, and neonatal death. If occult AF infection among women in preterm labor is a treatable cause of preterm birth, then treatment could markedly reduce both perinatal morbidity and mortality.

C-reactive protein in normal pregnancy.

Maternal serum C-reactive protein (CRP) has been studied extensively as an adjunct in the diagnosis of subclinical infection among pregnant women with preterm labor or preterm rupture of membranes. However, before the utility of CRP can be studied in pregnancies with these complications, the effects of normal pregnancy and labor on maternal serum CRP levels must be established. We determined CRP levels serially from 22 weeks' gestation until delivery in healthy pregnant women without antepartum complications. Median CRP values for women not in labor ranged from 0.7-0.9 mg/dL, depending on gestational age; 95% of the values were 1.5 mg/dL or lower. No consistent change in CRP levels with gestational age was found among serially sampled women not in labor. The median CRP value for women in labor at term was 1.3 mg/dL, and 32% of values were over 1.5 mg/dL. Median CRP values in normal pregnancies appear to be higher than standardized values for nonpregnant individuals, and CRP values are further elevated in labor. Understanding the physiology and temporal course of the increase in CRP in normal pregnancy and labor may help to clarify the appropriate use of CRP in complicated pregnancies.

Prevention of chickenpox in reproductive-age women: cost-effectiveness of routine prenatal screening with postpartum vaccination of susceptibles.

OBJECTIVE: To evaluate economic and clinical outcomes of a program of routine prenatal serotesting for varicella and postpartum vaccination of seronegative women. METHODS: An analytic cost-effectiveness model was constructed to compare the current strategy of no serotesting with 1) selective serotesting of pregnant women without a prior history of chickenpox and 2) serotesting of all pregnant women. In both serotesting strategies, seronegative women were vaccinated postpartum. The model followed a hypothetical cohort of 4 million women over 20 years. Costs and chickenpox disease outcomes during and outside of subsequent pregnancies were considered. The incremental cost-effectiveness (cost per adult chickenpox case prevented) of selective serotesting compared with the current strategy was measured. RESULTS: Compared to no testing, selective serotesting would prevent 43% (48,577 of 112,654) of adult chickenpox cases, save $21.8 million in discounted medical and work loss costs from the societal perspective, and cost $1126 per case prevented from the health payer's perspective (medical costs only). The model was sensitive to varicella seroprevalence and incidence of chickenpox among susceptible women but was relatively insensitive to the cost of serologic testing and vaccination. Compared with selective serotesting, the serotest-all strategy would prevent an additional 15,645 cases, at a societal cost of $7653 per additional case prevented. CONCLUSION: The selective serotesting strategy could prevent nearly half of chickenpox cases among this cohort and is cost-saving from the societal perspective. From the health payer's perspective, it compares favorably with other generally accepted preventive practices. It should be considered for prevention of chickenpox among women of childbearing age.

Asymptomatic maternal shedding of herpes simplex virus at the onset of labor: relationship to preterm labor.

OBJECTIVE: To determine if fetal growth restriction and prematurity are observed with subclinical shedding of herpes simplex virus (HSV) at the onset of labor. METHODS: Within 48 hours of delivery, cultures were taken from the cervix and external genitalia of 15,923 asymptomatic pregnant women without symptoms or signs of genital HSV infection; results were positive for HSV in 57. Each of these 57 women were compared with a control group composed of the three culture-negative women delivering immediately before and the three delivering immediately after each woman shedding HSV. RESULTS: The median birth weight for infants born to the 57 women with asymptomatic shedding was 3050 g, compared with 3360 g among the 342 women without asymptomatic shedding, a statistically significant difference (P < .002). These differences were due to very low birth weight (LBW) among the five infants of women with subclinical viral shedding secondary to recently acquired primary genital herpes; these five infants had a median gestational age of 33 weeks, compared with 37 weeks for the 14 infants of mothers with nonprimary, first-episode disease and 39 weeks for the 33 infants of women with reactivation disease, also a significant difference (P = .018). CONCLUSIONS: Asymptomatic genital shedding of HSV at the onset of labor because of subclinical primary genital HSV infection is associated with preterm delivery. Women who acquire genital HSV-2 before pregnancy and are shedding subclinically at the onset of labor experience no increase in adverse outcome. Thus, prevention of the prematurity and LBW associated with genital herpes means that acquisition of the infection in late pregnancy must be prevented.

Vaginal 5-fluorouracil for high-grade cervical dysplasia in human immunodeficiency virus infection: a randomized trial.

OBJECTIVE: To compare the efficacy and toxicity of topical vaginal 5-fluorouracil (5-FU) maintenance therapy against the effects of observation after standard treatment for high-grade cervical dysplasia in human immunodeficiency virus (HIV)-infected women and to evaluate the association between baseline CD4 count and time to recurrence. METHODS: In a phase III unmasked, randomized, multicenter, outpatient clinical trial, 101 HIV-positive women either received 6 months of biweekly treatment with vaginal 5-FU cream (2 g) or underwent 6 months of observation after standard excisional or ablative cervical treatment for cervical intraepithelial neoplasia (CIN). Papanicolaou smears and colposcopy were scheduled at regular intervals during the ensuing 18 months, with the primary end point being the time at which CIN of any grade recurred. RESULTS: Thirty-eight percent of women developed recurrence: 14 (28%) of 50 in the 5-FU therapy group and 24 (47%) of 51 in the observation group. Treatment with 5-FU was significantly associated with prolonged time to CIN development (P = .04). Observation subjects were more likely to have high-grade recurrences, with 31% developing CIN 2-3 compared with 8% in the 5-FU treatment arm (P = .014), and disease recurred more quickly in observation subjects as well. Baseline CD4 count was related significantly to time to recurrence (P = .04), with 46% of subjects with CD4 counts less than 200 cells/mm3 developing recurrence compared with 33% of subjects with CD4 counts at least 200 cells/mm3. Disease recurred more slowly in subjects who had received antiretroviral therapy than in antiretroviral therapy-naive subjects. There were no instances of grade 3 or 4 toxicity, and compliance with 5-FU treatment was generally good. CONCLUSION: Adjunctive maintenance intravaginal 5-FU therapy after standard surgery for high-grade lesions safely and effectively reduced recurrence of cervical intraepithelial neoplasia in HIV-infected women.

Intraperitoneal fetal transfusion under direct ultrasound guidance.

The outcomes of 77 fetal intraperitoneal transfusions in 35 pregnancies managed with direct ultrasound guidance and intensive perinatal management were reviewed. Patients were monitored with amniocentesis, and standard indications were used for timing of transfusions. The mean gestational age at first transfusion was 27.3 weeks (range 22-33). The overall mortality rate was 14% (five of 35). No immediate transfusion-related deaths occurred; all fetuses who were not hydropic at first transfusion survived (26 of 26). The mean gestational age at delivery was 33.6 weeks (range 25-36). One infant developed respiratory distress syndrome (RDS). Transfusion-related complications occurred in five cases (fetal colon infusions in two, fetal retroperitoneal infusion in two, and fetal abdominal wall hematoma in one). None of these infants required urgent delivery or suffered long-term sequelae. In nonhydropic fetuses, intraperitoneal transfusions under direct ultrasound guidance had a low incidence of morbidity and no mortality. These results should provide baseline data against which to compare new techniques, such as direct cord transfusion. With neonatal mortality rates of 10% and significant morbidity rates of 10-20% in infants delivered at 32 weeks who develop RDS, intraperitoneal transfusion should be considered in the 32- to 33-week fetus with marked pulmonary immaturity.

Characteristics of women in preterm labor associated with elevated C-reactive protein levels.

OBJECTIVE: To evaluate clinical, microbiologic, and histologic findings associated with elevated C-reactive protein levels among women in preterm labor or with preterm premature rupture of the membranes (PROM). METHODS: Obstetric data, serum C-reactive protein levels, and amniotic fluid (AF) and chorioamniotic membrane cultures and histology were obtained on 203 women presenting between 22-34 weeks' gestation in preterm labor or with PROM. RESULTS: Women with C-reactive protein greater than 1.5 mg/dL were more likely to deliver within 7 days of enrollment (54 of 68, 79%) than were women with normal C-reactive protein levels (45 of 135, 33%) (P < .001). The median C-reactive protein levels and association with rapid delivery did not differ between women with intact versus ruptured membranes. Elevated C-reactive protein levels were associated with a positive AF culture among women in preterm labor with intact membranes. To control for confounding by a long interval to delivery, only the group delivering within 7 days was considered for evaluation of C-reactive protein levels and placental and infant outcome. Among women delivering within 7 days, elevated C-reactive protein was associated with the development of clinical chorioamnionitis and with infant death before hospital discharge, but not with a positive membrane culture or histologic chorioamnionitis. CONCLUSIONS: Elevated C-reactive protein appears to be associated with AF infection, delivery within 7 days of admission, and infant death among women delivering preterm, but not with membrane infection or inflammation. Elevated C-reactive protein may be helpful in determining the need for AF culture and in targeting studies of antibiotic therapy among women in preterm labor or with preterm PROM.