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Objective: Compare the risk of HIV drug resistance in women stopping suppressive nelfinavir (NFV)-based or Nevirapine (NVP)-based antiretroviral therapy (ART) after pregnancy., Methods: Specimens collected after stopping ART were tested for drug resistance by an oligonucleotide ligation assay and consensus sequencing. When postpartum drug resistance was detected, specimens obtained at study entry and during ART were evaluated., Results: Sixteen of 38 women with ART-induced suppression of viral replication suspended ART postpartum. Resistance mutations were detected in 75% who stopped NFV-ART and in 50% who stopped NVP-ART. M184V, associated with Lamivudine resistance, was more frequent among those randomized to NFV-ART compared with NVP-ART (6 of 8 versus 1 of 8; P = 0.04), and nonnucleoside reverse transcriptase inhibitor resistance was detected in 4 of 8 stopping NVP-ART., Conclusions: HIV drug resistance was frequently observed among women who stopped suppressive NVP-ART or NFV-ART postpartum. This suggests that NFV-ART may have suboptimal potency, that staggering discontinuation of NVP-ART may be warranted, and/or ART adherence may be lax in women who choose to stop ART postpartum.

To assess the volume of genital fluid collected for measuring the HIV-1 RNA level in cervicovaginal fluid, phosphate-buffered saline containing 10 mM LiCl was used. Thirty-eight women provided 275 cervicovaginal specimens. The estimated median volume of cervicovaginal fluid was 0.51 ml (interquartile range, 0.33, 0.69).

We examined the relationship of proinflammatory vaginal cytokines and secretory leukocyte protease inhibitor (SLPI) with genital HIV-1 shedding after controlling for genital coinfections. Fifty-seven HIV-1-infected women in Seattle, WA (n = 38) and Rochester, NY (n = 19) were followed every 3-4 months for a total of 391 visits. At each visit, plasma and cervicovaginal lavage (CVL) were tested for HIV-1 RNA using qPCR. Vaginal samples were tested for bacterial vaginosis, yeast, hydrogen peroxide-producing Lactobacillus colonization, Trichomonas vaginalis, Neisseria gonorrhea, Chlamydia trachomatis, CMV, and HSV shedding. CVL interleukins (IL)-1β, IL-6, IL-8, and SLPI were measured using ELISA. Linear regression with generalized estimating equations examined effects of cytokine concentrations on CVL HIV-1 RNA, adjusted for plasma HIV RNA, and measured coinfections. CVL IL-1β and IL-8 were significantly associated with CVL HIV-1 RNA. This persisted after adjusting for plasma HIV-1 RNA. Higher levels of IL-1β were associated with higher concentrations of HIV-1 RNA in CVL (β = 0.25, 95% CI 0.09, 0.42), as were higher levels of IL-8 (β = 0.34, 95% CI 0.17, 0.50). Adjusting for the presence of the coinfections described, this relationship was attenuated for IL-1β (β = 0.16; 95% CI -0.01, 0.33) but still significant for IL-8 (β = 0.29; 95% CI 0.13, 0.45). The proinflammatory cytokines IL-1β and IL-8 are associated with higher cervicovaginal HIV-1 RNA concentrations, even after controlling for plasma viral load and vaginal microbial cofactors. This association suggests that there may be additional, noninfectious causes of inflammation that increase cervicovaginal HIV-1 shedding.

Objective: To compare genital HSV shedding among HIV-positive and HIV-negative women., Methods: Women with and without known HIV infection who delivered at the University of Washington Medical Center between 1989-1996 had HSV serologies done as part of clinical care. Genital swabs from HSV-2-seropositive women were evaluated by real-time quantitative HSV DNA PCR., Results: HSV-2 seroprevalence was 71% and 30% among 75 HIV-positive and 3051 HIV-negative women, respectively, (P < .001). HSV was detected at delivery in the genital tract of 30.8% of HIV-seropositive versus 9.5% of HIV-negative women (RR = 3.2, 95% CI 1.6 to 6.5, P = .001). The number of virion copies shed per mL was similar (log 3.54 for HIV positive versus 3.90 for HIV negative, P = .99)., Conclusions: Our study demonstrated that HIV-, HSV-2-coinfected women are more likely to shed HSV at delivery.

Background: HIV-infected women have a high prevalence of human papillomavirus (HPV) infection and are more likely to be infected with HPV genotypes that are considered high-risk and have the potential for progressing to cervical cancer. The currently available HPV vaccines protect against specific HPV genotypes that may not be the most important causes of dysplasia and potentially of cervical cancer in HIV-1-infected women. African women have been underrepresented in the studies of global prevalence of HPV genotypes., Methods: We compared the HPV genotype distribution in HIV-1-infected women from Seattle, Washington, USA and Nairobi, Kenya. The reverse line blot assay and DNA sequencing on cervicovaginal lavage (CVL) specimens were carried out., Results: The most commonly detected HPV types among the women from Seattle were HPV 56, 66, MM8, and 81; in contrast HPV 53, 33, and 58 were the most common HPV genotypes detected in the CVL specimens from the women in the Nairobi cohort. The HPV types associated with low-grade squamous intraepithelial lesions (LSIL) were HPV 53 and HPV 56. HPV types 58, 52, and 16 were associated with high-grade squamous intraepithelial lesions (HSIL)., Conclusions: A better understanding of HPV genotype distribution in the most affected regions of the world is essential to planning effective vaccine strategies if we are unable to demonstrate cross-protection between HPV genotypes included in the present vaccines and those prevalent in the different populations., (Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: We analyzed the vaginal fluid proteome to identify biomarkers of intraamniotic infection among women in preterm labor., Study Design: Proteome analysis was performed on vaginal fluid specimens from women with preterm labor, using multidimensional liquid chromatography, tandem mass spectrometry, and label-free quantification. Enzyme immunoassays were used to quantify candidate proteins. Classification accuracy for intraamniotic infection (positive amniotic fluid bacterial culture and/or interleukin-6 >2 ng/mL) was evaluated using receiver-operator characteristic curves obtained by logistic regression., Results: Of 170 subjects, 30 (18%) had intraamniotic infection. Vaginal fluid proteome analysis revealed 338 unique proteins. Label-free quantification identified 15 proteins differentially expressed in intraamniotic infection, including acute-phase reactants, immune modulators, high-abundance amniotic fluid proteins and extracellular matrix-signaling factors; these findings were confirmed by enzyme immunoassay. A multi-analyte algorithm showed accurate classification of intraamniotic infection., Conclusion: Vaginal fluid proteome analyses identified proteins capable of discriminating between patients with and without intraamniotic infection., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Objective: To examine trends in twin gestational age over time, with adjustment for potential confounding factors, and to assess twin pair mortality and respiratory support over time., Methods: Rates of preterm births, respiratory support, and neonatal mortality were calculated for 21,569 twin pairs born from 1980 to 2005 in Washington State, using birth certificate and hospital discharge data. Fetal death risks were determined on a "per-pair-at-risk" basis., Results: While the proportion of twins born at 24-31 weeks remained stable at 8%, the proportion born at 32-36 weeks increased from 28% to 48%, and the proportion at 37-42 weeks declined from 64% to 44% (P<0.0001). Controlling individually for a variety of factors, such as maternal age, race, parity, and mode of delivery did not diminish the highly significant trend of increasing preterm births (P<0.0001 for each). Twin pair neonatal mortality decreased significantly through time (P<0.0001); however, the rate of pairs with one or both infants requiring oxygen or ventilation increased significantly through time (P<0.0001). Fetal death risks declined for term twins., Conclusions: The proportion of twins born at 32-36 weeks' gestation has increased over time, along with requirement for respiratory support. Twin pair mortality decreased from 1980 to 2005.

Background: Mycoplasma genitalium is associated with cervicitis and pelvic inflammatory disease in nonpregnant women. We investigated associations between cervical M genitalium, demographic and behavioral risk factors for sexually transmitted infection and preterm birth among low-income Peruvian women., Methods: This case-control study, conducted at the Instituto Nacional Materno Perinatal, Lima, Peru, included 661 cases with a spontaneous preterm birth at <37 weeks and 667 controls who delivered at >or=37 weeks. Within 48 hours after delivery, subjects underwent interviews, medical record review, and collection of cervicovaginal specimens for M. genitalium, Chlamydia trachomatis, and Neisseria gonorrhoeae by nucleic acid amplification testing, and Trichomonas vaginalis by culture. Odds ratios and 95% confidence intervals were calculated for associations between M. genitalium, other genital infections and risk factors, and preterm birth. Multivariable logistic regression was used to adjust for potential confounders., Results: Cervical M. genitalium was detected in 3% of subjects and was significantly associated with C. trachomatis infection (P < 0.001) and preterm birth (4% vs. 2%; adjusted odds ratio: 2.5, 95% confidence interval: 1.2-5.0, P = 0.014), and marginally associated with T. vaginalis (P = 0.05). M. genitalium detection was also associated with younger maternal age (P = 0.003) but not with other risk factors for preterm birth. The association between cervical M. genitalium detection and preterm birth remained significant after adjustment for maternal age and coinfection with C. trachomatis or T. vaginalis., Conclusions: Cervical M. genitalium detection was independently associated with younger maternal age and preterm birth, suggesting that this organism may be an infectious correlate of spontaneous preterm birth.

We compared vaginal proinflammatory cytokine and secretory leukocyte protease inhibitor (SLPI) concentrations among pregnant and nonpregnant women according to bacterial vaginosis (BV) status. One-hundred and twenty-two women at 12-20 weeks' gestation and 133 nonpregnant controls had vaginal concentrations of interleukin (IL)-1β, IL-6, IL-8, and SLPI measured by enzyme immunoassay. Multivariable linear regression was used to evaluate factors independently associated with vaginal cytokine and SLPI response. Pregnancy and BV were both independently associated with increased vaginal concentrations of IL-1β and IL-8; pregnant women had increased concentrations of SLPI, while women with BV had decreased SLPI concentrations.

Objective: Bacterial vaginosis (BV) is associated with preterm delivery, but there is little evidence that treatment improves pregnancy outcomes. We examined whether oral or vaginal metronidazole treatment for BV in early pregnancy was more effective in restoring the normal vaginal environment., Methods: This was a randomized controlled trial comparing oral and intravaginal metronidazole for treatment of BV in early pregnancy (<20 weeks). Vaginal samples collected at baseline and 4 weeks after treatment were evaluated using gram stain, culture, colorimetric detection of sialidase, and immunoassay for measurement of proinflammatory cytokines interleukins-1beta, -6, -8 (IL-1beta, IL-6, IL-8) and secretory leukocyte protease inhibitor (SLPI). We compared the effect of treatment between groups (using chi-square and t test) and within individuals (McNemar's test)., Results: Of 126 subjects, 108 (86%) completed follow-up (55 oral, 53 intravaginal). Of the study population, 34% achieved therapeutic cure, and this was not different between treatment groups. BV-associated bacteria were significantly reduced in both groups, but few subjects regained colonization with protective lactobacilli. Among women who achieved therapeutic cure, the level of IL-1beta dropped significantly (p < 0.001) and SLPI increased (p = 0.003). More women in the vaginal treatment group had undetectable sialidase after treatment (p = 0.013)., Conclusions: Treatment with oral or intravaginal metronidazole in early pregnancy reduced colonization with BV-associated bacteria but was not effective in achieving therapeutic cure or in restoring healthy vaginal lactobacilli.

Background: Compartmentalization of HIV-1 between the genital tract and blood was noted in half of 57 women included in 12 studies primarily using cell-free virus. To further understand differences between genital tract and blood viruses of women with chronic HIV-1 infection cell-free and cell-associated virus populations were sequenced from these tissues, reasoning that integrated viral DNA includes variants archived from earlier in infection, and provides a greater array of genotypes for comparisons., Methodology/principal Findings: Multiple sequences from single-genome-amplification of HIV-1 RNA and DNA from the genital tract and blood of each woman were compared in a cross-sectional study. Maximum likelihood phylogenies were evaluated for evidence of compartmentalization using four statistical tests. Genital tract and blood HIV-1 appears compartmentalized in 7/13 women by >/=2 statistical analyses. These subjects' phylograms were characterized by low diversity genital-specific viral clades interspersed between clades containing both genital and blood sequences. Many of the genital-specific clades contained monotypic HIV-1 sequences. In 2/7 women, HIV-1 populations were significantly compartmentalized across all four statistical tests; both had low diversity genital tract-only clades. Collapsing monotypic variants into a single sequence diminished the prevalence and extent of compartmentalization. Viral sequences did not demonstrate tissue-specific signature amino acid residues, differential immune selection, or co-receptor usage., Conclusions/significance: In women with chronic HIV-1 infection multiple identical sequences suggest proliferation of HIV-1-infected cells, and low diversity tissue-specific phylogenetic clades are consistent with bursts of viral replication. These monotypic and tissue-specific viruses provide statistical support for compartmentalization of HIV-1 between the female genital tract and blood. However, the intermingling of these clades with clades comprised of both genital and blood sequences and the absence of tissue-specific genetic features suggests compartmentalization between blood and genital tract may be due to viral replication and proliferation of infected cells, and questions whether HIV-1 in the female genital tract is distinct from blood.

Understanding the dynamics and spread of human immunodeficiency virus type 1 (HIV-1) within the body, including within the female genital tract with its central role in heterosexual and peripartum transmission, has important implications for treatment and vaccine development. To study HIV-1 populations within tissues, we compared viruses from across the cervix to those in peripheral blood mononuclear cells (PBMC) during effective and failing antiretroviral therapy (ART) and in patients not receiving ART. Single-genome sequences of the C2-V5 region of HIV-1 env were derived from PBMC and three cervical biopsies per subject. Maximum-likelihood phylogenies were evaluated for differences in genetic diversity and compartmentalization within and between cervical biopsies and PBMC. All subjects had one or more clades with genetically identical HIV-1 env sequences derived from single-genome sequencing. These sequences were from noncontiguous cervical biopsies or from the cervix and circulating PBMC in seven of eight subjects. Compartmentalization of virus between genital tract and blood was observed by statistical methods and tree topologies in six of eight subjects, and potential genital lineages were observed in two of eight subjects. The detection of monotypic sequences across the cervix and blood, especially during effective ART, suggests that cells with provirus undergo clonal expansion. Compartmentalization of viruses within the cervix appears in part due to viruses homing to and/or expanding within the cervix and is rarely due to unique viruses evolving within the genital tract. Further studies are warranted to investigate mechanisms producing monotypic viruses across tissues and, importantly, to determine whether the proliferation of cells with provirus sustain HIV-1 persistence in spite of effective ART.

Background: Gingivitis has been linked to adverse pregnancy outcome (APO). Bacterial vaginosis (BV) has been associated with APO. We assessed if bacterial counts in BV is associated with gingivitis suggesting a systemic infectious susceptibilty., Methods: Vaginal samples were collected from 180 women (mean age 29.4 years, SD +/- 6.8, range: 18 to 46), and at least six months after delivery, and assessed by semi-quantitative DNA-DNA checkerboard hybridization assay (74 bacterial species). BV was defined by Gram stain (Nugent criteria). Gingivitis was defined as bleeding on probing at >or= 20% of tooth sites., Results: A Nugent score of 0-3 (normal vaginal microflora) was found in 83 women (46.1%), and a score of > 7 (BV) in 49 women (27.2%). Gingivitis was diagnosed in 114 women (63.3%). Women with a diagnosis of BV were more likely to have gingivitis (p = 0.01). Independent of gingival conditions, vaginal bacterial counts were higher (p < 0.001) for 38/74 species in BV+ in comparison to BV- women. Counts of four lactobacilli species were higher in BV- women (p < 0.001). Independent of BV diagnosis, women with gingivitis had higher counts of Prevotella bivia (p < 0.001), and Prevotella disiens (p < 0.001). P. bivia, P. disiens, M. curtisii and M. mulieris (all at the p < 0.01 level) were found at higher levels in the BV+/G+ group than in the BV+/G- group. The sum of bacterial load (74 species) was higher in the BV+/G+ group than in the BV+/G- group (p < 0.05). The highest odds ratio for the presence of bacteria in vaginal samples (> 1.0 x 104 cells) and a diagnosis of gingivitis was 3.9 for P. bivia (95% CI 1.5-5.7, p < 0.001) and 3.6 for P. disiens (95%CI: 1.8-7.5, p < 0.001), and a diagnosis of BV for P. bivia (odds ratio: 5.3, 95%CI: 2.6 to 10.4, p < 0.001) and P. disiens (odds ratio: 4.4, 95% CI: 2.2 to 8.8, p < 0.001)., Conclusion: Higher vaginal bacterial counts can be found in women with BV and gingivitis in comparison to women with BV but not gingivitis. P. bivia and P. disiens may be of specific significance in a relationship between vaginal and gingival infections.

Racial disparity in preterm birth is one of the most salient, yet least well-understood health disparities in the United States. The preterm birth disparity may be due to differences in how women experience their racial identity in light of neighborhood factors, psychosocial stress, or the prevalence of or response to genital tract infections such as bacterial vaginosis (BV). The latest research emphasizes a need to explore all these factors simultaneously. This cross-sectional study of parous women in King County, Washington, USA investigated the effects of household income, psychosocial stress, and neighborhood socioeconomic characteristics on risk of BV after accounting for known individual-level risk factors. Relevant demographic, socioeconomic, and medical data were linked to U.S. census socioeconomic data by geocoding subjects' residential addresses. It was found that having a low income was significantly associated with an increased prevalence of BV among African American but not White American women. A higher number of stressful life events was significantly associated with higher BV prevalence among both African American and White American women. However, perceived stress was not related to BV risk among either group of women. Among White American women, neighborhood socioeconomic status (SES) was univariately associated with increased BV prevalence by principal components analysis, but was no longer significant after adjusting for individual-level risk factors. No neighborhood SES effects were observed for African American women. These results suggest that both the effects of individual- and neighborhood-level risk factors for BV may differ importantly by racial group, and stressful life events may have physiological effects independent of perceived stress.

The persistent racial disparity in preterm birth (PTB)remains one of the most obvious yet poorly understood health disparities in the United States, and current evidence suggests that maternal stress, infection and inflammation may play an important role in the etiology of PTB. In this context, we assessed the complex relationships among racial identity; socioeconomic status (SES); psychosocial factors; and serum C-reactive protein (CRP), an inflammatory biomarker, among parous women in King County, WA. African-American women consistently reported a higher number of stressful life events than white American women (4.6 vs. 2.9, p < 0.001), as well as slightly higher levels of perceived stress and lower social support (24.7 vs. 22.2, p = 0.011, and 3.4 vs. 3.6, p = 0.06, respectively). In the multivariate analysis, African-American race, low-income status and their interaction were all independently associated with CRP; when further adjusted for proximal psychosocial, behavioral and infectious factors, race and income associations were significantly reduced. Stressful life events score was the single best proximal predictor of CRP levels (beta = 0.07 per event,p < 0.001), while perceived stress and social support were not significantly related to CRP. These results support the hypothesis that differences in CRP by racial identity and income may be mediated by differences in proximal risk factors, including stressful life events and health behaviors such as smoking. Objective life event stressors may be important to consider in future studies investigating a potential inflammatory etiology for preterm birth.

Objectives: To determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population., Methods: Twenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante- and postpartum comparisons were made using paired t-tests and using a 'bioequivalence' approach to determine confidence interval (CI)., Results: The average NVP Area Under the Curve (AUC) was 56 +/- 13 mcg(*)h/mL antepartum and 61 +/- 15 mcg(*)h/mL postpartum. The typical parameters +/- standard error were apparent clearance (CL/F)=3.51 +/- 0.18 L/h and apparent volume of distribution (Vd/F)=121 +/- 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80-1.02. The median (+/- standard deviation) cord blood to maternal NVP concentration ratio was 0.91 +/- 0.90., Conclusions: Pregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.

Background: Information on the subgingival microbiota in parous women is limited. The present study assessed 74 bacterial species at periodontal sites., Methods: Subgingival bacterial plaque was collected from women > or =6 months after delivery. Bacteria were assessed by the checkerboard DNA-DNA hybridization method. Gingivitis was defined as > or =20% of sites with bleeding on probing (BOP), and periodontitis was defined as radiographic evidence of bone loss and probing depths > or =5.0 mm., Results: A total of 197 women (mean age: 29.4 +/- 6.8 years; range: 18 to 46 years) were included in the study. Gingivitis was identified in 82 of 138 subjects without evidence of periodontitis (59.4%). Periodontitis was found in 59 women (32%). Higher bacterial levels in subjects with gingivitis compared to those without evidence of gingivitis were observed for Actinomyces neuii, Bifidobacterium bifidum, Corynebacterium pseudogenitalis, Porphyromonas endodontalis, Prevotella bivia, and Pseudomonas aeruginosa (P <0.001 for each). Higher bacterial levels in subjects with periodontitis compared to those without periodontitis (BOP not accounted for) were found for 32 of 79 species (P <0.001) including Lactobacillus iners, Haemophilus influenzae, Porphyromonas gingivalis, Tannerella forsythia (previously T. forsythensis), Prevotella bivia, P. aeruginosa, and Staphylococcus aureus. Binary univariate logistic regression analysis identified that P. aeruginosa (P <0.001) and T. forsythia (P <0.05) were independently predictive of periodontal status. The odds ratio of having P. aeruginosa at levels > or =1 x 10(5) in the sample and periodontitis was 3.1 (95% confidence interval: 1.6 to 5.9; P <0.001)., Conclusion: In addition to P. gingivalis and T. forsythia, a diverse microbiota, including P. aeruginosa, P. endodontalis, P. bivia, and S. aureus, can be found in subgingival plaque samples from women of child-bearing age with periodontitis.

Background: The effects of gestational nucleoside reverse transcriptase inhibitors (NRTIs) on mitochondrial DNA (mtDNA) are controversial. The effects of mtDNA depletion on mitochondrial function have not been assessed., Method: In peripheral blood mononuclear cells (PBMCs) from infants born to HIV-infected women and infants born to HIV-1-uninfected women, mtDNA copy numbers were determined by quantitative PCR; nuclear (COXIV)- and mitochondrial (COXII)-encoded polypeptides of the oxidative phosphorylation enzyme cytochrome c-oxidase (COX or complex IV) were quantified by Western blot., Results: Overall, 86 infants born to HIV-infected women and 50 controls were studied. HIV-infected mothers had a median CD4 count of 506 cells/microL; 59% had HIV RNA 50 copies/mL. No infant had clinical evidence of mitochondrial disease. The birth weight was lower (p = .016) and the body length higher (p = .002) in the HIV-exposed newborns. Eighty-one HIV-infected women had received gestational NRTIs (median duration 162 days). Median mtDNA copies/PBMC in the HIV-exposed infants were 505 (range, 120-1365) vs. 213 (27-426) in controls (p < .001). COX II/IV ratios were similar in both groups. Although mtDNA levels correlated inversely with maternal lactate, mitochondrial indices did not correlate with maternal CD4+ count, HIV RNA, smoking, or alcohol consumption., Conclusion: We found elevated mtDNA copy numbers in PBMC of infants born to HIV-infected women, the majority of whom received NRTI-based therapy, when compared to those born to healthy HIV-negative controls, but there was no difference in mtDNA-encoded respiratory chain protein. The clinical consequence of these findings is unknown and requires further investigations.

Background: Concomitant use of antiretroviral (ARV) and hormonal contraceptives may change the metabolism of each and the resulting safety profiles. We evaluated the safety and tolerability of depot medroxyprogesterone acetate (DMPA) among women on ARV., Study Design: HIV-infected women on selected ARV regimens or no ARV were administered DMPA 150 mg intramuscularly and evaluated for 12 weeks for adverse events, changes in CD4+ count and HIV RNA levels, and ovulation., Results: Seventy evaluable subjects were included, 16 on nucleoside only or no ARV, 21 on nelfinavir-containing regimens, 17 on efavirenz-containing regimens and 16 on nevirapine-containing regimens. Nine Grade 3 or 4 adverse events occurred in seven subjects; none were judged related to DMPA. The most common findings possibly related to DMPA were abnormal vaginal bleeding (nine, 12.7%), headache (three, 4.2%), abdominal pain, mood changes, insomnia, anorexia and fatigue, each occurring in two (2.9%) subjects. No significant changes in CD4+ count or HIV RNA levels occurred with DMPA. No evidence of ovulation was detected, and no pregnancies occurred., Conclusions: The clinical profile associated with DMPA administration in HIV-infected women, most on ARV, appears similar to that seen in HIV-uninfected women. DMPA prevented ovulation and did not affect CD4+ counts or HIV RNA levels. In concert with previously published DMPA/ARV interaction data, these data suggest that DMPA can be used safely by HIV-infected women on the ARV studied.

Background: To investigate the effect of exposure to protease inhibitor (PI) therapy in utero on cord blood lipids in infants born to mothers enrolled in AIDS Clinical Trials Group protocol 5084, a prospective, multicentre, observational study of antiretroviral therapy (ART) during pregnancy., Methods: Clinical outcome was determined in 80 infants born to women treated with PIs and 73 infants born to women treated with other antiretrovirals during pregnancy. Cord blood serum from 117 of these infants was assayed for total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein A1 (apoA1), apolipoprotein B100 (apoB) and lipoprotein (a). Covariates considered in the analysis included race/ethnicity, gestational age, infant gender, infant birth weight, mode of delivery, maternal tobacco and alcohol use, post-partum body mass index, and ART duration., Results: Cord blood total and HDL cholesterol, triglyceride, apoA1, apoB, lipoprotein (a) and apoB/apoA1 ratio were not different between the two groups. Cord blood lipid levels in these HIV-exposed infants were similar to those reported in other neonatal cohorts. Controlling for race/ethnicity, infants born to women treated with PIs had higher LDL cholesterol than those born to women not treated with PIs (29 mg/dl versus 27 mg/dl, P = 0.006)., Conclusion: Only LDL cholesterol was significantly higher in the cord blood of PI-exposed infants versus those not exposed to PIs in utero. As the difference between the two groups was small, the clinical relevance of the effect of maternal PI treatment on infant LDL cholesterol levels at birth is not clear.

Objective: To analyze dizygotic twinning rates and outcomes over a 25-year period., Methods: Birth and fetal death certificates from 1980-2004 in Washington State, USA, were analyzed retrospectively to find factors associated with the increase in sex-discordant twins through time. "Low" and "high" fertility treatment groups were defined according to demographic traits. Perinatal mortality was defined as fetal or neonatal death of one or both twins and Weinberg's rule was used to estimate mortality for monozygotic and dizygotic pairs., Results: Controlling simultaneously for maternal age, race, parity, and education did not eliminate the trend of increasing sex-discordant twins from 1992-2004 (M-H chi2 P=0.001). The "low" fertility group had a non-significant decline in sex-discordant twins (M-H chi2 P=0.24), whereas the "high" fertility group had a significant increase (M-H chi2 P=0.001). Perinatal mortality decreased for monozygtic twin pairs throughout the study period, but decreased until the mid-1990s and then increased slightly through 2004 for the dizygotic twin pairs., Conclusion: Advancing maternal age and increasing use of fertility treatments are largely responsible for the increase in dizygotic twins from 1980-2004 and may also be responsible for the stalling of the decline in perinatal mortality rate.

Unlabelled: The presence of semen in vaginal fluid, as identified by an acid phosphatase spot test, does not influence vaginal proinflammatory cytokine concentrations., Objective: Determine whether semen, as detected by acid phosphatase, influences vaginal cytokines or secretory leukocyte protease inhibitor concentrations., Methods: 138 pregnant women had vaginal fluid collected for Gram stain, acid phosphatase detection by colorimetric assay, and interleukin 1-Beta, interleukin-6, interleukin-8, and secretory leukocyte protease inhibitor measurement by enzyme immunoassay. Results for women with and without acid phosphatase were compared by Mann-Whitney test., Results: Of 138 subjects, 28 (20%) had acid phosphatase detected; of these, only 19 (68%) reported recent intercourse and 3 (11%) had sperm seen on Gram stain. There were no significant differences in proinflammatory cytokine concentrations; however, secretory leukocyte protease inhibitor concentrations were significantly higher among women with acid phosphatase., Conclusions: Proinflammatory cytokine measurement does not appear to be affected by the presence of semen, but secretory leukocyte protease inhibitor is significantly higher when semen is present. Detection of semen by acid phosphatase was associated with higher vaginal SLPI concentrations, however, the presence of semen did not appear to influence vaginal proinflammatory cytokine concentrations.

Objective: This study measures the relative performance of three methods for diagnosing bacterial vaginosis (BV) during pregnancy and assesses the implications of measurement for clinical practice and surveillance., Methods: A sample (n = 1,780) of English or Spanish speaking women, with a singleton intrauterine pregnancy and receiving prenatal care at a consortium of public health centers in Philadelphia were consecutively enrolled. Gram stain, clinician's diagnosis, and a commercial test were the three diagnostic methods used to assess BV. Sensitivity, specificity, and the positive and negative predictive values of clinical diagnosis and the commercial test were assessed using the gram stain/Nugent score as a gold standard., Results: The prevalence of BV, measured on the same population, differed considerably depending on the diagnostic test used. The measured prevalences were 55% (Gram stain), 28.5% (clinician's diagnosis), and 12.6% (commercial test). The prevalence of BV (diagnosed by gram stain) was twice as high among African American women compared to White women. Only 69% BV-positive high-risk women were treated for BV., Conclusions: Inaccurate diagnosis of BV leads to missed cases. The identification of true cases is critical for assigning treatment and for assessing treatment effectiveness. Clinician's routine diagnosis fell short of recommended procedures and performed poorly compared to gold standard in case ascertainment. This inability to ascertain cases may have an impact on our ability to prevent preterm birth.

Objectives: The aim of this study was to determine whether oral zidovudine (ZDV) given during labour would provide a similar systemic exposure to the established intravenous regimen used to prevent mother-to-child transmission in HIV-infected pregnant women., Methods: ZDV pharmacokinetic parameters following oral administration during labour were determined in 10 HIV-infected pregnant women in active labour. All subjects were converted to intravenous ZDV prior to delivery., Results: In cohort 1 (n=6), subjects received 300 mg oral ZDV every 3 h for three doses. Oral therapy was well tolerated but plasma ZDV concentrations were substantially lower than previously reported with continuous intravenous therapy. Based on the pharmacokinetic results from cohort 1, women in cohort 2 (n=4) received an initial 600 mg dose followed by two 400 mg doses every 3 h. ZDV area under the curve and concentrations in cohort 2 increased approximately in proportion to the increase in dose but varied 6-7-fold. In both cohorts, ZDV pharmacokinetic parameters suggested erratic absorption., Conclusions: While ZDV exposure improved with the increased dosing regimen, our sample size was small and larger studies are needed to establish whether oral ZDV administration during labour can consistently provide equivalent exposure to intravenous administration.

Dengue viral infections present a significant risk during pregnancy to both mother and fetus. A young woman at 13 weeks' gestation presented with fever and abdominal pain following a diarrheal illness after returning from Puerto Rico. Over the course of 5 days, she developed nausea, petechiae, severe thrombocytopenia, and acalculous cholecystitis. After a serologic diagnosis of acute infection with dengue virus, she was provided supportive care. An uncomplicated pregnancy led to delivery of a healthy infant at 40 weeks gestation. Travel during pregnancy to dengue-endemic areas poses a risk to both mother and fetus. Pregnancies complicated by dengue infection require close monitoring for potential maternal and fetal complications.

The objective of this study was to examine the associations between lower genital tract infection, racial group and preterm birth in the Vaginal Infections and Prematurity Study, a large prospective cohort study conducted between 1984 and 1989. This analysis included 11 910 women enrolled at 23-26 weeks' gestation with equal representation from self-identified African American, Hispanic and white women. Subjects were screened for Chlamydia trachomatis, Trichomonas vaginalis and bacterial vaginosis at study entry, and their pregnancy outcomes were ascertained after delivery. The primary outcome of interest was preterm delivery of a low-birthweight infant (<37 weeks and <2500 g). The associations between lower genital tract infection and preterm delivery of a low-birthweight infant were examined within each racial group, with adjustment for potential confounders using multivariable logistic regression. In this cohort, 6.4% of African Americans, 3.8% of Hispanics, and 4.4% of whites had a preterm delivery of a low-birthweight infant (P < 0.001). Lower genital tract infection was significantly associated with preterm delivery of a low-birthweight infant among African Americans, but not among other racial groups. The proportion of preterm birth associated with lower genital tract infection was 21% among African Americans and 5% among whites. The increase in infection-associated preterm birth among African Americans appears to be related both to an increased prevalence of lower genital tract infection, and also to an increased risk of preterm delivery of a low-birthweight infant in the context of lower genital tract infection.

Objective: The objective of the study was to determine whether protease inhibitors increase glucose intolerance and insulin resistance in pregnancy., Study Design: In this multicenter, prospective, observational study, 149 human immunodeficiency virus-1-infected pregnant women had fasting insulin, glucose, and C-peptide measured followed by a 1 hour, 50 g glucose test. Glucose intolerance was defined as a 1 hour glucose greater than 130 mg/dL. Glucose intolerance, homeostasis model assessment of insulin resistance and pancreatic beta-cell function, and pregnancy outcomes were compared between those taking protease inhibitors and those not., Results: Fifty-seven of 149 subjects (38%) had glucose intolerance. Body mass index, Hispanic ethnicity, and maternal age, but not protease inhibitors, were associated with glucose intolerance. There were no differences in insulin resistance, beta-cell function, or pregnancy outcome associated with protease inhibitor use., Conclusions: Protease inhibitors do not increase risk of glucose intolerance or insulin resistance among pregnant women.

Objective: To assess toxicities associated with highly active antiretroviral therapy (HAART) among HIV-1-infected pregnant women treated with nevirapine-based regimens according to Mozambican national guidelines., Study Design: Prospective cohort study., Methods: HIV-1-infected antiretroviral-naive pregnant women with CD4 counts < or =350 cells/microL were initiated on nevirapine, lamivudine, and stavudine or zidovudine and followed monthly. Severe hepatotoxicity was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > or =5-fold the upper limit of normal. Analyses were stratified by baseline CD4 count (<250 vs. 250-350 cells/microL)., Results: Among 146 pregnant women, 75 (52%) began nevirapine, lamivudine, and zidovudine and 71 (48%) began nevirapine, lamivudine, and stavudine. Overall, 79 (54%) women had CD4 counts <250 cells/microL, 7 (5%) had grade II hepatotoxicity, and 4 (3%) had severe (grade III or IV) hepatotoxicity. All 4 women with severe hepatotoxicity had baseline CD4 counts > or =250 cells/microL (P = 0.02). Rates of skin toxicity, anemia, and peripheral neuropathy did not differ by CD4 cell count group. Overall, 12 (8%) women changed or discontinued HAART as a result of drug toxicity., Conclusions: Severe hepatotoxicity from nevirapine-containing HAART in this cohort of pregnant women was more common at higher CD4 counts (6% vs. 0% among women with CD4 counts > or =250 cells/microL and CD4 counts <250 cells/microL, respectively), suggesting that laboratory monitoring is necessary when administering nevirapine-containing regimens to pregnant women with CD4 counts > or =250 cells/microL.

Objectives: To determine the effects of vaginal, cervical, and endometrial infections on shedding of HIV-1 RNA in the female genital tract., Design: Cross-sectional., Methods: Antiretroviral-naive women from Nairobi, Kenya with CD4 cell counts >or= 350 cells/mul had plasma and endocervical wick samples collected for HIV quantification by real-time RNA reverse transcriptase-polymerase chain reaction. Vaginal and cervical Gram stains and endometrial biopsies were obtained. Vaginal Gram stain was used to diagnose bacterial vaginosis and to quantify Lactobacillus levels., Results: Twenty-six of 50 (52%) women had detectable endocervical HIV-1 RNA with a median endocervical viral load of 1760 copies/ml (range: undetectable to 1 1,030,000 copies/ml). Women with decreased Lactobacillus had 15.8-fold [95% confidence interval (CI), 2.0-123] greater endocervical HIV-1 RNA than women with normal Lactobacillus levels. Women with plasma cell (PC) endometritis [>or= 1 PC/high-power field (hpf)] had a 15.8-fold (95% CI, 2.0-120) higher endocervical HIV RNA level than women without PC endometritis. Both these associations remained after controlling for plasma viral load. Cervicitis (>or= 30 polymorphonuclear leukocytes/hpf), however, was not associated with endocervical HIV-1 RNA shedding (P = 0.81)., Conclusions: In HIV-1-infected, antiretroviral-naive women without symptoms of pelvic inflammatory disease infection, abnormal vaginal flora and inflammatory cells in the endometrium affected HIV-1 shedding from the lower genital tract. These data suggest that both the upper and lower genital tracts contribute to female HIV-1 genital shedding.

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.

An interviewer orientation protocol and standardized interview can be an effective way of orienting multiple interviews to qualitative research. A standardized interview involves an actor taught to portray a research participant consistently in several interview encounters. In this article, the authors describe the interview protocol, and the development and application of a standardized interview. The benefits of using a standardized interview as a formative method to orient multiple interviewers include assessing the interviewers' integration of the interview protocol, the nonverbal and verbal presentation of the interview process between interviewers, and the general flow of the interview from interviewer to interviewer. As more qualitative research is conducted using multiple interviewers, the method of an interview protocol and subsequent standardized interview might be helpful when orienting interviewers to the challenges and promises of conducting research using a critical framework.

To determine if HIV-1 resistance testing of the blood predicts mutants in the genital secretions of ZDV-treated pregnant women, ZDV resistance mutations were assessed by an oligonucleotide ligation assay. ZDV resistance was detected in viral sequences from blood (16/48; 33%) and cervical secretions (6/24; 25%) collected during 57 pregnancies. The genotype of 11/69 (16%) resistance codons was discordant between blood and cervical virus of pregnant women near term. However, in only 1 (1.8%) of 57 pregnancies evaluated was resistant virus limited to the cervical secretions. ZDV-resistant virus is rarely limited to the female genital tract.

Placental efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) protect the developing fetus from exposure to potentially toxic xenobiotics. However, little is known about the expression of these transporters in human placentae of different gestational ages. Therefore, we quantified the expression of P-gp and BCRP in human placentae of different gestational ages. We also measured the expression of various nuclear regulatory factors such as the pregnane xenobiotic factor to determine whether their expression also changes with gestational age. Syncitial microvillous plasma membranes were isolated from human placentae of various gestational ages (60-90 days, 90-120 days, and full-term C-section placentae). P-gp and BCRP expression (protein) in these preparations were measured by Western blot analysis followed by an ELISA. Expression (mRNA) of P-gp, BCRP, and nuclear regulatory factors in the placentae were quantified by quantitative real-time PCR. P-gp expression (relative to that of alkaline phosphatase) was significantly (P < 0.05) higher (44.8-fold as protein; 6.5-fold as mRNA) in early gestational age human placentae (60-90 days) vs. term placentae. In contrast, BCRP (protein and mRNA) and nuclear regulatory factors (mRNA) expression in placental tissue did not change significantly with gestational age. However, placental expression of P-gp and human chorionic gonadotropin-beta (hCG-beta) transcripts was highly correlated (r = 0.73; P < 0.0001; Spearman rank correlation). Expression of P-gp, but not BCRP, decreases dramatically with gestational age in human placentae. This decrease in P-gp expression is not caused by a change in expression of nuclear receptor transcripts but appears to be related to hCG-beta expression. The placental P-gp expression appears to be upregulated in early pregnancy to protect the fetus from xenobiotic toxicity at a time when it is most vulnerable to such toxicity.

Objective: The purpose of this study was to compare maternal and neonatal morbidity among Somali immigrants, US-born blacks and whites in Washington state., Study Design: Washington state birth certificate data was linked to hospital discharge records comparing singleton deliveries among Somali immigrants with US-born blacks and whites between 1993 and 2001, in a 1:3 ratio. Outcomes were compared using unconditional multiple logistic regression models calculating odds ratios (ORs), and 95% confidence intervals (95% CIs)., Results: Five hundred seventy-nine pregnancies from Somali women were compared with 2384 and 2435 pregnancies from black and white women, respectively. Nulliparous Somali women were more likely to have a cesarean delivery than black or white control women, OR 1.6 (95% CI, 1.1-2.3) and 2.0 (95% CI, 1.4-2.8), respectively. Among all women who had cesarean deliveries, Somali women more commonly had cesarean deliveries associated with fetal distress and failed induction of labor. They were 9 times more likely than both control groups to deliver after 42 weeks gestation, and 4 times more likely than black women and 8 times more likely than white women to have oligohydramnios. Somali women were more likely to have gestational diabetes and significant perineal lacerations, and less likely to smoke. Newborns of Somali women were at increased risk for prolonged hospitalization, lower 5-minute Apgar scores, assisted ventilation, and meconium aspiration., Conclusion: Pregnancy outcomes should be evaluated within ethnically and culturally unique groups; Somali immigrants are a high-risk subpopulation.

Objective: To determine whether second-born twins (B) have higher morbidity and mortality than first-born twins (A), using a paired analysis., Study Design: We conducted a retrospective analysis of birth certificates and fetal and infant death certificates for 5138 twin pairs selected from those born in Washington State from 1989 to 2001. Twin A was vertex and delivered vaginally. Pairs were not size-discordant (< 20%) and had no malformations. Matched-pair odds ratios were calculated., Results: Twin B had more fetal distress (OR=6.0) and more low 5-min Apgar scores (OR=2.1) than Twin A, except at short delivery intervals. Pairs had relatively high rates of combined vaginal plus cesarean deliveries at delivery intervals 15 min., Conclusion: If prompt vaginal delivery of Twin B does not occur, the benefits of vaginal delivery for Twin A might not outweigh the risks of distress and low Apgar scores in Twin B and vaginal plus cesarean delivery for the mother.

This study evaluates the safety, tolerance, and pharmacokinetics of stavudine (d4T) in human immunodeficiency virus (HIV)-infected zidovudine (ZDV)-intolerant/refusing pregnant women and of single-dose d4T in their infants. Women received d4T and lamivudine (3TC) from enrollment until labor. During labor, women received oral 3TC and either intravenous or oral d4T. Infants received ZDV and 3TC for 6 weeks and a single dose of oral d4T at weeks 1 and 6. Mean maternal antenatal d4T pharmacokinetics (terminal plasma half-life [T1/2], 83.5+/-16.8 min; area under the plasma-concentration time curve [AUC0-infinity), 81.6+/-22.0 microg.min/mL; n=6) were not significantly different from those during labor (T(1/2), 87.3+/-24.7 min; AUC0-infinity, 88.1+/-16.6 microg.min/mL; n=6). Umbilical-cord and maternal plasma concentrations were not significantly different from one another. The oral clearance of d4T in infants was significantly greater at week 6 versus week 1 (6.8+/-1.0 vs. 5.6+/-1.2 mL/min/kg). There were no toxicities, in women or infants, that required discontinuation or modification of the study drug. No infants had positive HIV viral diagnostic tests. d4T with or without 3TC is a potential alternative to ZDV for HIV-infected pregnant women.

Objective: Two single-base polymorphisms of the tumor necrosis factor-alpha gene (TNF-alpha) at positions -863 and -308 are associated with variation in production of TNF-alpha (TNF-alpha). TNF-alpha genotypes were tested for association with adverse outcomes in mother-infant pairs with preterm labor., Study Design: We analyzed a cohort of 118 mother-infant pairs with preterm labor before 34 weeks' gestation. Polymerase chain reaction was used on extracted deoxyribonucleic acid for polymorphism assay. Outcomes included amniotic fluid TNF-alpha concentration, histologic chorioamnionitis, delivery gestational age, and composite neonatal morbidity. Statistical significance was determined by chi 2 and Kruskal-Wallis analysis of variance., Results: Mothers homozygous for the -863 polymorphism (AA) had significantly earlier deliveries ( P = .02), more chorioamnionitis ( P = .03), and greater composite neonatal morbidity ( P = .03). Neither maternal nor fetal carriage of the -308 polymorphism was associated with adverse outcome., Conclusion: In women with preterm labor before 34 weeks' gestation, maternal homozygous carriage of the -863 polymorphism may be associated with preterm delivery and adverse neonatal outcome.

Objective: To evaluate whether the fact that blood from premenopausal, ovulatory women shows a significant fluctuation in tumor necrosis factor-alpha (TNF-alpha) levels when tested randomly over time is related to the hormonal cycle., Study Design: In this pilot study, whole blood was collected from 8 women during the follicular, ovulatory and midluteal phases of the menstrual cycle. Ovulation was confirmed by luteinizing hormone surge and mid-luteal progesterone levels. For each subject at each phase of the menstrual cycle, TNF-alpha levels were measured at baseline and after stimulation of whole blood with 10 microg/mL of lipopolysaccharide (LPS). Supernatant was collected and assayed by enzyme-linked immunosorbent assay. TNF-alpha levels were compared with the Wilcoxon matched pairs signed rank sum test., Results: Whole blood unstimulated by LPS showed increasing TNF-alpha levels over the hormonal cycle, with significantly increased median levels during the luteal phase (903 pg/mL; range, 0-3707) as compared with the follicular phase (162 pg/mL; range, 0-656) (P = .03). Blood stimulated with LPS showed increased TNF-alpha levels overall but no association with cycle timing., Conclusion: TNF-alpha levels in unstimulated whole blood appear to be associated with menstrual cycle timing, with highest levels during the luteal phase. However, the lack of variation in TNF-alpha production after LPS stimulation suggests that experiments do not need to be timed with the menstrual cycle.

Our objective was to identify bacterial species present in culture-negative but 16S rDNA-positive amniotic fluid samples from women in preterm labor. Amniotic fluid from 69 women in preterm labor was cultured and examined for the proinflammatory cytokine interleukin-6 (IL-6). Polymerase chain reaction technology was used to detect highly conserved bacterial ribosomal DNA sequences (16S rDNAs). As previously reported, 16S rDNAs were identified in 15 (94%) of 16 culture-positive amniotic fluid samples, in 5 (36%) of 14 culture-negative samples with elevated IL-6, and in 1 (3%) of 39 culture-negative samples with low IL-6 levels. Direct sequencing was performed of 16S rDNAs from the 5 culture-negative amniotic fluid specimens with elevated IL-6, followed by database searches and phylogenetic analyses. The bacterial sequences identified included: two Leptotrichia sanguinegens, one human oral bacterium A33, one Fusobacterium nucleatum, and one Ureaplasma urealyticum. Identification and sequencing of 16S rDNAs in amniotic fluid is a promising technique to identify bacterial species associated with elevated IL-6 levels in culture-negative amniotic fluid that may contribute to the etiology of premature labor.

Context: Intra-amniotic infection (IAI) is commonly associated with preterm birth and adverse neonatal sequelae. Early diagnosis of IAI, however, has been hindered by insensitive or nonspecific tests., Objective: To identify unique protein signatures in rhesus monkeys with experimental IAI, a proteomics-based analysis of amniotic fluid was used to develop diagnostic biomarkers for subclinical IAI in amniotic fluid and blood of women with preterm labor., Design, Setting, and Participants: Surface-enhanced laser desorption-ionization/time-of-flight mass spectrometry, gel electrophoresis, and tandem mass spectrometry were used to characterize amniotic fluid peptides in 19 chronically instrumented pregnant rhesus monkeys before and after experimental IAI. Candidate biomarkers were determined by liquid chromatography-tandem mass spectrometry. Polyclonal antibodies were generated from synthetic peptides for validation of biomarkers of IAI. Amniotic fluid peptide profiles identified in experimental IAI were subsequently tested in a cohort of 33 women admitted to Seattle, Wash, hospitals between June 25, 1991, and June 30, 1997, with preterm delivery at 35 weeks or earlier associated with subclinical IAI (n = 11), preterm delivery at 35 weeks or earlier without IAI (n = 11), and preterm contractions with subsequent term delivery at later than 35 weeks (n = 11)., Main Outcome Measures: Identification of peptide biomarkers for occult IAI., Results: Protein expression profiles in amniotic fluid showed unique signatures of overexpression of polypeptides in the 3- to 5-kDa and 10- to 12-kDa molecular weight ranges in all animals after infection and in no animal prior to infection. In women, the 10- to 12-kDa signature was identified in all 11 patients with subclinical IAI, in 2 of 11 with preterm delivery without IAI, and in 0 of 11 with preterm labor and term delivery without infection (P<.001). Peptide fragment analysis of the diagnostic peak in amniotic fluid identified calgranulin B and a unique fragment of insulinlike growth factor binding protein 1, which were also expressed in maternal serum. Mapping of other amniotic fluid proteins differentially expressed in IAI identified several immunoregulators not previously described in amniotic fluid., Conclusions: This proteomics-based characterization of the differential expression of amniotic fluid proteins in IAI identified a distinct proteomic profile in an experimental primate chorioamnionitis model that detected subclinical IAI in a human cohort with preterm labor. These diagnostic protein expression signatures, complemented by immunodetection of specific biomarkers in amniotic fluid and in maternal serum, might have application in the early detection of IAI.

Objective: To compare the safety of nelfinavir and nevirapine-based antiretroviral treatment in HIV-1-infected pregnant women., Methods: In Pediatric AIDS Clinical Trials Group Protocol 1022, 38 antiretroviral-naive pregnant women at 10-30 weeks' gestation were randomized to nelfinavir or nevirapine with zidovudine plus lamivudine. The study was suspended because of greater than expected toxicity and changes in nevirapine prescribing information. The incidence of treatment-limiting hepatic or cutaneous toxicity was compared between groups for all subjects and for the subset with CD4 cell counts greater than 250 cells/microL at study entry., Results: Toxicity was seen in 1 (5%) of 21 subjects randomized to nelfinavir and 5 (29%) of 17 subjects randomized to nevirapine (P = 0.07). Within the nevirapine group, 1 subject developed fulminant hepatic failure and died, and another developed Stevens-Johnson syndrome. The one adverse event associated with nelfinavir occurred in a subject with a CD4 cell count less than 250 cells/microL. All 5 events among subjects with a CD4 cell count greater than 250 cells/microL were associated with nevirapine (P = 0.04)., Conclusions: Continuous nevirapine may be associated with increased toxicity among HIV-1-infected pregnant women with CD4 cell counts greater than 250 cells/microL, as has been observed in non-pregnant women.

Preterm premature rupture of membranes (PPROM) is responsible for 30% of neonatal morbidity and mortality in premature gestations. We sought to evaluate pregnancy outcomes in PPROM managed uniformly with antibiotics and steroids, and to determine what maternal factors influence latency. This was a retrospective analysis of 134 patients at 24 to 31.9 weeks with PPROM. Associations of maternal and pregnancy characteristics with latency were evaluated by chi-square for linear trend, nonparametric tests, or multivariable linear regression, as appropriate. Forty-three of 134 women (32%) had latencies greater than a week. Gestational age ( p < 0.001), admission white blood cell count ( p = 0.001), and amniotic fluid index ( p = 0.02) were independently predictive of latency. Histopathologic funisitis increased with pregnancy length. There were no fetal deaths or significant intraventricular hemorrhage past 28 weeks.

Objective: The purpose of this study was to determine whether size-discordant twin pairs have worse perinatal mortality and neonatal morbidity rates than nondiscordant pairs and whether the smaller twins of discordant pairs have worse perinatal outcomes than the larger twins., Study Design: We conducted a population-based, retrospective analysis of linked birth certificates and fetal and infant death certificates for 9590 twin pairs who were born in the state of Washington from 1987 through 1999. The Cochran-Mantel-Haenszel test, Student t test, and McNemar test were among the tests used to assess statistical significance., Results: Discordant twin pairs had higher rates of perinatal mortality, neonatal mortality, and 5-minute Apgar scores of <7, even after stratification by gestational age. Discordant pairs had lower pair weights at each gestational age and were more likely to include small-for-gestational-age infants. Compared with the larger twins, the smaller twins of discordant pairs had higher rates of perinatal mortality., Conclusion: Discordant pairs had worse perinatal outcomes within each gestational age category.

Objective: The purpose of this study was to determine whether the microbial hydrolytic enzymes, sialidase and prolidase, and immunoglobulin A against the Gardnerella vaginalis cytolysin (anti-Gvh IgA) increase the risk for early preterm birth (< or =34 weeks of gestation) among women with bacterial vaginosis or intermediate flora., Study Design: Two hundred eighteen afebrile women in preterm labor with intact membranes had a vaginal Gram stain performed, and sialidase, prolidase, and anti-Gvh IgA concentrations were determined., Results: Women with bacterial vaginosis or intermediate flora had significantly higher sialidase and prolidase concentrations than women with normal flora. Among women with bacterial vaginosis or intermediate flora, the women with sialidase had a higher rate of early preterm birth (P =.05). Sialidase had a sensitivity of 43% and specificity of 77% for early preterm birth. Prolidase and anti-Gvh IgA did not predict early preterm birth., Conclusion: Women in preterm labor with bacterial vaginosis or intermediate flora and detectable sialidase are at increased risk of early preterm birth.

Objective: We examined the hypothesis that amniotic fluid (AF) infection and elevated cytokine concentrations may cause neonatal injury beyond that expected solely from prematurity., Methods: The effects of exposure to AF infection and elevated cytokine concentrations were measured in 151 infants born to afebrile women in preterm labor with intact membranes at less than or equal to 34 weeks' gestation. Amniotic fluid was collected by amniocentesis for culture and determination of tumor necrosis factor-alpha and interleukin-6. Cytokine concentrations, stratified by AF infection, were compared for three gestational age groups. We then examined the associations between a positive AF culture or elevated AF tumor necrosis factor-alpha concentration and adverse neonatal outcomes, adjusted for birth weight., Results: Amniotic fluid from 45 (30%) of 151 pregnancies had microorganisms, an elevated tumor necrosis factor-alpha concentration, or both. Amniotic fluid cytokine concentrations were significantly higher among women in preterm labor at less than or equal to 30 weeks, compared with 31-34 weeks. Nine of 11 infants who died at less than or equal to 24 hours of age had AF infection or elevated AF tumor necrosis factor-alpha. For the 140 surviving infants, AF infection and/or an elevated AF tumor necrosis factor-alpha was associated with respiratory distress syndrome (adjusted odds ratio [OR] 1.7), grade 3-4 intraventricular hemorrhage (adjusted OR 2.2), necrotizing enterocolitis (adjusted OR 1.8), and multiple organ dysfunction (adjusted OR 3.0)., Conclusion: Among infants born at less than or equal to 34 weeks to women who have intact membranes and are initially afebrile, those exposed to AF bacteria or cytokines have more adverse neonatal outcomes than unexposed infants of similar birth weight.

Objective: To compare cytokine production after lipopolysaccharide stimulation of whole blood from women who were delivered of infants at term compared with women who were delivered of preterm infants with intra-amniotic evidence of infection or inflammation., Study Design: Whole blood samples from 12 women who were not pregnant and who had previously had preterm deliveries before 32 weeks complicated by intra-amniotic infection or inflammation and samples from 12 age- and race-matched control subjects were stimulated with Escherichia coli lipopolysaccharide. Tumor necrosis factor-alpha and interleukin-6 levels were quantified at 6 hours and interleukin-10 at 24 hours by enzyme immunoassay. Results were compared with use of the Wilcoxon rank sum test., Results: Tumor necrosis factor-alpha production was significantly higher in whole blood from women with histories of a preterm birth and intra-amniotic infection or inflammation (11,243 +/- 1030 pg/mL [mean +/- SEM]) compared with control subjects (3649 +/- 349 pg/mL) at a lipopolysaccharide concentration of 1 microg/mL (P =.002). There were no significant differences in interleukin-6 or interleukin-10 production., Conclusion: Women with previous early preterm deliveries who had evidence of intra-amniotic infection or inflammation had significantly higher tumor necrosis factor-alpha production after lipopolysaccharide stimulation of whole blood compared with women with previous term deliveries.