Sexually transmitted infections (STIs) including Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) pose a tremendous burden worldwide. In 2008, the World Health Organization (WHO) estimated that 105.7 million new CT and 106.1 million NG infections occured.1 Sexually transmitted infections remain highest in low- and middle-income countries, including in regions of Africa and Latin America. HIV-infected pregnant women represent a high-risk, neglected group for STIs.
Untreated chlamydial and gonococcal infections can have serious consequences in pregnant women. They may lead to fetal loss, premature rupture of membranes, and preterm labor and delivery.2–5 Maternal chlamydial infections may lead to conjunctivitis and pneumonia in infants.4 Gonococcal infections may also cause neonatal conjunctivitis and, in rare cases, can lead to disseminated infections in infants.3
In addition, STIs such as CT and NG have been postulated to increase the risk of HIV transmission from mother to child. Studies from nonpregnant women suggest that those STIs may increase genital HIV viral shedding, which may be attenuated by STI treatment.6,7 Other research has focused on a role for STIs in increasing HIV mother-to-child transmission (MTCT), particularly in utero transmission, by triggering placental inflammation or chorioamnionitis.8–15 However, few studies have provided direct support of causality, especially for CT and NG.16–19
Given limited published research documenting the prevalence of CT and NG in HIV-infected pregnant women in low- and middle-income countries and the potential impact of these infections on HIV MTCT, the following substudy evaluated rates of CT and NG infection in a high-risk group of HIV-infected mothers. We characterized rates of CT and NG infection by geographic distribution, sociodemographics, pregnancy, and HIV-related maternal parameters. We also wanted to determine if maternal CT and NG infection was associated with increased HIV MTCT.
METHODS
Study Design
This study was a substudy of the National Institute of Child Health and Human Development (NICHD) HIV Prevention Trials Network (HPTN) 040 trial. NICHD/HPTN 040 (P1043) was a phase 3, triple-arm, randomized, open-label, multicenter study aimed at the prevention of intrapartum HIV transmission to infants born to HIV-infected pregnant women, who had not received antiretrovirals drugs until labor and delivery due to late diagnosis of infection. The study evaluated the efficacy, safety, and tolerance of 3 different infant antiretroviral prophylaxis regimens. The study demonstrated that infants receiving 2- or 3-drug antiretroviral HIV prophylaxis had a decreased risk of acquiring intrapartum HIV infection than did those receiving zidovudine alone.20 Participants were enrolled between April 2004 and July 2010.
Study enrollment consisted of 1684 HIV-infected pregnant women diagnosed as being HIV infected at the time of labor and delivery. All mothers provided written informed consent. Enrollment occurred at multiple sites in Brazil, South Africa, Argentina, and the United States. Infants younger than 32 weeks were excluded from the study.
At the time of enrollment, all mothers were interviewed about risk behaviors including use of illegal substances, alcohol, and tobacco during pregnancy. Data were collected on history of STIs and STI symptoms but were unable to be analyzed due to insufficient number of responses. Information was obtained regarding receipt of prior prenatal care and obstetric history including prior preterm deliveries and stillbirths. Maternal plasma HIV RNA levels and T-lymphocyte subsets were obtained at the time of labor and delivery. In addition, syphilis testing was performed at the time of labor and delivery using Venereal Disease Research Laboratory (VDRL) test titers with confirmatory treponemal syphilis antibody tests, as per standard of care.21 Infant data from the time of birth were collected, including HIV antiretroviral treatment arm. Infants were followed up until 6 months of age for safety and toxicity monitoring in the parent study. The primary end point of the parent study was HIV infection status at 3 months of age.
HIV Diagnosis
HIV testing of infants occurred within 48 hours of birth, 14 days, 4 to 6 weeks, 3 months, and 6 months of age. Confirmatory HIV DNA testing was done for positive results. Diagnosis of infant HIV infection required 2 positive HIV DNA polymerase chain reaction (PCR; Roche Molecular Systems Inc, Basel, Switzerland) results collected on different days. During the primary study, infants with a positive HIV DNA PCR test result at birth and confirmatory results on repeat testing were classified as having in utero HIV infection. Infants with a negative HIV DNA PCR result at birth and positive results on subsequent testing were classified as intrapartum HIV infection. HIV laboratory assays were performed by quality assured laboratories supported by the NICHD and the International Maternal Pediatric Adolescent AIDS Clinical Trials group. All HIV-exposed infants enrolled in the study were formula fed.
Specimen Collection and Chlamydia and Gonorrhea Testing
Stored maternal urine samples collected at the time of labor and delivery or within 48 hours of giving birth were frozen and stored at study sites. Aliquots (7 mL each) of stored frozen urine were shipped for testing at Cepheid, Sunnyvale, CA. Urines were tested for the presence of CT and NG using the Xpert CT/NG assay. Results were reported as positive, negative, or indeterminate. Indeterminate test results were repeated up to 2 times, and those that remained indeterminate were excluded from data analysis.
Statistical Analysis
The Kruskal-Wallis test was used to compare the median differences for continuous variables (age in years, CD4 count, and log10 HIV viral load) with respect to categorical outcome (STI status: CT only, NG only, CT and NG coinfection, and uninfected). χ2 test was used to compare differences in STI prevalence for categorical variables. Univariate and multivariable logistic regression modeling was then used to examine the relationship of overall maternal STI status with demographic, substance use, pregnancy, and select characteristics including study site, categorical age, occupation, race/ethnicity, illegal substance use, alcohol use, tobacco use, prior preterm birth, prior stillbirth, prenatal care status, and mode of delivery. To further assess the association of potential risk factors with each STI group, stratified analyses were also performed. The covariates with a P value of 0.2 or less were selected to enter into the initial model selection. Covariates with an overall P value less than 0.05 were retained in the final model. To compare STI groups with respect to HIV MTCT as a categorical outcome, frequency distributions were done and P values were calculated with the exact test from Monte Carlo simulations. Odds ratio (OR) using 95% confidence interval (CI) and P values were calculated from exact logistic models to further evaluate the relationship between maternal STI groups and the outcome of HIV MTCT. All computations were done using SAS software v9.3 (Cary, NC).
Human Subjects
Both the parent trial and the substudy were approved by the relevant institutional review boards.
RESULTS
Urine samples from 1406 HIV-1–infected women were tested using the Xpert CT/NG assay on the GeneXpert platform. After the exclusion of 33 invalid or inconclusive results, data from participants with 1373 valid urine test results were included in the analysis (81.5% of the 1684 women enrolled in the parent study).
Chlamydia and Gonorrhea Prevalence
Of the 1373 HIV-infected pregnant women included in this study, 249 (18.1%) had CT, 63 (4.6%) had NG, and 35 (2.5%) were coinfected with both CT and NG. Overall, 277 (20.2%) of this sample were positive for CT, NG, or both CT and NG. Rates of CT and NG were highest in South Africa, where 21.3% (87) had CT and 7.6% (31) had NG. Rates were also high in Brazil, where 17.1% (160) were positive for CT and 3.4% (32) were positive for NG. In Argentina, there were no cases of NG, but CT was identified among 10.5% (2) of the 19 women. No cases of either CT or NG were found among the 7 women enrolled in the United States.
Chlamydia, Gonorrhea, and Association With Maternal Parameters
Of the 1373 HIV-infected pregnant women included in this analysis, 938 (68.3%), 409 (29.8%), 19 (1.4%), and 7 (0.5%) women were enrolled from study sites in Brazil, South Africa, Argentina, and the United States, respectively. This distribution is commensurate with the distribution of participants in the main study. The overall mean (SD) age of women at all study sites was 26.9 (6.4) years. Table 1 shows various study participant characteristics by STI status. Significant differences were noted by age (P < 0.0001). Women between 13 and 24 years of age or 25 and 29 years of age were 2.2 times (OR, 2.2; 95% CI, 1.6–3.1) or 1.7 times (OR, 1.7; 95% CI, 1.1–2.4) more likely to have an STI (CT, NG, or both) than those 30 years or older. Additional analysis revealed that younger age (13–24 years) was also specifically associated with any CT, NG, or coinfection. That association was most pronounced for younger women and CT and NG coinfection (OR, 6.2; 95% CI; 2.1–18.3; Tables 1–3).
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TABLE 1: Maternal Demographic, Pregnancy, and HIV-Related Characteristics by STI Status
TABLE 2: Logistic Regression Analysis Exploring Relationship of Overall STI (CT and/or NG Coinfection) With Maternal Demographics, Pregnancy, and HIV-Related Characteristics
TABLE 3: Logistic Regression Analysis Exploring Relationship of Individual Maternal STIs: CT, NG, and CT and NG Coinfection with Maternal Demographics and Pregnancy Parameters
High rates of illegal substance, tobacco, and alcohol usage in pregnancy were found in the sample: 111 (8.1%) women reported use of illegal substances, whereas 438 (32.1%) used tobacco and 476 (35%) used alcohol during pregnancy. Significant differences in usage by STI group were noted for illegal substance (P = 0.05) and tobacco use (P = 0.02). Illegal substance usage was associated with NG infection and coinfection in the initial unadjusted analysis. Only tobacco usage was significantly associated with overall STI (OR, 1.4; 95% CI, 1.1–1.9) as well as any CT (OR, 1.4; 95% CI, 1.0–1.8) or NG infection (OR, 1.8; 95% CI, 1.1–3.1) by adjusted logistic regression analyses (Tables 1–3).
Of the study sample, 845 (61.7%) women reported at least some prenatal care during their pregnancy, with significant differences noted by STI status (P < 0.001). Receiving prenatal care in pregnancy was protective against any STI (OR, 0.7; 95% CI, 0.6–0.98), with similar findings noted for adjusted analysis for any CT (OR, 0.7; 95% CI, 0.5–0.96), NG (OR, 0.5; 95% CI, 0.3–0.9), or CT and NG coinfection (OR, 0.3; 95% CI, 0.2–0.7). Women who were delivered by cesarean section were less likely to have an STI (OR, 0.5; 95% CI, 0.3–0.6), with similar findings also noted when evaluated specifically for any CT, NG, or coinfection (Tables 1–3).
Women also reported high rates of prior adverse pregnancy and neonatal outcomes: 252 (18.5%) women reported a history of preterm birth with significant differences found by STI group, and 59 (4.3%) reported a history of stillbirth. Although prior preterm birth was associated with any STI as well as any NG or CT and NG coinfection in unadjusted analyses, these were not significant findings with adjusted analyses. History of stillbirth was associated with any STI and CT infection in preliminary evaluation but was not significant after adjusted analyses (Tables 1–3).
The median maternal CD4 count at delivery was 458 (interquartile range [IQR], 291–663) cells/mm3, and the median log10 HIV plasma viral load was 4.2 (IQR, 3.6–4.7) copies/mL. No significant differences were noted by STI status. No associations were found between CD4 count or log10 HIV plasma viral load and overall STI status, CT, NG, or CT and NG coinfection. Viral load was also dichotomized using cutoffs of more than 20,000 as well as more than 25,000 copies/mL but continued to show no significant difference in the number of women with higher viral loads (>20,000 or >25,000) among STI groups (Tables 1 and 2).
Chlamydia, Gonorrhea, and HIV MTCT
There were 117 cases (8.5% transmission) of HIV MTCT in our study sample, of which 75 cases (64.1%) occurred in utero and 42 cases (35.9%) intrapartum. HIV MTCT rates were lowest among infants born to CT- and NG-uninfected mothers as compared with those infected with CT only or both CT and NG (8.1% vs. 10.7% and 14.3%, respectively; P = 0.04). There were no cases of HIV MTCT among NG-infected mothers. In utero HIV MTCT was the highest among mothers coinfected with CT and NG (8.6%) or mothers who had CT alone (7.5%). In contrast, HIV MTCT rates in women without an STI were 5.1% for in utero transmission and 3.0% for intrapartum HIV transmission. A marginally statistically significant association between CT-infected mothers and overall HIV MTCT was noted by logistic regression analysis (OR, 1.47; 95% CI, 0.9–2.3) with similar findings for in utero HIV MTCT (OR, 1.59; 95% CI, 0.9–2.7). Comparisons of HIV MTCT among women dually infected with CT and NG and those without these STIs demonstrated a 6.2% difference in HIV MTCT rates, although results were not statistically significant (Tables 4 and 5). In this subcohort, 129 women were VDRL positive (9.4%), a similar rate to that reported in the parent study of 10%.20 Twenty-nine women with syphilis (22.5% of the VDRL-positive women in this cohort) were also coinfected with CT, NG, or both. In this group, there were 5 transmissions, 4 in utero and 1 intrapartum. An analysis of syphilis coinfection in the 040 study has been recently published.22
TABLE 4: Distribution of Maternal STI Status and HIV MTCT
TABLE 5: Logistic Regression Analysis of Maternal STI Status and HIV MTCT
DISCUSSION
Prevalence of Chlamydia and Gonorrhea and Maternal Parameters
This study is notable for the high prevalence of CT (18.1%) and NG (4.6%) among a unique cohort of HIV-infected pregnant women with a late diagnosis of HIV and a possible association of CT infection with increased HIV MTCT. Limited published data exist on the prevalence of CT and NG in pregnant women in Latin America and Africa. Prior WHO estimates of CT and NG infections among women may underestimate the prevalence of these infections, particularly as they are often asymptomatic. For instance, WHO prevalence estimates of CT and NG are 2.6% and 2.3% among women in Africa, and 7.6% for CT and 0.8% for NG in the Americas.1
Our analysis of STI prevalence by country study site revealed that STI rates in this high-risk group of HIV-infected pregnant women were particularly elevated in South Africa (CT 21.3%, NG 7.6%) and in Brazil (CT 17.1%, NG 3.4%). Our sample's STI rates seem higher than most reported studies from Brazil, Argentina, and African countries.11,18,21,23–26
Our results that younger maternal age and a history of no prenatal care were associated with CT or NG infection have also been documented in prior studies.17,27–29 Lack of prenatal care and STIs has also been previously reported, especially with regard to higher rates of HIV and other STIs such as syphilis.30 In our study, although more than half of the sample had some form of prenatal care, it was clear that prenatal care had been suboptimal as mothers were only found to be HIV-infected at the time of delivery. Tobacco usage has also been associated as a risk factor for STIs, CT in particular, in prior studies.31,32 Although our study found high rates of substance use, adjusted analysis failed to confirm association with STIs such as NG. None of the women reported being sex workers, although information regarding exchange of sex for drugs or money was not collected.
Women in our sample also had high rates of prior adverse pregnancy outcomes. More than 18% reported a history of preterm birth, which is much higher than preterm birth rates reported in the general populations in the United States (12%), Brazil (9.2%), and South Africa (8%).33 Similarly, the prior stillbirth rate of 4.3% in our study population seems to be high, although it has been reported to range from 3.1 to 32.9 per 1000 total births in some high-income countries and in sub-Saharan Africa.34,35 Although differences in history of preterm birth and STI group were noted, no significant association was found after adjusted analysis. That initial association in the unadjusted analysis was interesting because STIs are a known risk factor for preterm birth.3,36–38
HIV MTCT
The collective results of this study seem to provide some support for the hypothesis that maternal STIs (CT and possibly CT in combination with NG) in pregnancy may predispose to an increased risk of HIV MTCT, particularly in utero transmission. However, the relationship was not noted for NG only–infected women, where there were no cases of HIV MTCT. One explanation for this lack of association for maternal NG infection and HIV MTCT may be due to the small number of NG only–infected women but should be interpreted cautiously. In addition, the ability to observe any effect of maternal STIs on intrapartum transmission may have been limited by the parent study's objective of evaluating antiretroviral prophylaxis regimens to prevent intrapartum HIV transmission. Because the interventions were effective in preventing intrapartum HIV acquisition, a much smaller number of intrapartum infections occurred.
Overall, our findings seem consistent with one of the primary studies to find a positive association between STIs such as CT or NG and increased risk of HIV MTCT, which was a randomized controlled trial of 1078 HIV-infected pregnant women evaluating the role of vitamin supplements and HIV MTCT.16 Although NG infection in the study population was only 1% and those infected were treated, they found that NG-infected mothers had a 5.5-fold increased risk for intrauterine HIV transmission; CT was not part of their evaluation.16 However, our findings contrast with other studies including one from Thailand that did not show increased HIV MTCT in spite of high STI rates, and the Rakai, Uganda, STI treatment intervention study that failed to decrease HIV MTCT in spite of lowering rates of STIs among pregnant women.17–19,39 Another phase 3 clinical trial in sub-Saharan Africa (HPTN 024) also did not show improvement in either HIV MTCT or pathological chorioamnioitis with antenatal and intrapartum antibiotics given to reduce rates of chorioamnionitis from other genital tract infections such as bacterial vaginosis and Trichomonas vaginalis.9,11,40
Maternal plasma viral load is considered one of the main predictors of HIV MTCT, although our study found no differences in maternal plasma HIV viral load by STI group even when stratified by those with viral loads more than 20,000 or more than 25,000 copies/mL, which may pose higher risks of MTCT. Other commonly cited MTCT risk factors include low CD4 counts, increased exposure to maternal blood or cervicovaginal secretions, and chorioamnionitis.12,16,41 Maternal plasma viral load was not significantly different in mothers coinfected with STIs in comparison with those uninfected with STIs. The role of STIs as a risk factor for increased HIV MTCT has been suggested by observational studies in pregnant women with genital tract infections including herpes simplex virus 2, bacterial vaginosis, human papillomavirus, and syphilis.13 Multiple studies in nonpregnant women have suggested that STIs including CT and NG may increase the risk of HIV cervicovaginal viral shedding possibly from inflammation-induced recruitment of HIV-infected cells in secretions, T-cell activation resulting in increased replication of HIV, and disruption of the mucosal epithelial barrier.6,7,42,43 Increased HIV shedding is estimated to range by as much as 1.5- to 1.8-fold for CT and 1.8- to 2.4-fold for NG,42,43 but may be reduced by STI treatment.6,7
Apart from genital tract infections triggering cervicitis, which may increase HIV MTCT via enhanced cervicovaginal HIV viral shedding,13,44,45 some studies suggest that STIs may also play a role in increased HIV MTCT by causing chorioamnionitis via acute or chronic placental membrane inflammation.8,12,14–16 The presence of chorioamnionitis itself may lead to a 2.9- to 7.6-fold increased risk of HIV MTCT, especially in utero transmission.8,14 Additional studies in our same NICHD HPTN 040 cohort of mother-infant pairs demonstrated a significant association between maternal syphilis and HIV MTCT, particularly with in utero HIV transmission.22,46 Similarly, in a subpopulation of nearly 1000 infants studied in our cohort, congenital cytomegalovirus (CMV) infection was highly prevalent in the group, particularly among HIV in utero–infected infants.47 One hypothesis is that the findings of this study in conjunction with our other NICHD HPTN 040 results may suggest that it is placental inflammation triggered by these infections (CT, CT and NG, syphilis, and/or CMV) that may be facilitating HIV transmission, possibly promoted by immune activation enhancing the expression of CCR5 T-cell receptors that increase viral infectivity.48
One limitation of our study was that although maternal CD4 counts and plasma HIV viral load did not differ significantly by STI status, maternal HIV cervicovaginal viral shedding studies were not performed. Because cervicovaginal samples were not collected during the study, we were also unable to test for other reproductive tract infections such as bacterial vaginosis, T. vaginalis, and herpes simplex virus. Maternal and congenital syphilis was analyzed previously in another substudy,22 whereas the present study is focused mainly on CT and NG coinfections. However, given the results of all of our subanalyses, we plan to report results and overlap of infectious disease processes in 040 in a separate publication. This report includes CT, NG, syphilis, and CMV in respect to HIV perinatal transmission. Furthermore, as a substudy, the sample size was based on convenience. As a result, the ability to detect small differences in MTCT between STI groups was affected by insufficient power, particularly for our MTCT rates that were less than 17%. Our sample size for the MTCT analysis was further affected by the 74 (5.4%) infants with unknown HIV status who were lost to follow-up or died before the 3-month study end point. The lack of HIV status for those infants may have weakened the relationship between STI group and HIV MTCT in our cohort, as 14 (18.9%) infants had mothers with an STI.
CONCLUSIONS
This study provides important information about the prevalence of CT and NG infection among neglected groups such as HIV-infected pregnant women presenting late for care. With 1 in 5 women infected with CT and/or NG in our sample, certain vulnerable groups such as young women with undiagnosed HIV infection seem to also be at high risk for other STI coinfection during pregnancy. Although further studies powered to detect HIV MTCT differences among STI-infected women are needed, this study provides some evidence to suggest that untreated CT and possibly coinfection with CT and NG may be a risk factor for increased HIV MTCT in populations such as ours. Given the improved ability to decrease HIV intrapartum MTCT rates to as low as 2% with infant antiretroviral prophylaxis regimens in HIV-infected, late-presenting women (as in our NICHD HPTN 040 cohort), perhaps renewed efforts should be placed on also addressing potential unnecessary risk factors for in utero transmission, which may be as high as 9% for high-risk mothers with an untreated HIV and an STI. Given that screening and treatment of STIs in many countries around the world is not routine and continues to rely on the “syndromic approach,” our study results may also underscore the need for prenatal laboratory-based STI screening and treatment programs in combination with existing efforts to identify pregnant women at high risk for undiagnosed HIV infection. Although more definitive evidence is needed, such programs may aid in preventing adverse pregnancy and neonatal outcomes, including the potential to further minimize the risk of HIV MTCT.
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