Risk Factors for Intrapartum Transmission
A number of factors were strongly associated with risk of presumed intrapartum transmission, including maternal age, race/ethnicity, antenatal cigarette smoking, hard drug use, CD4+ cell percentage, viral load, and antiretroviral treatment and infant gestational age and birth weight (Tables 2 and 3). The rate of presumed intrapartum transmission declined dramatically over time, ranging from 13.9% in 1990-1992 to 0.5% in 1999-2001. There was a strong monotonic increase in the risk of intrapartum transmission with increasing DROM, ranging from 3.9% among those with elective cesarean section or a very brief DROM to 34.5% among those with exceptionally long DROM (P < 0.0001). Risk of intrapartum transmission was strongly related to geometric mean viral load during pregnancy, with risks ranging from <1% among those with undetectable viral load to 27% among those with the highest viral load. For mothers who did not receive antenatal antiretroviral therapy, the risk of intrapartum transmission was estimated to be 12.8%, whereas for those receiving highly active antiretroviral therapy, the risk was <1%.
We examined the association between premature birth (birth at <37 weeks' gestation) and intrapartum transmission in substrata defined by DROM. The association between premature birth and intrapartum transmission appears to be strongest among those with long DROM. Considering those with DROM of >4 hours, the estimated risk of transmission among those infants born premature was 22% (23 of 104) compared with 9% (33 of 369) among full-term infants. In contrast, for those with DROM of ≤4 hours, the association between prematurity and intrapartum transmission was not strong: the estimated risk of intrapartum transmission among premature infants was 6% (7 of 120) compared with 4% (32 of 758) among full-term infants.
Relative Proportion of In Utero Versus Intrapartum Transmission
Among HIV-1-infected children, the proportion of those infected in utero increased over time from 27% in 1990-1992 to 54% in 1997-1998 and, most recently, 80% in 1999-2001 (Table 3; P = 0.072 for trend). For the infected infants, only DROM differentiated those with presumed in utero infections from those with presumed intrapartum infections (P = 0.009).
Association Between Risk Factors and Time of Transmission, Controlling for Maternal Antenatal Viral Load and Antiretroviral Treatment
Maternal antenatal viral load and antiretroviral treatment were likely to confound the relationships between many variables of interest because they were strongly associated with both modes of transmission and were also strongly associated with many of the other variables of interest. To assess the degree to which these other variables were associated with transmission controlling for viral load and antiretroviral treatment, we fit a logistic regression model for each risk factor that was significant in the bivariate analysis.
With regard to in utero transmission, after controlling for viral load and antiretroviral treatment, low birth weight remained significantly associated with in utero transmission (Table 4). Maternal hard drug use was no longer significantly associated with in utero transmission; however, on the basis of the confidence interval, the data are still consistent with a possible 3-fold increased odds of in utero transmission among those who used hard drugs. Calendar year of delivery and DROM were no longer associated with in utero transmission after controlling for viral load and antiretroviral treatment.
With regard to intrapartum transmission, after controlling for viral load and antiretroviral treatment, age, CD4+ cell percentage, calendar year of delivery, preterm birth, low birth weight, and DROM all remained significant predictors (Table 5). Race/ethnicity, hard drug use, and cigarette smoking were not statistically significant predictors after controlling for viral load and antiretroviral treatment.
Associations Allowing for Misclassification
Tables 4 and 5 also present estimated associations between risk factors and time of transmission based on the assumption that 20% of those infants with in utero transmission were misclassified and 20% of those infants with intrapartum transmission were misclassified. The estimated associations were substantially the same as the estimates arrived at when there was no allowance for misclassification, although the P values are somewhat higher.
The timing of the first positive HIV-1 culture or DNA PCR assay is often used to distinguish between in utero and intrapartum transmission. Our results provide support for the accuracy of this approach to the classification of infants. Using results of virologic assays up to 7 days of age to differentiate between in utero and intrapartum transmission, we observed a very strong association between increasing DROM and presumed intrapartum transmission and a lack of a consistent association between increasing DROM and presumed in utero transmission. Because DROM can logically only affect transmission occurring during the intrapartum period, these results are consistent with the hypothesis that HIV-1-infected children with negative HIV-1 culture and DNA PCR assays during the first week of life acquired the infection during the intrapartum period and those with a positive virologic assay at up to 7 days of age acquired the infection during the intrauterine period.
Additional support for the use of virologic assays up to 7 days of age to differentiate in utero and intrapartum transmission can be gleaned from several clinical trials comparing different prenatal prophylaxis regimens. Lallemant et al16 reported on a comparison of 2 antenatal regimens of zidovudine prophylaxis (starting at 28 vs. 35 weeks' gestation). In this study, in utero infection was defined as an infant with a positive HIV-1 DNA PCR assay within 7 days of birth. Presumably any difference between the regimens should be attributable to the longer regimen, further reducing the risk of in utero transmission; consistent with this hypothesis, the study did find a significant difference in the rate of presumed in utero infections by duration of antenatal zidovudine therapy (1.6% with long vs. 5.1% with short antenatal zidovudine treatment).
Additional data from the WITS that support use of this definition of in utero infection include the finding of a higher CD8+ and CD8+HLA-DR+ (activated) lymphocyte percentage during the first week of life for HIV-1-infected infants with the first positive virologic assay in the first 7 days of life compared with infected infants with positive virologic assays later, consistent with in utero infection; the infants with later positive assays were not different than uninfected infants at birth but had increased CD8+ and CD8+HLA-DR+ percentages similar to those for the infants with early positive tests by 1 month of age, consistent with intrapartum timing of transmission.17
Despite this support for the use of our definition of presumed in utero infection, the distribution of age at the first positive HIV-1 culture does not separate clearly into 2 distinct intervals; therefore, there is no natural cutoff to distinguish time of transmission, and some misclassification is inevitable.18 However, our analyses demonstrated that the standard analytic approaches are robust to small degrees (20%) of misclassification.
The association between low birth weight and in utero transmission observed in our study has also been reported by other investigators.3,6 This association could be explained in several different ways. One possibility is that in utero infection impedes fetal growth.19 Another possibility is that there is a common risk factor for both slow fetal growth and in utero transmission (such as poor nutrition or prenatal care).20,21 A third possibility is that children with slower fetal growth are more susceptible to in utero transmission.
A number of studies, primarily in the era before antiretrovirals, that evaluated risk factors for perinatal HIV-1 transmission observed an association between preterm birth and higher risk of transmission.2,22-26 Consistent with the findings of Kuhn et al,2 we observed that this association was mainly among those infants with intrapartum transmission. This suggests that the association between premature birth and transmission may be due to an increased susceptibility of premature infants to HIV-1 infection, rather than to an effect of HIV-1 infection on gestation. Consistent with this conclusion is our finding that the association between preterm birth and intrapartum transmission was strongest among those infants with long DROM. It has been suggested that the increased susceptibility of preterm infants to HIV-1 might be due to their immature immune systems, increased permeability of neonatal mucosal barriers,27 or low levels of maternal antibodies because active placental transfer of immunoglobulin G from mother to infant is low until ∼32 weeks' gestation.28
Use of antiretroviral therapy and potency of antiretroviral therapy have increased over time, and maternal antenatal viral load has decreased over time in the WITS, with concomitant decreases in the overall rate of perinatal transmission.29 Maternal antenatal viral load and antiretroviral therapy are associated with both in utero and intrapartum HIV-1 transmission, and as might be expected, the absolute rates of both in utero and intrapartum transmission have also declined over time. However, although the absolute number of infections has decreased, the relative rate of in utero infection appears to have increased over time in the WITS, from 27% in 1990-1992 to 80% in 1999-2001.
It had been speculated that with the increase of interventions that take place around the time of delivery (eg, intrapartum antiretroviral administration and elective cesarean section), the proportion of HIV-1-infected infants who acquired the infection in utero would increase.30 The use of intravenous zidovudine during labor was uncommon before 1994, when the results of PACTG 076 became available; however, after 1994, this became standard of care for HIV-1-infected women in the United States.31,32 Although a change in the use of this intrapartum antiretroviral intervention may have accounted for some of the proportional shift in the timing of transmission immediately after 1994, it does not account for the continued shift in relative timing of transmission over time, with the largest shift occurring between 1997-1998 and 1999-2001. This shift is likely secondary to an increase in elective cesarean delivery after the 1999 publications of a randomized trial and large meta-analysis and subsequent recommendations by the American College of Obstetricians and Gynecologists and the U.S. Public Health Service Task Force for elective cesarean delivery for HIV-1-infected women with RNA levels near delivery of >1000 copies/mL.31,33-35 In our study, the rate of elective cesarean sections increased from 5% before 1999 to 25% for births in 1999 or later. Although elective cesarean delivery was not found to be significantly protective in our study (P = 0.11), in 18% of cases the medical records did not contain information about whether cesarean delivery was elective or nonelective in nature, compromising our ability to find a difference, and the number of women undergoing cesarean delivery was small compared with other studies.34,35
In addition, in our analysis DROM remained significantly associated with intrapartum transmission, even when controlling for antenatal viral load and antiretroviral therapy. Because elective cesarean delivery occurs before any membrane rupture, it effectively reduces membrane rupture to 0, and one would anticipate that it would substantially reduce intrapartum transmission, while not affecting in utero infection. It should be noted that DROM and mode of delivery were unknown for ∼18% of our study sample. However, because the probability of having missing information on these variables is unlikely to be related to the HIV status of the infant, we do not think that these missing data would introduce a large bias.
In summary, although perinatal transmission of HIV-1 has significantly decreased over time, the few infants who currently become infected appear more likely to have been infected during the in utero period. Risk factors for in utero transmission included maternal drug use, viral load, and antiretroviral therapy. These data suggest that interventions to further reduce perinatal transmission in the United States would include identification of maternal HIV infection before, or early in, pregnancy, improved access to and provision of drug treatment of addicted HIV-infected pregnant women, and use of highly active antiretroviral combination therapy starting early in pregnancy to provide maximal suppression of viral replication. Some researchers have reported higher rates of disease progression among infants infected in utero.36 Further research is needed to determine whether there have been differences over time in the proportion of infants at higher risk of rapid disease progression.
Principal investigators, study coordinators, program officers, and funding included the following: Clemente Diaz and Edna Pacheco-Acosta (University of Puerto Rico, San Juan, PR; U01 AI 034858); Ruth Tuomala, Ellen Cooper, and Donna Mesthene (Boston/Worcester Site, Boston, MA; 9U01 DA 015054); Phil La Russa and Alice Higgins (Columbia Presbyterian Hospital, New York, NY; U01 DA 015053); Sheldon Landesman, Edward Handelsman, and Ava Dennie (State University of New York, Brooklyn, NY; U01 HD 036117); Kenneth Rich and Delmyra Turpin (University of Illinois at Chicago, Chicago, IL; U01 AI 034841); William Shearer, Susan Pacheco, and Norma Cooper (Baylor College of Medicine, Houston, TX; U01 HD 041983); Joana Rosario (National Institute of Allergy and Infectious Diseases, Bethesda, MD); Robert Nugent (National Institute of Child Health and Human Development, Bethesda, MD); Vincent Smeriglio and Katherine Davenny (National Institute on Drug Abuse, Bethesda, MD); and Bruce Thompson (Clinical Trials & Surveys Corp., Baltimore, MD, N01 AI 085339). Scientific Leadership Core included Kenneth Rich (principal investigator) and Delmyra Turpin (study coordinator) (1 U01 AI 050274-01).
Additional support has been provided by local Clinical Research Centers as follows: Baylor College of Medicine, Houston, TX; NIH GCRC RR000188; Columbia University, New York, NY; NIH GCRC RR000645.
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Keywords:© 2005 Lippincott Williams & Wilkins, Inc.
timing of transmission; vertical transmission; misclassification; secular trends; antiretroviral therapy