Magder, Laurence S.*; Mofenson, Lynne†; Paul, Mary E.‡; Zorrilla, Carmen D.§; Blattner, William A.∥; Tuomala, Ruth E.¶; LaRussa, Phil#; Landesman, Sheldon**; Rich, Kenneth C.††
Mother-to-child HIV-1 transmission can occur in utero, intrapartum, or postnatally through breast-feeding. Different factors may influence HIV-1 transmission during each of these time periods, and hence interventions to reduce transmission during each of these periods may also require different preventive strategies. Many studies that have evaluated risk factors for transmission have pooled together all cases of transmission. If some of the risk factors do indeed differ, pooling in utero cases with intrapartum or postnatal cases could lead to an underestimate of the impact of some risk factors and perhaps a failure to identify others. Some studies have tried to distinguish risk factors for transmission occurring during these different time points.1-7
One difficulty in distinguishing risk factors for transmission during different time periods is determining which children have acquired infection in utero and which have acquired it during delivery. The usual approach has been to base the classification on whether the child is positive or negative by HIV-1 culture or DNA polymerase chain reaction (PCR) assay during the first 48 hours of life.8 However, it is possible that this approach could lead to some misclassification, which could reduce the ability to distinguish risk factors for the 2 types of transmission. In addition, virologic testing during the first 48 hours of life may not always be available.
The Women and Infants Transmission Study (WITS) is an ongoing, prospective, multicenter, longitudinal study of maternal-infant HIV-1 transmission in non-breast-feeding infants in the United States that began enrollment in 1989. We used the WITS data and a definition of presumed in utero transmission based on the timing of the first positive HIV-1 culture or DNA PCR assay to identify distinct risk factors for in utero and intrapartum transmission. In addition, we used probabilistic approaches to allow for the possibility that some of the children were misclassified with respect to the timing of transmission using our definitions. Finally, we evaluated trends in the proportion of in utero and intrapartum transmission over time in the WITS.
The WITS is an ongoing, multicenter, prospective cohort study evaluating factors associated with perinatal HIV-1 transmission in the United States and the natural history of HIV-1 disease in pregnant women and their infants, as described previously.9 Enrollment began in 1989 and is ongoing at study centers in New York, NY; Boston/Worcester, MA; San Juan, PR; Chicago, IL; and Houston, TX. The institutional review boards at each of the separate sites approved all parts of the WITS protocol, and informed consent was obtained from all women.
HIV-1-infected women are enrolled during pregnancy and evaluated up to 3 times during pregnancy and at delivery. At each visit, detailed medical and behavioral questionnaires are administered, physical examination is performed, and blood samples are collected for laboratory evaluations. Obstetric data are abstracted from medical records. Maternal urine samples obtained at study entry and during labor or immediately after birth undergo drug toxicology screening; positive urine tests are confirmed by gas chromatography-mass spectrometry.
CD4+ lymphocyte count is determined at each visit, and serial HIV-1 RNA levels in stored samples are measured, as previously described.10 Antiretroviral treatment is at the discretion of the clinical provider. Some women had >1 pregnancy in the cohort. For this study, we included only the first singleton WITS pregnancy for each woman.
Infants are examined and have peripheral venous blood samples obtained during the first 6 days of life (after April 1994, visits occurred and blood samples were obtained within the first 48 hours after birth and again at 6-10 days) and then at 1, 2, 4, 6, 9, 12, and 18 months of age and every 6 months thereafter. Virologic tests to define infant infection status at these visits include HIV-1 peripheral blood mononuclear cell culture and/or HIV-1 DNA PCR assay, as previously described.11,12 None of the infants are breast-fed.
Definition of HIV Infection
Before June 1998, infants were defined as HIV infected based on ≥2 positive HIV-1 peripheral blood mononuclear cell cocultures. After June 1998, HIV-1 DNA PCR assay was used in place of the HIV-1 culture. Positive results of HIV-1 DNA PCR assay were confirmed by HIV-1 RNA PCR assay or HIV culture. Using culture, an infant was categorized as uninfected if the infant had ≥2 negative culture results at or after 1 month of age, at least 1 negative culture result at or after 6 months of age, and no positive culture results. Using DNA PCR assay, an infant was categorized as uninfected if the infant had 3 negative results at separate visits at or after 1 month after birth with no positive results. Infants not meeting these criteria were classified as having an indeterminate infection status and were excluded from this analysis.
Definition of Presumed In Utero and Intrapartum Infection
One commonly accepted approach has been to assume that those infants with positive virologic assays in the first 48 hours after birth acquired the infection in utero and that those with negative virologic assays during the first week and positive virologic assays thereafter acquired the infection during delivery.8 Because the WITS did not collect infant blood specimens during the first 48 hours of life until April 1994, ∼31% of HIV-1-infected children with positive blood specimens during the first week of life were not tested until after 48 hours of age; therefore, for the purpose of this study, we defined presumed in utero infection to include infants for whom the first HIV-1 virologic test was positive during the first 7 days of life and presumed intrapartum infection to include infants who had negative HIV-1 virologic tests during the first 7 days of life but subsequently were found to be infected.
Definitions and Measurement of Risk Factor Variables
Maternal HIV load was measured at variable times during pregnancy and delivery. For this analysis, we used the geometric mean of all viral load measurements during pregnancy to define antenatal viral load. Similarly, maternal CD4+ lymphocyte percentage was measured at variable times during pregnancy; for this analysis, we used the arithmetic mean of all CD4+ cell percentage measurements during pregnancy to define antenatal CD4+ cell percentage.
Maternal hard drug use (defined as use of opiates and/or cocaine) was ascertained by self-report and/or urine toxicology screening-proven use of drugs during any perinatal or delivery visit, as previously described in greater detail.13 Women who either reported drug use or tested positive for drug use were considered to be hard drug users.
Antiretroviral treatment during pregnancy was defined as follows: highly active antiretroviral therapy, a treatment regimen including ≥3 drugs, 1 of which was a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor or the 3-drug combination of zidovudine, lamivudine, and abacavir; combination therapy, either 2 drugs, 1 of which could be a protease inhibitor or nonnucleoside reverse transcriptase inhibitor, or ≥2 drugs that did not include a protease inhibitor, nonnucleoside reverse transcriptase inhibitor, or the combination of zidovudine, lamivudine, and abacavir; and monotherapy, treatment with a single drug.
Data on duration of membrane rupture (DROM) and mode of delivery were acquired by medical chart review. Information on DROM was missing for 309 women (18%). Information to enable determination of whether a cesarean delivery was elective or nonelective was missing for 311 women (18%).
The definition of presumed in utero or intrapartum transmission failed to classify a small number of infected children (32 [19.3%] of 166) because they were not tested for HIV-1 in the first 7 days of life. To exclude these children from the analysis would result in falsely low estimated rates of vertical transmission. We included these children in the analysis by assuming that the probability of not being tested for HIV-1 in the first 7 days of life was the same whether the child acquired infection in utero or during delivery. Then we used likelihood-based inference accounting for this missing data mechanism.14 This is equivalent to assuming that those infants whose timing of transmission was unclassifiable were infected in utero and during delivery in the same proportion as that observed among those who were classifiable and is similar to the approach of Bertolli et al.5 By using the likelihood approach, the resulting P values and confidence intervals also appropriately account for the uncertainty in classifying those infants without an HIV-1 test in the first 7 days of life. In addition, estimation of the association of risk factors with presumed time of transmission under the assumption of specified degrees of misclassification was performed by specifying the sensitivity and specificity of the definition of presumed in utero transmission and inserting these values into the likelihood function, using an extension of the method described by Magder and Hughes.15 P values were calculated based on likelihood ratio tests. The Wald approach was used to calculate confidence intervals. Logistic regression was used to estimate the association between various risk factors and the time of transmission, while controlling for maternal viral load and antiretroviral treatment.
Considering only the first singleton births, there were 1797 children born in the WITS cohort between January 1990 and January 2001; births were evenly distributed in calendar time from 1990 to 2000. One hundred sixty-six children (9%) were determined to have perinatal HIV-1 infection, 1543 (86%) were classified as uninfected, and 88 (5%) were classified as indeterminate.
Of the 88 children classified as indeterminate, 13 (15%) were so classified because no HIV culture or DNA PCR assay result was available. The remaining 73 infants were classified as indeterminate because they lacked an HIV culture or DNA PCR assay result after 6 months of age, which was required to fulfill the definition of uninfected. Of these 73 infants, 5 had a single positive virologic test but lacked the second positive virologic test that was required to fulfill the definition of HIV infected. The proportion of children with indeterminate results was similar by maternal age, race, and viral load, the child's gestational age and birth weight, and other key predictors. The proportion of children classified as indeterminate increased slightly from 3% in 1990 to 7% in 2000.
This analysis is based on data for the remaining 1709 infants for whom HIV-1 infection status is known. The overall rate of perinatal HIV-1 transmission in the WITS was 9.7%; the transmission rate has decreased over time, from 70 (18.1%) of 385 children in 1990-1992 to 5 (1.6%) of 312 in 1999-2000. For most infected children (94%), the HIV-positive determination was based on HIV-1 peripheral blood mononuclear cell culture rather than HIV-1 DNA PCR assay.
Time of Transmission
The timing of the first positive HIV-1 culture or DNA PCR assay for the 166 infected children is given in Table 1. Forty-five children had a positive HIV-1 culture or DNA PCR assay in the first week of life (group A) and are classified as cases of presumed in utero infection. Of the children with presumed in utero infection, 31 (69%) had their first positive test within the first 48 hours of life, and none had a negative HIV-1 culture or DNA PCR assay before the positive assay. Eighty-nine infected children (group B) had a negative HIV-1 culture or DNA PCR assay during the first week of life but positive tests thereafter; these children are presumed to have acquired HIV-1 infection during delivery. The remaining 32 infected children (group C) could not be classified with respect to the timing of infection because they lacked virologic testing during the first week of life and their first HIV-1 test result was positive. If we assume that those children in group C acquired the infection in utero and during delivery in the same proportion as that observed among those able to be classified as to the time of infection, then ∼11 of these children would have acquired the infection in utero. This results in an estimated absolute rate of in utero infection of 3.3% (56 of 1709 children) among the overall cohort and an absolute estimated rate of intrapartum transmission (among those without in utero infection) of 6.7% (110 of 1653 children). For the cohort of 166 HIV-1-infected children, 56 (33.7%) are presumed to have acquired the infection in utero, and 110 (66.3%), during delivery.
Risk Factors for In Utero Transmission
We next examined the association between various maternal and child characteristics and time of transmission (Tables 2 and 3). In utero transmission was significantly associated with maternal hard drug use during pregnancy, maternal antenatal viral load, antiretroviral treatment during pregnancy, and low birth weight. In addition, the rate of presumed in utero transmission declined steadily from a high of 4.9% in 1993-1994 to 1.6% in 1999-2001 (P = 0.0025). There was a statistically significant association between presumed in utero transmission and DROM. However, the trend was not monotonic: the lowest rates of in utero transmission were among those with relatively long DROM (10-50 hours), whereas among the few with exceptionally long DROM, the estimated rate of in utero transmission was highest.
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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© 2005 Lippincott Williams & Wilkins, Inc.