ELECTRONIC ARTICLE |

* Department of Epidemiology and Biostatistics, University of South Carolina, School of Public Health, Columbia, South Carolina
Division of Epidemiology, Department of Health and Environmental Control, Columbia, South Carolina
| ABSTRACT |
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Methods. We retrospectively ascertained information on zidovudine prescription and other characteristics of HIV-infected pregnant women and children for birth cohort years 1993, 1995, 1996, and 1997 using HIV/acquired immunodeficiency syndrome registry data from a state health department supplemented by medical record reviews.
Results. The transmission rate decreased from 12.5% in 1993 to 4.6% in 1997. The proportions of HIV-1-infected mothers and children who were prescribed all 3 arms of zidovudine increased from 68% in 1995 to 93% in 1997. Unadjusted and adjusted odds ratios for the relationship between the prescription of 3 arms of zidovudine and the infants HIV status were 0.19 (95% confidence interval: 0.050.84) and 0.15 (95% confidence interval: 0.020.96), respectively.
Conclusion. Perinatal HIV-1 transmission rates have decreased over time. This study demonstrates the effectiveness of the rapid implementation of the United States Public Health Service recommendations for the comprehensive use of zidovudine among HIV-1-infected pregnant women in a predominantly rural state.
Key Words: HIV infection disease transmission prevention and control zidovudine female infant newborn population surveillance
Abbreviations: HIV, human immunodeficiency virus AIDS, acquired immunodeficiency syndrome ACTG 076, AIDS Clinical Trial Group 076 USPHS, United States Public Health Service STD, sexually transmitted disease OR, odds ratio CI, confidence interval
| INTRODUCTION |
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Zidovudine is the first antiretroviral medication approved worldwide for the treatment of HIV/AIDS. It is also the first drug to be used in a clinical trial of HIV-infected pregnant women to determine its efficacy in reducing perinatal HIV transmission.3 This randomized trialAIDS Clinical Trial Group 076 (ACTG 076)demonstrated a reduction of perinatal HIV transmission with zidovudine by almost 70%.3
Since the successful use of zidovudine in HIV-infected pregnant women in the ACTG 076, recommendations have been published for the use of zidovudine to reduce perinatal HIV infection.4 In addition, other studies have demonstrated the success of zidovudine in reducing perinatal HIV transmission.510 The US and European epidemiologic studies demonstrating striking decreases in the perinatal transmission of HIV from prophylactic (zidovudine) administration have used data from hospitals, public health clinics, and private physicians offices. This study uses data from a population-based HIV/AIDS surveillance database from a state that has HIV infection reporting by name. The objective of this study was to explore the relationship between zidovudine prescription and perinatal HIV-1 transmission among mother-child pairs in which the mother is known before delivery to be infected with HIV.
| METHODS |
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The transmission rate for each birth cohort year was defined as the number of HIV-1-infected infants in a birth cohort year divided by the total number of infants in the sample born during the birth cohort year. The transmission rate for each arm of zidovudine use was defined as the number of HIV-1-infected infants whose mothers were prescribed a certain level of zidovudine divided by the total number of infants whose mothers were prescribed that level of zidovudine.
Zidovudine prescription, the dependent variable, was categorized into 4 levels and used for descriptive purposes: all 3 arms (during pregnancy, delivery, and neonatally), 2 arms (only 2 of the 3 arms), 1 arm (only 1 of the 3 arms), and 0 arms (no zidovudine prescription). The zidovudine prescription variable used for modeling was dichotomized as "all 3 arms versus not all 3 arms," meaning that it was prescribed during pregnancy, during labor, and for the neonate versus not being prescribed for all 3 arms. Because mother-child pairs would not have been prescribed all 3 arms of zidovudine in 1993 (the year before the United States Public Health Service [USPHS] recommendations), the sample was restricted to birth cohort years 1995 to 1997 for the analysis of transmission rate by Zidovudine (N = 217). The sample was further restricted to women who had CD4 counts during pregnancy and who did not have missing illicit drug use information. The final sample size was 149 mother-child pairs. HIV infection was defined as infants who were classified as having HIV or AIDS by the current Centers for Disease Control and Prevention pediatric HIV/AIDS case definition.11 Uninfected infants were defined as those who had seroreverted or who were born exposed to HIV-1 but whose infection status had not been determined as of May 1, 1999.
Maternal age was defined as mothers age at the time of delivery and was calculated by taking the difference between the mothers date of birth and the delivery date (infants date of birth). The initial time criteria for CD4 count/mm3 during pregnancy was those measured 6 months before pregnancy, during pregnancy, and 6 months after pregnancy (N = 143). Six additional mother-child pairs were identified when the CD4 count/mm3 time criteria was extended to those measured 12 months before pregnancy, during pregnancy, and 12 months after pregnancy. Alcohol use, cigarette use, and illicit drug use were defined as occurring during pregnancy and were recorded from medical records. Prenatal care was determined using the Kotelchuck Adequacy of Prenatal Care Index.12 This index uses 2 subscales: the Adequacy of Initiation of Prenatal Care, which takes into account the month in which prenatal care was initiated, and the Adequacy of Received Services, which describes the proportion of recommended prenatal care visits made, adjusted for gestational age at birth. These 2 subscales were combined to produce a summary index with 5 levels that describe prenatal care: Adequate Plus, Adequate, Intermediate, Inadequate, and No prenatal care. The maternal county of residence at the time of HIV-1 diagnosis was dichotomized into urban counties and rural counties. Rural counties were those in which >50% of the population in the county live in the rural areas of the county, whereas urban counties were defined as those in which >50% of people in the county live in the urban areas of the county.13 Sexually transmitted disease (STD) was defined as 1 of the following STDs having been diagnosed during pregnancy: syphilis, gonorrhea, chlamydia, or herpes. Chorioamnionitis was defined as an infection of the chorionic/amniotic sac as recorded on the medical record. Premature rupture of membranes was dichotomized into having ruptured membranes >4 hours versus
4 hours before delivery and was calculated by taking the difference between the membrane rupture time and date and the delivery time and date (infants date and time of birth). Type of delivery was dichotomized into vaginal or caesarean section and was abstracted from the medical record. Missing and unknown observations for chorioamnionitis and all zidovudine prescription variables were assumed not to have occurred. Missing and unknown for type of delivery was assumed as vaginal delivery.
Stratified analysis was used to examine the relationship of the covariates with HIV infection status of the infant. The Mantel-Haenszel procedure, adjusting for 1 variable at a time in a model of zidovudine and HIV transmission, was used to select potential confounding factors for initial inclusion in the logistic model. The covariates included maternal age at delivery, race/ethnicity, CD4 counts during pregnancy, alcohol use, smoking, illicit drug use, STDs, maternal county of HIV diagnosis, type of health insurance, prescription of zidovudine before this pregnancy, and prenatal care. To reduce possible multicollinearity by having associated variables in the same model, we used
2 tests and Fishers exact tests to test the association of each covariate with the others. A
2 test for trend was used to test for trends in zidovudine prescription from 1995 through 1997. Unconditional logistic regression was used for estimating the relative risk (odds ratio [OR]) and 95% confidence interval (CI) for the zidovudine prescription and HIV infection status of the infant while simultaneously adjusting for potential confounding variables. Effect modification for the association of zidovudine prescription and HIV infection status of the infant by chorioamnionitis, premature rupture of membranes, and type of delivery was assessed using the likelihood ratio test. Interaction terms were retained in the model when they were statistically significant at
= 0.05 level. Confounders were defined as variables that changed the odds ratios of the exposure-outcome relationship by approximately 5% to 10% or more. Variables that contributed to the model using the likelihood ratio test at
= 0.05 were considered strong risk factors. The final model included the major independent variable, all variables identified as confounders, and strong risk factors for the association between zidovudine prescription and HIV infection status of the infant.
| RESULTS |
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Table 2 presents the distribution of selected characteristics of HIV-infected mothers by zidovudine prescription status. In each birth cohort year, the percentage of mother-child pairs that were prescribed all 3 arms of zidovudine increased. Eighty percent of the black mothers compared with 94% of the white mothers were prescribed all 3 arms of zidovudine. One hundred percent (100%) of the mothers with 0 to 199 CD4 counts/mm3, which constitutes AIDS,14 81% with 200 to 499 CD4 counts/mm3, and 78% with
500 CD4 counts/mm3 were prescribed all 3 arms of zidovudine. The majority of mothers who drank alcohol, smoked cigarettes, used illegal drugs during pregnancy, and had received a diagnosis of an STD during pregnancy had been prescribed all 3 arms of zidovudine. A slightly higher proportion of the women who lived in rural areas than those who lived in urban areas had been prescribed all 3 arms of zidovudine.
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500/mm3. It is interesting that women who resided in rural counties at the time of HIV diagnosis were 1.73 times more likely to have been prescribed all 3 arms of zidovudine compared with women who resided in urban counties. In addition, women who experienced premature rupture of membranes >4 hours before delivery were 3 times more likely to have received all 3 arms of zidovudine. As expected, women with inadequate prenatal care were somewhat less likely to have been prescribed all 3 arms of zidovudine as compared with women who had adequate care (OR: 0.75; 95% CI: 0.321.73).
Table 3 presents the distribution of selected characteristics of HIV-infected mothers by infants HIV infection status. Mother-child pairs that were prescribed all 3 arms of zidovudine were less likely to have an infected infant (crude OR: 0.19; 95% CI: 0.050.84), translating to an 81% reduction in the risk of perinatal transmission of HIV-1. As expected, women with 0 to 199 CD4 counts/mm3 were almost 2 times more likely to have an infected infant (OR: 1.97; 95% CI: 0.3311.77) compared with women with
500 CD4 counts/mm3. Women who participated in risky behaviors, such as drinking alcohol, smoking cigarettes, and using illegal drugs, or received a diagnosis of an STD were more likely to have an infected infant compared with women who did not participate in those risky behaviors. Living in rural counties as compared with living in urban counties at the time of HIV diagnosis essentially did not increase the risk of having a HIV-infected infant. In addition, women who had inadequate prenatal care and women who were prescribed zidovudine before pregnancy were more likely to have an infected infant than women without these characteristics.
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| DISCUSSION |
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This study also demonstrates how quickly a small, southern, rural state responded to the recommendations for the use of zidovudine in HIV-1-infected pregnant women and their children4; the proportions of HIV-1-infected mothers and their children being offered all 3 arms of zidovudine increased from 68% in 1995 to 93% in 1997 (P = .003). In another population-based study of 4 states that assessed the implementation of the USPHS guidelines in 1993, 1995, and 1996, the proportions of women and children who were offered prenatal, intrapartum, and neonatal zidovudine increased from 27% to 85%, 5% to 75%, and 5% to 76%, respectively.21 Nationally, the percentage of women and children who received any zidovudine increased from 7% to 91%, and the percentage of those who received all 3 arms of zidovudine increased to 61%.22 The percentage of women and children who received all 3 arms of zidovudine in our study from 1995 to 1997 is 73.7%, which is higher than the national figure.
Our unadjusted OR for the relationship of being offered all 3 arms of zidovudine and the HIV infection status of the infant was 0.19 (95% CI: 0.050.84), but after adjustment for CD4 count, illicit drug use, and maternal age, the OR was reduced to 0.15 (95% CI: 0.02- 0.96). The adjusted OR for the transmission of HIV-1 comparing those who were offered prenatal zidovudine with those who were not offered zidovudine controlling for CD4 count was 0.36 (95% CI: 0.140.92) in 1 study.20 Simonds et al16 reported an unadjusted OR of 0.60 (95% CI: 0.40.9; P = .01) for the use of both prenatal and neonatal zidovudine on HIV transmission. In our study, the sample was too small to compare women who were offered prenatal zidovudine with those who were not offered zidovudine. However, when we compared women who were offered or prescribed any zidovudine with women who were offered or prescribed no zidovudine controlling for CD4 count, the adjusted OR for the transmission of HIV-1 was 0.85 (95% CI: 0.322.29). In another southern predominantly rural state, the transmission rate for mothers and children who received any zidovudine was 5.7% (5/87) compared with that of mothers and children who did not receive any zidovudine 18.9% (20 of 106; P = .007).
In the present study, there was no difference in the transmission rates between mothers who took any zidovudine (7.6% [17 of 223]) compared with mothers and infants who had no zidovudine (7.3% [6 of 82]; P = .93). The lack of difference in the transmission rates could have occurred because we underestimated the transmission rates. Among those who had no zidovudine (N = 82) were 25 children with an unknown HIV status at the time of analysis. When a 25% transmission rate was applied as was observed in the ACTG 076 clinical trial,3 we estimated the transmission rate in our population to be 14.6%. Among those who had any zidovudine (N = 223) were 48 children with unknown HIV status at the time of analysis. Of those, 84% (38 of 48) received all 3 arms of zidovudine. When a 6.4% transmission rate was applied as was observed by a multistate enhanced perinatal surveillance evaluation funded by the Centers for Disease Control and Prevention,23 we estimated the transmission rate to be 8.5%.
The strength of this study is that it is population based. The sample came from the HIV/AIDS surveillance registry of a state health department, and this study sample of women is representative of the HIV-1-infected pregnant women in this geographically defined population. The other studies that examined the relationship between zidovudine use and HIV-1 transmission have been clinic based8,9,15,1720 and may not be generalizable to all populations of HIV-1-infected women and their children. However, there are limitations to our study. The small sample size accounts for large variances and wide CIs of the estimate of risk. Another limitation of this study is its inability to measure compliance with the zidovudine regimen as described.
These analyses included only the women with recorded CD4 counts and drug use. Both factors were identified as confounders, and the missing data were excluded to accommodate the logistic modeling. In the collection of these data, the prenatal care record (located in the obstetrical and gynecological offices) and the HIV medical care records (eg, the Ryan White Care Consortia) were not routinely abstracted because of lack of personnel, and we believe that the missing CD4 counts would be contained in those records.
Bias could have been in operation in the selection of the total sample (N = 305), but it is unlikely. The women and children who were included were those who had been reported to the HIV/AIDS surveillance registry as HIV or AIDS cases. Women who were not reported to the surveillance registry for one reason or another may have different characteristics and ultimately different risks for having an HIV-1-infected infant, which could result in an underestimation of the HIV-1 perinatal transmission rate. To explore this possibility, HIV/AIDS Surveillance staff conducted a match of the HIV/AIDS registry with the Vital Records Live Birth registry to identify HIV-1-infected women who had given birth in the state in calendar years 1993, 1995, and 1996. The sensitivity of the surveillance system was found to be >80% for all 3 years. The sensitivity was calculated as the number of mother-child pairs that were identified via the vital records live birth and HIV/AIDS surveillance data match divided by the number of children born exposed to HIV-1 in the state as determined by the Survey of Childbearing Women.24
| CONCLUSION |
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| ACKNOWLEDGMENTS |
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We thank Lynda Kettinger for administrative support, Terri Stephens for SAS programming support, JoAnn Lafontaine for administrative and database management support, and the HIV/AIDS Surveillance staff for the collection and maintenance of the data for this project.
| FOOTNOTES |
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Reprint requests to (N.S.H.) Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention, Surveillance Branch, 1600 Clifton Rd, MS E-47, Atlanta, GA 30333. E-mail: nharris{at}cdc.gov
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This article has been cited by other articles:
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L. M. Mofenson Successes and Challenges in the Perinatal HIV-1 Epidemic in the United States as Illustrated by the HIV-1 Serosurvey of Childbearing Women Arch Pediatr Adolesc Med, May 1, 2004; 158(5): 422 - 425. [Full Text] [PDF] |
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