Correspondence: Correspondence should be addressed to Dr. F.Parazzini at: Istituto di Ricerche Farmacologiche `Mario Negri', via Eritrea 6220157, Milano, Italy
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Abstract |
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Key words: epidemiology/HIV infection/risk factors/vertical transmission
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Introduction |
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In this paper, we analyse the temporal trends in the rate of vertical HIV transmission in Italy by looking at a data set of over 1000 pregnant HIV-positive women collected retrospectively (19881990) and then prospectively (19901995) by a multicentre study group (Italian Collaborative Study), which included 13 major obstetric departments. The data on this large number of women provides an opportunity to evaluate the changes in the characteristics of the HIV-infected obstetric population and the impact of obstetric management in different calendar periods.
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Materials and methods |
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The diagnosis of maternal HIV infection was based on HIV antibody status by ELISA and Western blot commercial kits. Mothers were characterized by the CD4+ lymphocyte count, done close to delivery (mostly during the third trimester of pregnancy). Lymphocyte counts have been available for all women since 1989.
If a woman delivered more than one baby in different pregnancies during the study period, only information regarding the first singleton livebirth was considered.
A total of 1040 women entered the study (mean age 26 years, range 1644). At the time of data analysis, the HIV-1 status of the babies was known in 848 cases (81.5%). Infants were not breast fed. They were followed up till 18 months. Children were monitored for signs and symptoms of possible HIV-related illness. Serological tests (ELISA and Western blot commercial kits) were repeated at 12 and 18 months. A child was classified as HIV infected if he/she fulfilled one of the following conditions: (i) positive serological test at 18 months or more; (ii) developed clinical signs and symptoms or died because of clinical conditions related to AIDS before 18 months.
A total of 573 cases was included in previous analyses (European Collaborative Study, 1994).
Data analysis
We computed the vertical HIV transmission rate per calendar year from 1988 to 1995, using the number of infected children as numerator and the total number of children with known infection status as denominator.
To take account in the analysis of temporal trends in vertical HIV transmission rates, changes in clinical characteristics and mode of delivery, rates were directly standardized according to CD4+ count (<400, 400), gestational age at delivery (<37,
37 weeks), and mode of delivery (vaginal delivery or Caesarean section), taking the population of 1988 as reference.
To analyse details of the risk of HIV vertical transmission, we computed the odds ratios (OR) of the association between several factors and the infant's HIV serological status, together with their 95% approximate confidence intervals (CI), by the MantelHaenszel procedure (Mantel and Haenszel, 1959). When a factor could be classified in more than two levels, the statistical significance of the association was assessed by the 2 test for trend (Mantel, 1963
). To account simultaneously for the effects of several potential confounding factors, we used unconditional multiple logistic regression, with maximum likelihood fitting, to obtain OR and their corresponding 95% CI (Breslow and Day, 1980
). Included in the regression were terms for the factors significantly associated with the risk of mother-to-child HIV infection in age-adjusted analysis conducted considering the whole data set.
We also computed the proportion of HIV infected children attributable to factors statistically associated with the risk of mother-to-child infection. The attributable risk percentage (aetiological fraction, attributable fraction), representing the proportion of infected children in this study that would not have occurred if the effect(s) associated with the risk factor(s) of interest was/were absent, is a useful measure of public health and prevention relevance. The attributable risk for any given set of risk factors can be computed using the multivariate relative risk estimates and the distribution of these factors among HIV infected children only.
Thus, using the multivariate relative risks, population attributable risks were computed for each separate factor, and the factors combined, using the method described by Bruzzi et al. (1985), which provides a summary attributable risk (AR) for multiple factors, after allowance for confounding. The method requires information only on the joint distribution of the risk factors among infected children and on the adjusted OR associated with each risk factor. Provided that unbiased OR estimates are obtained and that the infected children can be assumed to be representative of all cases in the population in terms of exposure distribution, this method can be applied. It has to be noted that, whenever risk factors are not mutually exclusive, their combined attributable risk will differ from the simple sum of the attributable risks of each factor.
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Results |
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The distribution of maternal characteristics according to infection status of the children and calendar year is considered in Table II. Considering the overall series, the risk of HIV vertical transmission was higher in women with low CD4 count in pregnancy (OR <400, versus
400 1.8, 95% CI 1.12.9). Similar findings emerged when the analysis was conducted in strata of the two quadrennia.
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In the analysis of temporal trends in vertical HIV transmission rates, we computed standardized rates for all the factors found to be significantly associated with the risk of HIV vertical transmission in both calendar periods (Table IV). The frequency of Caesarean section increased from 26.5% in 19881991 to 36.2% in 19921995. Consequently, most temporal differences disappeared after standardization for mode of delivery, but the rate in 1995 was still lower than in 19881994. No difference was observed between crude rates and rates standardized for CD4+ count, and gestational age at birth.
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Discussion |
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The potential limitations of the study should be considered. This is an analysis of time trends and determinants of HIV vertical transmission in women of only one country. We think however that it is interesting to analyse in detail data from a specific country, in consideration of the more similar epidemiological characteristics of women considered and modalities of assistance to pregnancy. A large proportion of cases analysed in this paper have already been included in previous publications (European Collaborative Study, 1994). This analysis is focused however on some aspects (for example, the analysis of attributable risks) not presented in previous published papers. Although the study included ~1000 HIV infected mothers, it had low statistical power to identify an increase in the risk of vertical HIV transmission of two or more for factors with a prevalence lower than 30% in the study population. The proportion of missing data was generally limited, and there is no reason to think that infant HIV status is associated with the probability of missing data, since data were collected at delivery.
Information was limited on the role of zidovudine in reducing vertical HIV transmission (only 71 women reported zidovudine use in pregnancy in 19921995) and should be interpreted cautiously, since the drug was not given at random. However, the estimated OR of vertical HIV infection related with zidovudine use in pregnancy did not change after taking account of potential covariates of the treatment, i.e. CD4 levels and modalities of HIV infection in the mother. With these limitations, however, we did not find any association between zidovudine use in pregnancy and risk of vertical HIV-1 transmission. Similar findings emerged from a study with similar general design conducted in the USA between 1989 and 1994 (Landesman et al., 1996). These are not consistent with findings from a large clinical trial conducted in the USA showing a marked reduction of HIV infection among infants born to women treated with zidovudine (Connor et al., 1994
). Results from non-randomized studies must be considered cautiously, and neither our data nor the American study indicate for how long treatment was given during pregnancy and whether women had received the drug before pregnancy and the infants were treated after birth. Further, it is possible that some confounding factors can explain the lack of association between ziduvudine in pregnancy and risk of vertical HIV-1 transmission. Along this line, it should be considered that in this series only a small proportion of women were treated with ziduvudine in pregnancy.
There is consistent evidence that low CD4+ levels are associated with an increased risk of vertical HIV transmission. For example, in the American Women and Infants Transmission Study, the risk of mother-to-child HIV transmission was about double in mothers with CD4+ cells <29% compared to those with 29% (Landesman et al., 1996
). Other studies in European and African populations (Ryder et al., 1989
; St Louis et al., 1993
; European Collaborative Study, 1996
) gave similar results. Few data are available on how blood antigen levels affect the risk of HIV vertical transmission.
Analysis of the Collaborative European Study (including about 570 of the women considered in the present paper) suggested that Caesarean section may reduce the risk of HIV-1 vertical transmission (European Collaborative Study, 1994). A meta-analysis including data from 11 studies and about 3200 cases indicated that the reduction associated with Caesarean section amounted to ~20% (Dunn et al., 1994
). However, the Women and Infants Transmission Study conducted in the USA (Landesman et al., 1996
) and French perinatal cohorts (Mandelbrot et al., 1996
) did not confirm these data.
In this study, the estimated OR for vertical HIV transmission was 0.3 in women who delivered by Caesarean section in comparison with those who delivered vaginally, confirming the protective effect. The consistency of the protection in different calendar periods gives some strength to this association. The higher proportion of Caesarean sections in the period 19921995 in comparison with 19881991 partly explains the lower vertical transmission rates in recent years. In fact, the standardized rate of vertical transmission for mode of delivery was similar for all periods considered.
The association between low birth weight and mother-to-child infection has been analysed in several studies, but the results are conflicting (Lepage et al., 1993; Nair et al., 1993
; Monfenson, 1994
; Abrams et al., 1995
). At least two American and African studies have shown an increased risk for low birth weight infants, but others did not confirm this. The association between low birth weight and vertical HIV transmission, may possibly be explained by the confounding effect of intravenous drug use in pregnancy, which is associated both with low birth weight and HIV vertical transmission or a more advanced stage of HIV infection in the mother. We did not find any association between birth weight and risk of mother-to-child HIV infection. However, we did find an association between preterm birth and risk of vertical HIV transmission. A similar association was seen in the Women and Infants Transmission Study and Prenatal cohorts (Landesman et al., 1996
), but no association emerged between gestational age and risk of vertical HIV transmission in other studies (Ryder et al., 1989
; Bucceri et al., 1997
).
A USA study (Landesman et al., 1996) suggested that when the duration of ruptured membranes is 4 h or more, mother-to-child HIV-1 transmission increases by ~5% and the risk of vertical transmission tends to rise with the time of ruptured membranes. In this study, we only had information on the duration of ruptured membranes for the period 19921995, but we did not find any association with risk of HIV vertical transmission.
Finally, with regard to the proportion of HIV infected children attributable to the various factors, ~10% of infected children are attributable to preterm birth, a factor not preventable, but ~50% of HIV infected children were preventable by Caesarean section.
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Notes |
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References |
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Submitted on April 21, 1998; accepted on October 7, 1998.