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Determinants of Mother-to-Infant Human Immunodeficiency Virus 1 Transmission Before and After the Introduction of Zidovudine Prophylaxis
The Italian Register for Human Immunodeficiency Virus Infection in Children
Arch Pediatr Adolesc Med. 2002;156:915-921.
ABSTRACT
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Background Randomized controlled trials have demonstrated that zidovudine therapy
decreases the mother-to-infant transmission of human immunodeficiency virus
1 (HIV-1). Data from large observational studies may provide further important
findings on the effectiveness at the population level of combined treatments
in decreasing transmission.
Objective To evaluate time trends in prophylactic interventions and the determinants
of transmission both before and after the introduction of antiretroviral prophylaxis,
and in treated and untreated mother-infant pairs after 1995.
Design and Setting Analysis of prospective data on 3770 children born to HIV-1–infected
women between 1985 and 1999 and reported to the Italian Register for HIV Infection
in Children.
Main Outcome Measures Logistic regression random effects models were used to estimate crude
and adjusted odds ratios for several factors potentially influencing vertical
transmission for 2 periods—1985 through 1995 (January 1, 1985, through
December 31, 1995) and 1996 through 1999 (January 1, 1996, through December
31, 1999), and between treated and untreated children after 1995.
Results The transmission rate was 15.5% in the 1985-1995 period and 5.8% in
the 1996-1999 period. By 1999, prophylactic interventions had greatly increased.
Antiretroviral treatment (ART) usage was 89.9%, (55.1% combination ART) and
the elective cesarean delivery rate was 81.3%. In multivariate analysis, only
elective cesarean delivery was associated with a lower risk of mother-to-infant
transmission before 1995. After 1995, nonbreastfeeding and receipt of ART
were protective whereas elective cesarean delivery was not significantly protective
in multivariate analysis. Transmission risk was reduced by 76% with an incomplete
zidovudine regimen, 88% with a complete regimen, and 93% when the mother received
combination ART. In the 1996-1999 period, the transmission rate for nonbreastfeeding
mother-infant pairs was 8.6% with elective cesarean delivery, 4.4% with any
ART, and 2.4% with these interventions combined.
Conclusion Prophylactic interventions, and in particular ART, reduced perinatal
HIV-1 transmission at a population level in Italy.
INTRODUCTION
AT THE END of 1994 the randomized controlled Pediatric AIDS [aquired
immunodeficiency syndrome] Clinical Trial Group (PACTG) protocol 076 clearly
demonstrated that a 3-part regimen of zidovudine treatment during pregnancy,
labor, and the neonatal period decreases the mother-to-infant transmission
of human immunodeficiency virus 1 (HIV-1) by about 70%.1
Subsequent observational studies have confirmed the effectiveness of this
practice.2-3 In the late 1990s,
randomized controlled trials demonstrated the protective effects of elective
cesarean delivery4 and exclusive formula feeding,5 each reducing transmission risk by approximately half.
A further reduction in transmission, up to 87%, for these 3 interventions
combined has been reported by cohort studies6-7
and a recent population survey.8 Current American
treatment guidelines for HIV-1–infected pregnant women recommend the
use of potent antiretroviral treatment (ART), in addition to zidovudine prophylaxis,9 while European recommendations are less aggressive
owing to concerns about effects on fetal growth.10
Only recently have data from larger cohorts been published on the effects
of combined ART on mother-to-infant transmission and infant outcome.2 Findings suggest that combined ART may further decrease
mother-to-infant transmission.
Data from observational studies offer the opportunity of providing important
measures of the effectiveness of treatments at the population level that clinical
trials cannot.11 Thus, it is crucial to monitor
trends in prophylactic practices, therapeutic intervention usage, and mother-to-infant
transmission rates using population-based surveillance. Recent population-based
surveys in the United States12 and Great Britain8 have found significant declines in mother-to-infant
transmission rates associated with increased use of interventions. Herein
we use data from the Italian Register for HIV Infection in Children to evaluate
time trends in prophylactic interventions and the determinants of mother-to-infant
transmission both before and after the introduction of the PACTG 076 protocol,
and in treated and untreated mother-infant pairs after 1995.
SUBJECTS, MATERIALS, AND METHODS
DATA COLLECTION
Instituted in 1985, The Italian Register for HIV Infection in Children
is a nationwide multicenter study of children perinatally exposed to HIV-1
infection. The register's data come from a network of 106 voluntarily participating
pediatric clinical centers located throughout Italy that aim to enroll all
infants born to mothers with documented HIV-1 infection during pregnancy or
at the moment of delivery and is representative of the overall population
of exposed infants in Italy.13-14
All children are enrolled, whether they are followed up prospectively or retrospectively
from birth, but only those followed up prospectively are included in studies
on risk factors or the course of infection.12
Data regarding mother-infant pairs are collected as previously described.13-15 In particular, baseline
information is collected on the infant's demographics, age at first observation,
mother's risk factors for HIV-1 infection, mother's place of origin, mother's
clinical condition at delivery (defined according to the Centers for Disease
Control and Prevention [CDC] classification system for HIV-1–infected
adults16), mode of delivery, gestational age,
type of feeding, and whether the woman had other children after her HIV-1
infection had been diagnosed. Starting in 1989, information on ARTs during
pregnancy was collected as treated or not treated; from 1993 onward, data
on type of therapy and gestational age at the beginning and end of therapy
were also included. Before the PACTG 076 protocol, zidovudine had been administered
to pregnant women in selected centers in our country13;
thereafter, the PACTG 076 protocol prophylactic regimen was introduced, though
not universally or simultaneously.
Both baseline and follow-up visits record information on infant infection
status, HIV-1 antibodies (assessed by enzyme-linked immunosorbent assay and
Western blot test), and viral markers (proviral DNA, and/or virus culture,
and/or free and complexed p24 antigenemia). Following the CDC recommendations
for HIV-1 infection in children,17 infection
is diagnosed by the persistence of HIV-1 antibodies after 18 months, or before
18 months, by detection of viral markers on at least 2 occasions. Infants
whose infection status is indeterminate are followed up at least until infection
status can be ascertained. The register has no information available concerning
maternal viral load at the time of delivery, concomitant infections, and treatments
prior to pregnancy. The maternal immunologic condition at the time of delivery
is known in a few cases.
CASE DEFINITION
Children were classified as infected, uninfected, or indeterminate.
Indeterminate children were either lost to follow-up or died prior to HIV-1
diagnosis, or had indeterminate HIV-1 status (because they were either younger
than 18 months and had not seroreverted or detection of viral markers was
only performed once) when the study was closed. Negative proviral DNA or viral
cultures carried out at birth are not used to assign infection status. We
considered an incomplete PACTG 076 protocol to be anything less than all 3-part
regimens,18 based on the similarity of results
for having 1- or 2-part regimens and so as to increase the statistical power.
Women who received zidovudine therapy prior to the publication of the PACTG
076 protocol results were classified as having an incomplete PACTG 076 protocol
regimen. We defined combined ART in mothers as both double (2 nucleoside reverse
transcriptase inhibitors [NRTIs]) and triple (NRTI and 1 protease inhibitor,
or 3 NRTIs, or 2 NRTIs and 1 nonnucleoside reverse transcriptase inhibitor)
combined ART.
STATISTICAL ANALYSIS
Analyses were performed on data reported up to December 31, 2000, on
children born to an HIV-1–positive mother between June 1, 1985, and
December 31, 1999, and whose follow-up started within the first month of life.
Trends in vertical transmission rates, use of ART, and elective cesarean delivery
from June 1, 1985, to December 31, 1999, were estimated; 1985 and 1986 were
combined owing to low numbers and considered as the reference group.
Logistic regression random effects models were used to estimate crude
and adjusted odds ratios for several factors potentially influencing vertical
transmission for 2 periods—1985 through 1995 (January 1, 1985, through
December 31, 1995) and 1996 through 1999 (January 1, 1996, through December
31, 1999)— and for the estimate crude and adjusted odds ratios occurring
between treated and untreated children after 1995, with clinical center considered
as a random effect. Children with the same mother and twins were treated independently
since excluding them from the analysis did not change the results. The periods
were chosen based on the timing of the gradual introduction of zidovudine
prophylaxis in Italy following the publication of the results of the PACTG
076 protocol at the end of 1994.13 The factors
considered were maternal clinical condition at time of delivery based on the
CDC classification (ie, asymptomatic, HIV-1–related symptoms but not
clinical AIDS, clinical AIDS, unknown16); exposure
category to HIV-1 of the mother (ie, injection drug use, sexual exposure,
transfusion, other/unknown); mother's area of origin in an HIV-1 endemic area
or not; gestational age (ie,  32, 33-36, 37-39,  40 weeks, or unknown);
infant sex; mode of delivery (ie, elective cesarean section, emergency cesarean
delivery, cesarean delivery type unknown, vaginal delivery, or unknown); type
of infant feeding (ever breastfeeding, exclusively formula feeding, or unknown);
and type of prophylactic ART received in the perinatal period (ie, none, incomplete
PACTG 076 protocol, complete PACTG 076 protocol, or maternal combined ART).
In the "Results" section below some categories of variables are grouped based
on similarities in the estimated coefficients in the preliminary multivariate
analyses. A CD4-positive, T-lymphocyte count at the time of delivery was among
the factors initially considered. However, many of the mothers had missing
data and this variable was strongly associated with maternal clinical condition
(ie, the lower the CD4-positive, T-lymphocyte count, the more advanced the
CDC clinical category). Thus, this variable was excluded from the final analyses.
To assess the bias due to incomplete follow-up of indeterminate children,
analyses were done first excluding, then including such children, considering
those who died prior to definitive diagnosis as infected and all others as
uninfected.
RESULTS
MOTHER-INFANT PAIRS
By the end of December 1999, 3770 infants born to HIV-1–positive
women had been reported to the register within 1 month of birth. Characteristics
of mothers and children in the 1985-1995 and 1996-1999 periods are reported
in Table 1. The proportion of
mothers reporting sexual contact as an HIV-1 risk factor increased from 23.3%
to 34.8% over the 2 study periods. Injection drug use remained the most common
risk factor for HIV-1 infection in mothers but decreased from 71.0% in the
1985-1995 period to 47.5% in the 1996-1999 one. The number of HIV-1–positive
women giving birth increased in 1998 (295 births) and 1999 (332 births), after
slightly declining for several years from 305 births in 1990 to 238 in 1997.
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Table 1. Characteristics of Mothers and Infants for Periods 1985-1995
and 1996-1999*
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PROPHYLACTIC INTERVENTIONS OVER TIME
Antiretroviral therapy usage increased from 8.1% of mother-infant pairs
in the 1985-1995 time to 78.7% in the 1996-1999 time. Table 2 shows types of antiretroviral regimens administered to mothers
during pregnancy. Median duration of treatments was 5 months (range, 1-9 months).
During the 1985-1995 period, the median duration was 3 months (range, 1-8
months), whereas during the 1996-1999 period, the median duration was 5 months
(range, 1-9 months). The difference between duration in the 2 different periods
was statistically significant (P = .001). The most
frequently used triple-combination therapy in the 1996-1999 period was zidovudine,
lamivudine, and indinavir (n = 27). By 1999, 89.9% of 332 mother-infant pairs
received ART: 55.1% received combined ART, 22.9% complete PACTG 076 protocol,
and 11.1% an incomplete PACTG 076 protocol regimen. Intrapartum and neonatal
prophylaxis consisted of zidovudine therapy in all but the few cases where
nevirapine therapy was used. Of the 289 women receiving combined ART, 66 (22.8%)
received only intrapartum zidovudine, 5 infants (1.7%) received only oral
zidovudine, 136 mother-infant pairs (47.0%) received both treatments, and
82 (28.4%) received none. Zidovudine therapy was part of the antepartum regimen
for 232 women (80.3%). Of the 57 women who did not have zidovudine as part
of their combination regimen, 42 (73.7%) had 1 or both of the other 2-part
regimens of the PACTG 076 protocol.
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Table 2. Type of Antiretroviral Regimens Administered to the Mother
According to the Infant's Year of Birth, 1985-1995, 1996-1999, and Each Year
After 1996 in Detail*
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The proportion of elective cesarean deliveries increased from 16.6%
in the 1985-1995 period to 64.2% in the 1996-1999 one. Rates remained stable
at around 13% until 1993, rising from 19.6% in that year to 81.3% in 1999.
Breastfeeding decreased from 3.4% to 1.4% over the 2 study periods, with only
16 women breastfeeding in the 1996-1999 period.
MOTHER-TO-INFANT TRANSMISSION RATE OVER TIME
The percentage of indeterminate infants was stable at under 10% per
year until 1998 and 1999 when the proportions were 13.2% and 18.7%, respectively.
The proportion of indeterminate children who died prior to diagnosis was 12.0%
(25/209) in the 1985-1995 period and 3.8% (5/130) in the 1996-1999 period
(P = .01).
Excluding indeterminate children, the vertical transmission rate was
18.5% (95% confidence interval [95% CI], 14.0%-23.6%) in the 1985-1986 period
and remained stable until 1996 when incidence began to steeply drop, reaching
4.4% (95% CI, 2.3%-7.6%) in 1999. When indeterminate children were included,
rates in the 1985-1986 period were 17.7% (95% CI, 13.5%-22.6%), falling to
3.9% (95% CI, 2.1%-6.6%) in 1999.
DETERMINANTS OF MOTHER-TO-INFANT TRANSMISSION
Risk factors for mother-to-infant transmission in the 1985-1995 period
and the 1996-1999 one for the 3431 children with known infection status are
presented in Table 3. In the 1985-1995
period, after adjusting for all other factors, CDC clinical categories B or
C increased the odds of transmission by 53% (P =
.004), elective cesarean delivery reduced transmission by 46% (P = .001).
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Table 3. Risk Factors for Vertical Transmission of HIV-1, 1985-1995
and 1996-1999*
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In the 1996-1999 period, in multivariate analysis, risk of transmission
was reduced by 76% in mother-infant pairs receiving an incomplete PACTG 076
protocol regimen, by 88% in those receiving all 3-part regimens, and by 93%
for those in which the mother received combination ART (P<.001 for all categories) compared with no treatment. The 50% reduction
in transmission attributable to elective cesarean delivery was of borderline
statistical significance (P = .08). While breastfeeding
was not associated with infection in the period prior to 1996, in the 1996-1999
period, children who were breastfed were 10 times more likely to be infected
than those who were bottle-fed (P = .001). The mother-to-infant
transmission rate in breastfeeding women was 21.7% in the 1985-1995 period
and 53.8% in the 1996-1999 one.
INFLUENCE OF SINGLE AND COMBINED INTERVENTIONS
The separate and combined effects of type of feeding, mode of delivery,
and ART in the periods 1985-1995 and 1996-1999 and overall are presented in Table 4. For breastfeeding mothers without
any prophylactic interventions, the transmission rate was 23.4% in the earlier
period and 71.4% in the later, but the 95% CI in the second period was very
large (29.9%-96.3%) owing to the few women who breastfed. Transmission rates
were similar in both periods for nontreated, nonbreastfeeding mother-infant
pairs without elective cesarean delivery (18.5% vs 24.3%) and with elective
cesarean delivery (10.0% vs 8.6%). For nonbreastfeeding mother-infant pairs
without elective cesarean delivery and receiving any type of therapy, transmission
rates were higher in the earlier (15.3%) than in the later (4.4%) period.
After 1995, the transmission rate in nonbreastfeeding mother-infant pairs
receiving any type of therapy with elective cesarean delivery was 2.4%.
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Table 4. Effects of Type of Feeding, Mode of Delivery and Antiretroviral
Therapy on Mother-to-Child Transmission Rates, 1985-1995, 1996-1999, and Overall
Period
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In the 1996-1999 period the nonbreastfeeding pairs with elective cesarean
delivery had a transmission rate of 4.2% (7/167) with an incomplete PACTG
076 protocol regimen, 2.6% (5/195) with a complete PACTG 076 protocol regimen,
and 0.52% (1/192) when the mother received combined ART. In the 289 mothers
who took some form of combined ART during pregnancy, zidovudine therapy was
not prescribed in 59 (20.4%) (though 3 of these women received nevirapine
therapy). One child was infected in the no-zidovudine group (1.9%) and 3 (1.3%)
in the zidovudine group.
COMMENT
Since 1996, the use of interventions directed to prevent mother-to-infant
HIV-1 transmission and changes in treatment of adult HIV-1 infection, including
potent combined therapies, has greatly increased in practices in Italy, with
concomitant reductions in transmission. The transmission rate was more than
27% in the absence of any intervention. Antiretroviral treatment in mothers
for their own health or prophylactic interventions, including zidovudine treatment
in mother-infant pairs, elective cesarean delivery, and combined with formula
feeding, reduced the risk by more than 90%.
Even where use of all 3 interventions was reported, more than 2% of
infants became infected. This point should be adequately discussed when counseling
an infected woman who is considering pregnancy. Strategies should be designed
to further reduce the risk, possibly acting on transmission that occurs early
in pregnancy and that may not be prevented by current interventions.13 The benefits of new approaches can only occur if
infected women are diagnosed before or very early in pregnancy. On the other
hand, mother-infant pairs not receiving ART accounted for almost two thirds
of the transmission in the 1996-1999 period. This mainly reflects a failure
to identify HIV-1 infection until or even after delivery, but it also reflects
the refusal of some women to take antiretroviral drugs owing to safety or
other concerns. As seen elsewhere,19 the proportion
of women infected by sexual contact has increased in recent years in Italy.
The reduced awareness of at-risk behavior in women infected via the sexual
route20 supports recommendations for routine
testing of all pregnant women.
We found a clear hierarchy of effectiveness of interventions in both
study periods, with transmission decreasing as interventions were combined.
Transmission rates were similar for each combination in both periods except
when therapy was included. For prophylaxis with or without elective cesarean
delivery, transmission rates were higher in the earlier period, reflecting
the lack of a clear prophylaxis protocol whereas elective cesarean delivery
was likely to be carried out correctly in both periods. Antiretroviral prophylaxis
seems to be the most effective intervention, but our findings suggest that
the best prophylactic strategy is a combined intervention. In fact, although
the effect of cesarean delivery was not statistically significant after 1996,
we observed the largest reduction in transmission in the group where all prophylactic
interventions were used.
We found the complete PACTG 076 protocol regimen to be more effective
in preventing mother-to-infant HIV-1 transmission than an incomplete regimen.
However, an incomplete regimen alone exerts some protective effect. The diffuse
use of combined ART in HIV-1–infected women for clinical indications
seems to contribute to the reduced transmission rate and there was an indication
that combined ART plus the other part of the PACTG 076 protocol regimen may
be more efficacious than that with zidovudine monotherapy. The risk of transmission
in mothers receiving combined ART agrees with those reported in other studies.2-3 Guidelines for HIV-1–infected
pregnant women recommend that zidovudine prophylaxis should be associated
with combined ART9 since, at present, only
zidovudine and nevirapine therapies have been demonstrated to effectively
prevent mother-to-infant transmission.1, 21
In our study, 95% of women receiving combined ART had zidovudine included
in their regimen and/or as part of the other 2 parts of the PACTG 076 protocol.
Whether perinatal HIV-1 transmission may be equally preventable by other combined
antiretroviral regimens independent of whether zidovudine is included or not
remains to be seen. Confirmation of this observation would ideally come from
clinical trials. Questions remain regarding the long-term safety for the child
of combinations of antiretroviral drugs in pregnancy that will only be answered
by the follow-up of large numbers of indeterminate children.
By 1999, four fifths of the infants reported to the register were delivered
by elective cesarean delivery. The estimated 50% reduction in transmission
attributable to elective cesarean delivery after adjusting for zidovudine
prophylaxis is consistent with the findings of other studies3, 6, 8
where the adjusted odds ratio ranged from 0.39 to 0.43, even though, similar
to the report from Great Britain,8 this result
was of borderline statistical significance in the 1996-1999 period. In treated
mother-infant pairs this effect was reduced to about 30% and was not significant.
However, the strong correlation between antiretroviral prophylactic therapy
and mode of delivery could have partly masked the effectiveness of elective
cesarean delivery. Supporting this interpretation, the transmission rate was
2.4% in nonbreastfeeding mother-infant pairs receiving prophylactic ART and
having an elective cesarean delivery, compared with a rate of 4.4% with no
breastfeeding and prophylaxis alone, consistent with reports of 2% and 4%,
respectively, in the European Collaborative Study.3
The importance of avoiding breastfeeding was confirmed. Breastfeeding
was rare in both study periods and was a significant risk factor for mother-to-infant
HIV-1 transmission only in the 1996 through 1999 period when prophylactic
interventions had come into widespread use. Based on our results, the population
attributable risk (or etiologic fraction) of breastfeeding is approximately
10% even when the prevalence of breastfeeding is less than 2%.
While the Italian Register for HIV Infection in Children is population
based and, therefore, able to reliably monitor intervention usage and its
influence on HIV-1 mother-to child transmission, some biases may be present.
The most important potential bias is related to the 339 children (9.0% of
the total) who were still indeterminate at the time of the analysis. To evaluate
this bias we repeated the analyses, including indeterminate children, assuming
that deceased children were infected and those lost to follow-up were uninfected.
Uninfected children, being asymptomatic, may be more likely to be lost to
follow-up before final definition of infection status. Conversely, infants
who died before a definitive diagnosis are likely to have been HIV-1 infected.
The fact that the results of the analyses including and excluding those of
indeterminate status are consistent suggests that the bias due to indeterminate
children should not be very large.
These population-based data clearly demonstrate the effectiveness of
prophylactic interventions in reducing mother-to-infant transmission in Italy,
confirming the results of randomized trials and cohort studies. Given that
transmission rates are very low, more women receive ART before pregnancy,
and treatment regimens continue to diversify, it may be increasingly difficult
to assess the importance of other ARTs and combined approaches with clinical
trials. Observational studies, including population-based surveillance, may
provide the most practical and reliable method to monitor intervention usage
and HIV-1 mother-to-infant transmission rates.
| What This Study Adds
Trials demonstrated that exclusive formula feeding or elective cesarean
delivery or a 3-part regimen of zidovudine therapy during pregnancy, labor,
and the neonatal period, significantly decreases the mother-to-infant transmission
of HIV-1. Observational studies offer the opportunity of providing important
measures of the effectiveness of each or combined prophylactic interventions
at the population level.
A clear hierarchy of effectiveness of interventions (antiretroviral
prophylaxis, exclusive formula feeding, and elective cesarean delivery) was
found. Antiretroviral prophylaxis (and, in particular, combined antiretroviral
prophylaxis) was the most effective intervention, but transmission decreased
as interventions were combined. The effectiveness of prophylactic interventions
in reducing mother-to-infant transmission is clearly demonstrated at a population
level, confirming the results of randomized trials and cohort studies.
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AUTHOR INFORMATION
Accepted for publication May 15, 2002.
| The Italian Register for HIV Infection in Children
Writing Committee
Department of Pediatrics, University of Florence,
Florence: Maurizio de Martino, MD; Luisa Galli, MD. Department of Pediatrics, University of Turin, Turin: Pier-Angelo Tovo,
MD; Clara Gabiano, MD. AIDS and Sexually Transmitted Disease
Unit, Istituto Superiore di Sanità, Rome: Patrizio Pezzotti,
Dstat; Theresa M. Wagner, MPH; Giovanni Rezza, MD.
Participants of the Italian Register for HIV Infection
in Children
Ancona: P. Osimani, MD. Bari: D. De Mattia, MD; C. Di Bari, MD. Bergamo: M. Ruggeri, MD. Bologna: F. Baldi, MD; M.
Ciccia, MD; M. Lanari, MD; M. Masi, MD; V. Venturi, MD. Bolzano: L. Battisti, MD. Brescia: M. Duse,
MD. Brindisi: P. G Chiriacò, MD. Cagliari: R. Cavallini, MD; C. Dessì, MD; C. Pintor, MD. Catanzaro: E. Anastasio, MD. Chieti: G. Sabatino, MD. Como: M. Sticca, MD. Cuneo: G. Pomero, MD. Ferrara:
T. Bezzi, MD. Florence: E. Chiappini, MD; M. De Luca,
MD; P. Gervaso, MD. Forlì: M. T. Cecchi, MD. Genoa: D. Bassetti, MD; C. Gotta, MD; R. Rosso, MD; A.
Timitilli, MD. Imperia: U. Tondo, MD. Mantova: P. Mussini, MD. Milan: D. Bricalli,
MD; A. Bucceri, MD; G. Ferraris, MD; M. Giovannini, MD; F. Mosca, MD; R. Lipreri,
MD; A. Plebani, MD; E. Riva, MD; S. Riva, MD; A Viganò, MD; G. V. Zuccotti,
MD. Modena: M. Cellini, MD. Naples: W. Buffolano, MD; A. Guarino, MD; L. Tarallo, MD. Padua: R. D'Elia, MD; C. Giaquinto, MD; O. Rampon, MD. Palermo: E. R. Dalle Nogare, MD; A. Romano, MD. Pavia: D. Caselli, MD; A. Maccabruni, MD. Pisa:
R. Consolini, MD. Parma: G. Benaglia, MD. Reggio Emilia: C. Magnani, MD. Roma: G. Anzidei,
MD; A. M. Casadei Pistilli, MD; G. Castelli Gattinara, MD; S. Catania, MD;
C. Facente, MD; P. Falconieri, MD; C. Fundarò, MD; O. Genovese, MD;
C. Rendeli, MD. Sassari: S. Bionda, MD. Taranto: L. Cristiano, MD. Turin: S. Garetto,
MD; C. Riva, MD; E. Palomba, MD. Trapani: V. Portelli,
MD. Trento: A. Mazza, MD. Trieste: C. Salvatore, MD. Varese: A. Pellegatta,
MD. Verona: M. Molesini, MD.
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Corresponding author and reprints: Maurizio de Martino, MD, Department
of Pediatrics, University of Florence, via Luca Giordano 13, I-50132 Florence,
Italy (e-mail: maurizio.demartino{at}unifi.it).
This study was supported by the Italian Ministero della Sanità, Istituto Superiore di Sanità, Progetto AIDS 2000, Rome.
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