52
Distinct Risk Factors for Intrauterine and Intrapartum Human
Immunodeficiency Virus Transmission and Consequences for Disease
Progression in Infected Children
Louise Kuhn, Richard W. Steketee, Jeremy Weedon,
Elaine J. Abrams, Genevieve Lambert, Marukh Bamji,
Ellie Schoenbaum, John Farley, Steve R. Nesheim,
Paul Palumbo, R. J. Simonds, and Donald M. Thea, for
the Perinatal AIDS Collaborative Transmission Study
Columbia University, Medical and Health Research Association Inc.,
Harlem Hospital Center, and Metropolitan Hospital Center, New
York, and Lebanon Hospital and Montifore Hospital, Bronx, New
York; Centers for Disease Control and Prevention and Emory
University, Atlanta, Georgia; University of Maryland, Baltimore;
University of Medicine and Dentistry of New Jersey, Newark
Predictors and prognosis of intrauterine and intrapartum human immunodeficiency virus
(HIV) transmission were investigated among 432 children of HIV-infected women in the
Perinatal AIDS Collaborative Transmission Study. Timing of transmission was inferred from
polymerase chain reaction or viral culture within 2 days of birth. Proportions of infections
due to intrauterine transmission were similar among women using (29%) or not using zidovudine (30%). Preterm delivery was strongly associated with intrapartum transmission (relative
risk, 3.7; 95% confidence interval [CI], 2.2–6.1), particularly among infants delivered longer
after membrane rupture, but was not associated with intrauterine transmission. Progression
to AIDS or death increased 2.5-fold (95% CI, 1.1–5.8) among intrauterine infected children,
adjusting for preterm delivery, and maternal CD4 cell count. Early transmission appears
unlikely to explain instances of zidovudine failure. Preterm infants may be more vulnerable
to HIV acquisition at delivery, especially if membrane rupture is prolonged. Intrauterine
infection does not appear to increase risk of preterm delivery.
The timing of maternal-infant human immunodeficiency virus (HIV) type 1 transmission can be inferred from the results
of virus-specific diagnostic tests (mostly DNA polymerase chain
reaction [PCR] or viral culture) on samples drawn near birth
[1]. These tests, which have excellent diagnostic sensitivity and
specificity among children, when done close to birth identify
fewer than one-third of those later known to be HIV-infected
[2–8]. It is assumed that in these infected newborns with negative test results, the amount of circulating virus has yet to
replicate to detectable levels due to recent infection, most likely
about the time of delivery. Infection detectable earlier (within
48 h of birth according to the working definition proposed to
guide this thinking [1]) is, conversely, assumed to have been
acquired in utero.
Intrauterine infection has been hypothesized to cause rapidly
progressive HIV disease. In a study of 150 HIV-infected chilReceived 8 April 1998; revised 26 August 1998.
Presented in part: Conference on Global Strategies for the Prevention of
HIV Transmission from Mothers to Infants, Washington, DC, 3–6 September 1997; 5th Conference on Retroviruses and Opportunistic Infections,
Chicago, 1–5 February 1998.
Informed consent was obtained from all subjects. The Institutional Review
Boards of all the institutions involved reviewed and approved the study.
Financial support: CDC cooperative agreements.
Reprints or correspondence: Dr. Louise Kuhn, Sergievsky Center, Columbia University, 630 W. 168th St., New York, NY 10032 (lk24@
columbia.edu).
The Journal of Infectious Diseases 1999; 179:52–8
q 1999 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/99/7901-0008$02.00
dren, PCR or culture positivity in the first week of life was
associated with a 3-fold increased risk of severe manifestations
of HIV infection [9]. Other smaller studies have also reported
modest associations [5, 6, 8], but only one report (n 5 8) [10]
shows an association when early infection is defined using time
intervals proposed by the working definition. Since the sensitivity of PCR and culture increases rapidly in the first week of
life [2, 11–13], wider time intervals may be less able to distinguish intrauterine from intrapartum infections.
A further limitation of previous studies of timing of infection
and disease progression is that they have mostly not controlled
for other maternal and perinatal factors associated with prognosis. For example, advanced maternal disease and preterm
delivery have both been associated with faster disease progression among infected children [14, 15]. If advanced maternal
disease increases the likelihood of intrauterine transmission or
if preterm delivery results from intrauterine infection, then these
variables (rather than the timing of transmission) may explain
prognosis. Identification of separate timing-specific risk factors
for maternal-infant HIV transmission may help to clarify alternative explanations for any increases observed in the severity
of disease in intrauterine-infected children.
In a large multisite study of HIV-infected children, we tested
whether the timing of transmission, inferred from the results
of early PCR or viral cultures in the first 2 days of life, is
associated with disease progression, independent of maternal
and perinatal characteristics. We also investigated the specificity
of maternal and perinatal factors for either intrauterine or in-
JID 1999;179 (January)
Intrauterine and Intrapartum HIV Infection
trapartum HIV transmission. We previously showed that intrapartum characteristics, particularly duration of membrane
rupture, are associated with intrapartum but not intrauterine
transmission [16], suggesting that the use of early virus-specific
diagnostic tests to identify the timing of transmission may be
valid. Here we extend this analysis to examine other transmission risk factors, including preterm delivery and maternal zidovudine use. Clarification of whether these risk factors affect
intrauterine or intrapartum transmission may help illuminate
mechanisms of transmission.
Methods
Study population. HIV-infected pregnant women and their delivered children were followed as part of the Perinatal AIDS Collaborative Transmission Study. Clinical sites in New York City,
Newark, New Jersey, Baltimore, and Atlanta participate in this
Centers for Disease Control and Prevention (CDC) collaborative
project. Pregnant and parturient HIV-infected women were recruited at these sites from 1985 to the present. For this analysis,
432 liveborn infants who had HIV-1 DNA PCR or viral culture
results available for samples drawn within 2 calendar days of birth
(inclusive) were included. Children known to have been breast-fed
or whose HIV status could not be determined were excluded.
Study protocol. Staff at each site collected a common set of
clinical and laboratory data. Maternal clinical and interview data,
collected during pregnancy and after delivery, included CD4 and
CD8 T lymphocyte counts, clinical symptoms, and use of antiretroviral drugs, including zidovudine. Obstetric and neonatal data
were collected for all deliveries. Maternal lymphocyte data collected
during pregnancy or !1 month after delivery was used in this study.
All infants in this analysis had blood drawn within 2 calendar
days of birth for laboratory analysis. Results from cord blood were
not included. All children were tested again at months 1, 2, 4, and
6 and at 3-month intervals thereafter. Infected children were retained in the cohort and were examined at regular intervals according to standard protocols.
Laboratory analysis. Samples were tested for HIV DNA by
PCR using methods previously described [5]. Heparin-treated
blood samples were shipped at room temperature overnight for
separation and storage at 2707C until testing. Viral cultures were
done at two of the sites using standard methods [17]. Lymphocyte
subset determination was performed using flow cytometry
procedures.
Definitions.
Children were considered infected if they were
HIV-seropositive, confirmed by Western blot at >18 months of
age, had two or more positive PCR tests or viral cultures at any
age, had an AIDS-defining illness, or if they died with an HIVrelated condition [18].
Intrauterine infection was presumed if a child was infected and
had a positive PCR or viral culture within 2 calendar days of birth.
Intrapartum infection was presumed if an infected child had negative results within this interval (adapted from the working definition [1]).
Statistical analysis. The unit of analysis was the pregnancy.
Only the first-born of multiple births was retained (all multiple
births were concordant for HIV status). Siblings were retained,
53
since analysis of these data found the outcomes of subsequent
pregnancies were independent [19]. Risk factor information referred
to each pregnancy separately.
Intrauterine transmission rates were calculated as the number
with intrauterine infections divided by the total number of infants
(marginal probability), and intrapartum transmission rates as the
number with intrapartum infections divided by the number who
survived without intrauterine infection, that is, only among the
subgroup with early negative results (conditional probability). Intrauterine and intrapartum transmission rates were compared by
perinatal and maternal characteristics using Mantel-Haenszel estimates of relative risks (RRs). Multiple logistic regression was
used to estimate adjusted odds ratios (ORs) for each perinatal and
maternal characteristic adjusted for the other characteristics
investigated.
The probability of AIDS-free survival by results of early PCR
or culture was described using Kaplan-Meier lifetable methods and
tested using log-rank tests. The CDC pediatric AIDS surveillance
definition was used, excluding lymphoid interstitial pneumonitis.
Time from birth to AIDS diagnosis or death was calculated among
children with these events; children who survived AIDS-free were
censored at the age they were last seen. Proportional hazards models were used to estimate adjusted RR.
Results
HIV infection was identified in 67 (16%) of the 432 infants:
19 (28%; 95% CI, 18–41) were positive at <2 days of life, and
48 (72%; 95% CI, 59–82) were negative at this time. The risk
of intrauterine transmission was 4.4% (95% CI, 2.7–6.9). The
risk of intrapartum transmission was 11.6% (95% CI, 8.8–15.2).
Results were similar regardless of whether infants were tested
by PCR or viral culture: 398 infants had PCR results, 77 had
culture results, and 43 had both (all concordant). Positive results were found in 16 (27%) of 59 infected children with early
PCR results and 3 (25%) of 12 infected children with early viral
culture results. At their next test, 43 (90%) of 48 infected children with negative early tests were positive; 3 children had a
negative test result at ∼1 month and the remaining 2 at older
ages. The cumulative probability of at least one positive PCR
or viral culture result by age 1 month was 89% (95% CI, 71–
100).
Risks of Intrauterine and Intrapartum HIV Transmission
Maternal zidovudine use.
Unadjusted intrapartum HIV
transmission was slightly, but not significantly, lower when
mothers used zidovudine during pregnancy (10%) than when
they did not (13%; RR, 0.7; 95% CI, 0.4–1.3) (table 1). Adjusting for markers of severity of maternal disease (CD4 percentage and clinical status), zidovudine use was associated with
a substantial and significant reduced risk of intrapartum transmission (OR, 0.3; 95% CI, 0.1–0.7) and remained significant
with further adjustment for preterm delivery and duration of
membrane rupture (table 2). Maternal zidovudine use was not
54
Kuhn et al.
JID 1999;179 (January)
Table 1. Risk of intrauterine HIV transmission (infected children with positive polymerase chain reaction
or culture results within 2 days of birth) and intrapartum HIV transmission rates (infected children with
negative results) by perinatal and maternal characteristics among 432 infants of HIV-infected mothers.
Intrauterine
Characteristic
Zidovudine prescribed
No
Yes
Gestation
Term >37 weeks
Preterm !37 weeks
Mode of delivery
Cesarean
Vaginal
Duration of membrane rupture prior to delivery
0–3 h
>4 h
Clinical stage
Asymptomatic
Symptomatic/AIDS
Maternal CD4 cell count
>500/mL
!500/mL
Maternal CD4 cell %
>29
!29
Maternal CD4:CD8 ratio
>0.5
!0.5
NOTE.
Intrapartum
No.
Transmission
% (n)
Relative risk
(95% CI)
Transmission
% (n)
Relative risk
(95% CI)
221
163
5.4 (12)
3.7 (6)
0.7 (0.3–1.8)
13.4 (28)
9.6 (15)
0.7 (0.4–1.3)
350
66
4.3 (15)
6.1 (4)
1.4 (0.5–4.1)
8.4 (28)
30.6 (19)
3.7 (2.2–6.1)
74
331
4.1 (3)
4.5 (15)
1.1 (0.3–3.8)
14.1 (10)
10.8 (34)
0.8 (0.4–1.5)
178
151
3.9 (7)
4.0 (6)
1.0 (0.3–2.9)
5.8 (10)
16.6 (24)
2.8 (1.4–5.7)
186
128
6.5 (12)
2.3 (3)
0.4 (0.1–1.3)
5.7 (10)
17.6 (22)
3.1 (1.5–6.3)
217
204
5.1 (11)
3.9 (8)
0.8 (0.3–1.9)
9.2 (19)
14.3 (28)
1.6 (0.9–2.7)
214
176
5.1 (11)
3.4 (6)
0.7 (0.3–1.8)
8.4 (17)
13.5 (23)
1.6 (0.9–2.9)
235
139
6.0 (14)
2.2 (3)
0.4 (0.1–1.2)
9.0 (20)
13.2 (18)
1.6 (0.8–2.7)
CI, confidence interval.
significantly associated with reduced intrauterine transmission
in univariate (table 1) or multivariate models (table 2), although
the point estimates of the unadjusted RRs and adjusted ORs
suggested a protective effect of an similar order of magnitude
to that observed with intrapartum transmission. Zidovudine
may not have affected intrauterine or intrapartum HIV transmission differentially. An almost identical percentage of HIV
infections were due to intrauterine transmission among women
who used zidovudine (29%; 6/21) compared with those who did
not (30%; 12/40).
The study included mother-child pairs enrolled before and
after demonstration of beneficial effects of zidovudine to prevent HIV transmission. Thus, it includes women who used zidovudine specifically to prevent transmission and women who
Table 2. Adjusted odds ratios (ORs) for the risks of intrauterine transmission (model 1)
and intrapartum transmission (model 2) associated with perinatal and maternal characteristics
among 432 infants of HIV-infected mothers.
Model 1
Characteristic
Zidovudine prescribed
No
Yes
Gestation
Term >37 weeks
Preterm !37 weeks
Duration of membrane rupture prior to delivery
0–3 h
>4 h
Clinical stage
Asymptomatic
Symptomatic/AIDS
Maternal CD4 cell count
>500/mL
!500/mL
a
Model 2
a
Adjusted OR (95% CI)
Adjusted OR (95% CI)
0.44 (0.11–1.76)
0.38 (0.14–0.98)
1.61 (0.30–8.49)
4.21 (1.54–11.50)
0.65 (0.17–2.44)
2.66 (1.01–6.96)
0.69 (0.17–2.82)
4.00 (1.54–10.35)
0.86 (0.22–3.30)
1.42 (0.57–3.56)
NOTE. CI, confidence interval.
a
ORs for each covariate are adjusted for all other variables shown in table.
JID 1999;179 (January)
Intrauterine and Intrapartum HIV Infection
55
Figure 1. Gestational age distribution of uninfected infants and intrauterine- and intrapartum-infected infants of HIV-seropositive mothers
intrapartum transmission remained strong and significant after
adjustment for zidovudine use, duration of membrane rupture,
maternal clinical stage, and CD4 cell count (table 2).
When further stratified by duration of membrane rupture,
the association between preterm delivery and intrapartum
transmission was found only among infants born longer after
membrane rupture (table 3). Among infants born >4 h after
rupture of fetal membranes, 40% of preterm and 11% of term
infants had intrapartum HIV transmission (RR, 3.8; 95% CI,
1.9–7.8); if born <3 h after rupture, 6% of both preterm and
term infants had intrapartum HIV transmission (OR, 0.9; 95%
CI, 0.1–6.8).
Preterm delivery was significantly associated with intrapartum HIV transmission among women who used zidovudine
during pregnancy or during the perinatal period and among
those who had not. The association was also significant when
stratifying by markers of the severity of maternal disease.
Intrapartum characteristics. Rupture of fetal membranes
took zidovudine therapeutically. At least 94% of mother-child
pairs received zidovudine at one or more of the times specified
by AIDS Clinical Trials Group 076 protocol (i.e., to the mother
during the third trimester and at delivery; to the infant postnatally). However, only 37% of pairs received zidovudine at all
three time points.
Preterm delivery. Preterm infants had a substantially increased risk of intrapartum HIV infection but did not have
increased risk of intrauterine HIV infection. The intrapartum
HIV transmission rate was 31% among preterm infants compared with 8% among term infants (RR, 3.7; 95% CI, 2.2–6.1)
(table 1). As a continuous variable, the distribution of gestational age was similar among uninfected and intrauterineinfected infants (12% of uninfected infants were born before 37
weeks vs. 21% of intrauterine-infected infants, P 5 .21 ), but
intrapartum-infected children were more likely than uninfected
infants to be born earlier (40% born before 37 weeks, P 5
.02) (figure 1). The association between preterm delivery and
Table 3. Risk of intrauterine and intrapartum HIV transmission by preterm delivery and duration of membrane
rupture prior to delivery.
Intrauterine HIV transmission
Characteristic
No.
%
Duration of membrane rupture before delivery, 0–3 h
Term >37 weeks
Preterm !37 weeks
Duration of membrane rupture before delivery, >4 h
Term >37 weeks
Preterm !37 weeks
173
155
18
150
117
33
4.0
4.5
0.0
4.0
2.6
9.1
NOTE.
CI, confidence interval.
Relative risk (95% CI)
Undefined
3.5 (0.8–16.7)
Intrapartum HIV transmission
%
6.0
6.1
5.6
16.7
10.5
40.0
Relative risk (95% CI)
0.9 (0.1–6.8)
3.8 (1.9–7.8)
56
Kuhn et al.
JID 1999;179 (January)
Figure 2. Survival of HIV-infected children by timing of transmission
14 h before delivery (the median duration in the study population) significantly increased the risk of intrapartum HIV infection (RR, 2.8; 95% CI, 1.4–5.7) but did not increase the risk
of intrauterine HIV infection (RR, 1.0; 95% CI, 0.3–2.9) (table
1). Similar associations between the duration of membrane rupture and transmission were observed among vaginal and cesarean deliveries separately, but no independent associations between either intrauterine or intrapartum HIV transmission and
mode of delivery were observed. Data were too sparse to classify cesarean deliveries as undertaken before membrane rupture
and onset of labor. Other intrapartum variables investigated
(duration of labor, episiotomy or perineal lacerations, and internal fetal monitoring) were not associated with intrauterine
or intrapartum HIV transmission (data not shown).
Severity of maternal disease. Markers of severity of maternal disease were weakly but not significantly associated with
transmission in unadjusted analyses (table 1), but after adjustment for zidovudine use the associations were statistically significant. Maternal counts of !500/mL CD4 cells (OR, 2.1; 95%
CI, 1.1–4.1), CD4 percentage !29 (OR, 2.3; 95% CI, 1.1–4.7),
and clinical symptoms or AIDS (OR, 3.7; 95% CI, 1.6–8.2)
were each significantly associated with increased intrapartum
HIV transmission adjusting for zidovudine use only. In the full
multivariate model, only maternal clinical stage remained significantly associated with intrapartum transmission (table 2).
Intrauterine infection was not increased among women with
clinical symptoms or AIDS nor among women with low CD4
T lymphocyte cell counts, percentages, or CD4:CD8 ratios (ta-
ble 1) nor were there any associations with intrauterine transmission after adjusting for any of the other variables.
Timing of transmission and disease progression in HIV-infected
children. HIV-infected children with positive PCR or culture
results within the first 2 days of life had a 2-fold higher risk of
progression to AIDS or death (RR, 1.9; 95% CI, 0.9–4.2) and
a higher overall mortality (RR, 2.3; 95% CI, 0.8–5.2) than
infected children with negative results (figure 2). By age 1 year,
43% of intrauterine-infected children had developed AIDS or
died compared with 29% of intrapartum-infected children (logrank test, P 5 .12). Progression to AIDS or death among HIVinfected children with positive PCR or culture results within 2
days of birth was significantly increased (RR, 2.5; 95% CI,
1.1–5.8) after adjusting for preterm delivery (RR, 4.3; 95% CI,
1.8–9.9) and low maternal CD4 cell counts (RR, 1.6; 95% CI,
0.7–3.5).
Discussion
Events at the time of delivery cannot influence events that
preceded them. Thus, our finding that the duration of
membrane rupture prior to delivery was associated with intrapartum but not intrauterine transmission was internally consistent. This is reassuring since the analysis relies on the inference that the results of virus-specific diagnostic tests can be
used to identify the timing of transmission. Other attempts to
test the validity of the working definition have also shown reasonable internal consistency. For example, modeling time to
JID 1999;179 (January)
Intrauterine and Intrapartum HIV Infection
development of child-specific antibodies to particular HIV proteins estimated that a third of infants were infected before delivery, consistent with estimates based on early PCR results [20].
Children with positive viral cultures in the first week of life had
increased percentages of CD8 and HLA-DR1 lymphocytes (a
marker that appears on lymphocytes shortly after activation)
than those with later positive results [21].
We found strong and significant reductions in intrapartum
transmission associated with maternal zidovudine use, suggesting that zidovudine is important in reducing transmission
that occurs at delivery. Associations between zidovudine use
and intrauterine transmission, although not statistically significant, were consistent with the inference that zidovudine use
may also result in some reduction in intrauterine transmission.
There was no evidence that the proportion of intrauterine infections was increased among infected children whose mothers
used zidovudine. These findings suggest that failure of zidovudine to prevent transmission in some instances cannot simply
be accounted for by transmission early in pregnancy. Other
mechanisms will need to be investigated if interventions to reduce maternal-infant HIV transmission below thresholds
achievable with the standard of care antiretroviral protocol [22]
are to be developed.
Preterm delivery has been associated with an increased risk
of HIV transmission in this [18] and most of the other large
cohort studies [15, 23–26]. However, it could not be determined
from these previous studies whether preterm delivery was a
cause or a consequence of HIV transmission. By separating
intrauterine from intrapartum infections in this analysis, we
observed that preterm infants had a substantially increased risk
of intrapartum infection over term infants, but preterm and
term infants were equally likely to acquire intrauterine infection. This suggests that intrauterine infection is unlikely to precipitate preterm delivery; rather, preterm infants are at increased risk of acquiring infection at the time of delivery.
The increased risk of intrapartum infection with preterm delivery was restricted to infants delivered following longer rupture of membranes, supporting the notion that preterm infants
are more vulnerable to prolonged exposure to HIV at delivery.
Vulnerability may be related to immature mucosal barriers or
to failure to acquire protective levels of neutralizing antibody,
since passive transfer of maternal antibody across the placenta
may occur late in pregnancy. The one intervention trial specifically targeting perinatal transmission, using manual cleansing of the birth canal with chlorexidine, found reduced transmission among children born after longer rupture of
membranes [27]. Many of these children may also have been
born preterm, as premature rupture of membranes is an important initiator of preterm delivery. Current clinical trials and
intervention programs may inadvertently exclude many preterm
deliveries by recruiting through prenatal clinics. Efforts should
57
be made to ensure that preterm deliveries are included in intervention programs.
We found no evidence that the severity of maternal disease
was associated with intrauterine HIV transmission. However,
it was associated with intrapartum HIV transmission. Low maternal CD4 T lymphocyte counts have been associated with
increased shedding of HIV-infected cells from the cervix and
vagina [28, 29]. Thus, markers of the severity of maternal disease may indicate the extent of viral exposure at delivery. Transplacental transmission may require other mechanisms.
We found a 2-fold increase in progression to severe disease
or death among HIV-infected children who had virus detected
by PCR or culture within the first 2 days of life, supporting
the thesis that intrauterine infection has a worse prognosis than
intrapartum infection. The association was independent of preterm delivery and severity of maternal disease. (In this analysis,
these factors slightly masked the unadjusted association between intrauterine transmission and disease progression, because they were independent risk factors for disease progression
and were associated with intrapartum transmission.) Early positivity of virus-specific tests can, however, only partially account
for the variability of disease progression observed in HIVinfected children. While more than half (56%) of children with
rapidly fatal HIV infections had early positive results, almost
a quarter (23%) of those with a less severe course also had
positive results.
Early PCR or culture results may capture, in addition to
information about the timing of transmission, information
about host or viral factors related to viral replication. Children
with evidence of early infection have higher median HIV RNA
values in the early months of life than children with late infection [30]. Higher levels of HIV RNA in the first 2 months
are strongly predictive of poor prognosis [30, 31]. Viral phenotypes with more efficient replication, or that are not curtailed
by host immune responses, may reach detectable levels sooner
than variants with slower replication [32]. For patient-care purposes, clinicians should recognize that HIV-infected children
with early positive PCR or viral culture results are likely to
progress more rapidly.
Our results suggest that prevention of preterm delivery, particularly prevention of premature rupture of membranes, may
help reduce maternal-infant transmission even in the absence
of other interventions. It is, however, a tragic reality of the HIV
epidemic in the United States that the women most likely to
be infected are also those who are the least well-integrated into
primary health care services, and who may have multiple other
risk factors for poor reproductive outcomes. The potential to
reduce maternal-infant HIV transmission using zidovudine prophylaxis has raised the urgent need for active outreach to identify HIV-infected women and to bring them into medical care
early in pregnancy. Possible benefits of good prenatal care in
58
Kuhn et al.
reducing the risk of preterm delivery adds further importance
to these efforts.
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