Mechanisms of Transmission
HIV may be transmitted from mother to infant in three ways:
Diagnosis of Perinatally Acquired HIV Infection
Bryson and colleagues[38] have
proposed a definition of the timing of HIV infection. Early transmission (or in
utero) is defined as that which may be detected within the first 48 hours
of life. Late transmission (or intrapartum) is defined as negative
virologic evaluations during the first week, with evidence of HIV detection
between 7 and 90 days of age in the absence of breastfeeding. Employing viral
culture, approximately 15% of HIV-infected infants have detectable levels of
virus in the blood within 48 hours of birth,[39,40]
indicating that these infections may have occurred during in
utero development. Another study using HIV culture as the diagnostic
method demonstrated a sensitivity of 24% in the first week of life which
increased to 85% by 1 month of age.[41]
Using polymerase chain reaction (PCR) technology, HIV-1 DNA was detected in 38%
of 271 infected infants studied within 48 hours of birth.[42] These data would indicate that as
much as 62% to 85% of perinatal transmission may occur in the intrapartum
or neonatal periods. Approximately 93% of HIV-infected infants will demonstrate
presence of viral markers by 14 days of life with PCR testing, and essentially
100% within 30 to 90 days of birth.[39-43] This
excludes infants who are breastfed by HIV-infected mothers, for in this setting
HIV transmission may occur throughout the duration of breastfeeding.
Factors Which Influence the Risk of Perinatal HIV Transmission
Maternal HIV viral load. Clinically or immunologically
advanced HIV disease in the mother has consistently been associated with higher
likelihood of transmission to the infant.[16,37]
Thus, the European Collaborative Study found that a CD4+ cell count less than
700 cells/mm3 was associated
with increased risk of maternal-fetal transmission,[16] while Mayaux and colleagues noted a 43% transmission
rate among women whose CD4+ cell counts were less than 200 cells/mm3, versus 15% when the CD4+ count was
over 600 cells/mm3.[44] Of note, the subsequent course of
HIV disease in the infected children has also been correlated with the severity
of maternal HIV disease during pregnancy. Blanche and colleagues demonstrated a
statistically increased risk of death during the first 18 months of life in
those infants whose mothers had more advanced clinical disease, presence of p24
antigenemia, and/or lower CD4+ cell count at the time of delivery.[45] In addition, studies have
demonstrated that an increased maternal virus load is associated with an
increased risk of in utero transmission.[46,47] In utero transmission, in turn, appears
to correlate with an increased rate of disease progression in the infant.[48-50]
Multiple studies have confirmed the importance of maternal viral load in
predicting the risk of HIV transmission to the infant.[51-53] Dickover and colleagues studied
92 HIV-seropositive pregnant women and their 97 infants, of whom 20 (21%) were
subsequently proved to be perinatally infected.[54] A maternal HIV-1 RNA level over 50,000 copies/mL at
delivery was associated with increased transmission: 75% of the 20 transmitters
had viral load greater than 50,000 copies/mL compared with only 4 (5.3%) of the
nontransmitters. In contrast, none of the 63 women with viral load less than
20,000 copies/mL transmitted HIV to their infants. Forty-two of the mothers
received zidovudine during pregnancy, resulting in significant decreases in
HIV-1 RNA levels in plasma; none of these women transmitted HIV to the newborn.
However, 4 zidovudine-treated women with persistently high HIV-1 RNA levels did
transmit HIV-1. These data would suggest that maternal HIV-1 viral load is an
important determinant of perinatal transmission, and also suggests the
possibility of a threshold below which perinatal transmission would probably
not occur. However, transmission may occur even with undetectable levels of HIV
RNA.[55]
The importance of HIV-1 viral load in predicting perinatal transmission was
also addressed by Sperling and colleagues, as part of the Pediatric AIDS
Clinical Trials Group (PACTG) Protocol 076 Study Group, which evaluated the
efficacy of zidovudine in the prevention of perinatal transmission.[55] In this placebo-controlled trial of
402 mother-infant pairs, the rate of transmission of HIV-1 was 7.6% with
zidovudine, and 22.6% in those who received placebo (P<.001). In
the placebo group, a high viral load at study entry (14 weeks of gestation) or
delivery was associated with increased likelihood of HIV transmission, with a
40% transmission rate in those women with the highest levels of HIV-1
(>15,700 copies/mL on the RT-PCR assay, and >7,530 copies/mL on the
branched DNA assay). Of interest, while zidovudine was associated with a
reduction in perinatal transmission and a median 0.24 log10 decrease in plasma viral RNA, a
reduction in viral RNA from baseline to delivery was not significantly
associated with the risk of transmission. Further, zidovudine was effective in
reducing transmission at all HIV-1 RNA levels, even the lowest. These data
suggest that high HIV-1 viral load is associated with perinatal transmission in
untreated women. Further, the ability of zidovudine to reduce such transmission
is only partially explained by its ability to lower viral load in the mother.
It is possible that ZDV may reduce perinatal transmission by providing
prophylaxis directly to the infant, since this antiretroviral readily crosses
the placenta.
Despina and colleagues recently assessed the predictive value of maternal
HIV-RNA load in perinatal HIV transmission by performing a meta-analysis of 9
cohorts involving 1115 maternal-child pairs.[56]
The overall rate of transmission in untreated women was 21.3%. As the HIV-1
viral load increased, so did the rate of transmission, rising from 5% in women
with <1000 copies/mL to 15% in those with 1000 to 9999 copies/mL and 37% in
those with HIV-RNA levels over 10,000 copies/mL. In pregnant women receiving
antiretroviral therapy, the perinatal transmission rate was 5% for those with
<1000 copies/mL; 7% for those with viral loads between 1000 and 9999
copies/mL; and 18% for those with over 10,000 copies/mL. The risk of transmission,
based solely on HIV-1 RNA levels in plasma, thus appears attenuated in patients
receiving antiretroviral therapy. However, while maternal HIV-RNA levels are
quite helpful in predicting the average risk of transmission in a group of
women, such information is of more limited use in predicting outcome in
individual patients, since an absolute threshold of safety has not been proven.[55]
Table I: Predictive Value of Maternal Viral Load for HIV
Transmission[56]
|
Viral load (copies/mL) |
Rate of
Perinatal HIV Transmission |
|
|
Untreated Women |
Treated
Women |
|
|
<1000 |
5% |
5% |
|
1000-9999 |
15% |
7% |
|
>10,000 |
37% |
18% |
Garcia and colleagues measured HIV-1 RNA in 552 pregnant, HIV-1-infected
women enrolled in the Women and Infants Transmission Study (WITS).[57] Increasing geometric mean levels of
plasma HIV-1 RNA were associated with an increasing risk of transmission (Table
II).
Table II: Maternal Viral Load and HIV Transmission in the WITS Study
[57]
|
HIV-1 RNA
(copies/mL) |
Number
transmitting/total |
Percent
transmission |
|
<1,000 |
0/57 |
0% |
|
1,000-10,000 |
32/193 |
16.6% |
|
10,001-50,000 |
39/183 |
21.3% |
|
50,001-100,000 |
17/54 |
30.9% |
|
>100,000 |
26/54 |
40.6% |
On multivariate analysis, higher maternal plasma HIV-1 RNA
level, lack of receipt of zidovudine therapy according to ACTG protocol 076,
low birth weight of the infant, and time from rupture of membranes of delivery
>4 hours were all statistically associated with risk of perinatal
transmission. This study would thus suggest that while HIV-1 RNA level is
highly predictive of transmission, other factors are also important.
Further analysis of Pediatric ACTG study 185 was also recently published by
Mofenson and colleagues.[58]
In this study of 480 pregnant women with advanced HIV-1 disease, all received
zidovudine during and after pregnancy, as did the infants. Half of the women
were also randomized to receive HIV-1 hyperimmune globulin monthly during
pregnancy and once to the neonates at birth. In this study, baseline HIV RNA at
the time of first testing during pregnancy was statistically correlated with
eventual perinatal transmission.
At the time of delivery, several factors were associated with increased risk
of transmission, including higher maternal HIV-1 RNA levels, higher levels of
maternal HIV p24 antibody, and presence of chorioamnionitis. No perinatal
transmission occurred among the 84 women who had undetectable HIV RNA (<500
copies/mL) in plasma at baseline, or the 107 women who had undetectable levels
at delivery.
These studies would thus indicate that HIV-1 RNA is a powerful predictor of
HIV-1 transmission. However, obstetrical factors are also important, such as
prolonged intervals between amnionic membrane rupture and delivery, and
presence of chorioamnionitis.
Other maternal factors. Aside from more advanced HIV
disease, additional maternal factors have been associated with an increased
chance of perinatal transmission.
Maternal cigarette smoking has been associated with a statistically
significant, 3-fold increased risk of perinatal HIV-1 transmission, in women
with low CD4+ cell counts.[59]
Further, mothers who transmitted HIV to their infants were more likely to have
clinical chorioamnionitis than those who did not transmit, as demonstrated in a
study by Nair and colleagues.[60]
While use of illicit injection drugs during pregnancy has been associated
with an increased risk of perinatal HIV infection, a past history of injection
drug use poses no increased risk.[59,61]
Furthermore, geographic origin, educational history, parity, or marital status
are not associated with change in risk for transmission.[16,45,60]
Older maternal age, with increasing risk for each 5-year increment over 25
years, has been associated with an increased risk of perinatal transmission,[44] although the majority of studies
have not confirmed this relationship.[16,45,60]
Obstetrical factors: premature rupture of the membranes.
Premature rupture of the amniotic membranes has been associated with higher
risk of perinatal HIV transmission, probably related to increased duration of
fetal exposure to infected cervicovaginal secretions. The Women and Infants
Transmission Study (WITS) enrolled 525 women who delivered live singleton
infants, in whom the serostatus was known. In those mothers whose membranes
ruptured more than 4 hours prior to delivery, the rate of perinatal
transmission was 25%, versus 14% among those whose membranes ruptured 4 hours
or less prior to the time of delivery.[61]
This increased risk was independent of the mode of delivery. On multivariate
analysis, ruptured membranes for over 4 hours nearly doubled the risk of
transmission. Premature rupture was also shown to be a significant factor in
predicting perinatal transmission by Burns and colleagues,[59,62] independent of maternal CD4+ cell
count. The impact of membrane rupture over 4 hours is also evident among women
who have been treated with antiretroviral agents during pregnancy.[61,63]
Obstetrical factors: mode of delivery. Initial studies
indicated similar rates of HIV transmission in children born after vaginal or
cesarean deliveries.[9,25,64]
However, recent data would indicate that elective cesarean section (C-section)
may be very effective in reducing perinatal transmission of HIV-1. These
discrepancies may be secondary to the fact that elective C-section negates the
possibility of premature rupture of the membranes. Differences in results could
also have been caused by the possible inclusion of women who underwent
nonelective C-section; and by the potential bias that some obstetricians may be
more or less likely to perform C-sections on HIV-infected patients with more
advanced clinical disease.
The European Collaborative Study, based on 721 children born to 701 mothers,
demonstrated that elective C-section was associated with a decreased risk of
perinatal transmission (relative risk = 0.56); however, these results were not
statistically significant.[16]
A subsequent report from this group again noted a decreased risk of perinatal
HIV transmission after C-section.[22]
In another study, Duliege and colleagues evaluated data from prospectively
identified twins whose mothers were HIV-infected.[65] Among first-born twins, 52% of the transmission risk
was found to be related to vaginal delivery.
More recently, Read and colleagues performed a meta-analysis of North
American and European studies, each consisting of at least 100 mother-child
pairs, to determine the role of elective C-section in decreasing perinatal
transmission.[66] The primary
analysis included data from 8533 mother-child pairs. After adjusting for use of
antiretroviral therapy, maternal stage of HIV infection, and infant birth
weight, the risk of perinatal transmission was decreased by approximately 50%
in those women who underwent elective C-section, when compared with other modes
of delivery (odds ratio, 0.43; 95% confidence limit, 0.33 to 0.56). Similar
results were found when the control population was limited only to those women
with rupture of the membranes immediately prior to delivery. When all
C-sections were compared with all vaginal deliveries in this meta-analysis, use
of C-section remained predictive of decreased risk of transmission, although
not to the same degree as that seen with elective C-section alone.
Among women who did not receive antiretroviral therapy, a transmission rate
of 10.4% was documented after elective C-section, versus 19% after vaginal
delivery.[66] Of importance,
use of antiretroviral therapy during pregnancy as well as elective C-section
resulted in a decrease of perinatal transmission of approximately 87%. Among
the 196 women who took antiretroviral agents and had an elective C-section, the
vertical transmission rate was 2%. Among 1255 mothers who took antiretroviral
agents but underwent other modes of delivery, the perinatal transmission rate
was 7.3%. It is important to note, however, that no maternal virologic data
were available from the 15 studies that were included in this meta-analysis.
Further, even though there was clearly a significant association between
elective C-sections and decrease in perinatal HIV transmission, no conclusions
can be drawn about what additional benefit, if any, an elective C-section would
have in preventing perinatal transmission from mothers with undetectable plasma
levels of virus.
Table III: Perinatal HIV Transmission Rates Among Women Receiving
Antiretroviral Therapy and/or Elective Cesarean Section[66]
|
|
Antiretroviral Therapy
|
No Antiretroviral Therapy
|
|
Elective C-section |
2% |
10.4% |
|
No Elective C-section |
7.3% |
19% |
Of interest, a second study performed in a French cohort of patients,
evaluating the association between elective C-section and perinatal HIV-1
transmission rates, only noted a clear benefit of this procedure when it was
performed in conjunction with antiretroviral treatment of the mother.[67] Mandelbrot and colleagues reported a
perinatal transmission rate of 17.5% for vaginal deliveries, 15.6% for
nonelective C-sections, and 17.5% for elective C-sections in a group of 1877
women who received no antiretroviral therapy during pregnancy. However, for 872
women who received ZDV treatment during gestation there was a significant
association between mode of delivery and perinatal transmission. Transmission
rates were 6.6% for vaginal deliveries, 11.4% for nonelective C-sections, and
0.8% for elective C-section (P=0.002) with an odds ratio for elective
C-section of 0.2 (95% CI, 0.0-0.9). Similar to the Read study,[66] maternal virologic data were not
available for analysis in the French study.
A recent prospective randomized clinical trial has confirmed the advantage
of elective C-section.[68] The
European Mode of Delivery Collaboration study randomized 370 infants born to
HIV-infected mothers to delivery via either elective C-section (170 infants) or
vaginal delivery (200 infants). At 18 months, the rate of HIV transmission to
the infants was 1.8% among those born by C-section, and 10.5% among those
assigned to vaginal delivery. No serious side effects were noted among women
who underwent elective C-section, and the rate of postpartum
complications was very small.
Recent data on the rate of infectious complications after surgical
deliveries in HIV-infected women are conflicting. WITS reported a morbidity
rate associated with elective cesarean delivery of 19%.[69] Morbidity due to infections,
including endometritis, wound infections, and urinary tract infections,
occurred in 11% of elective C-sections and in 21% of nonelective C-sections.
For vaginal deliveries these rates were 8% for women receiving instrumental
assistance and 4% for women with noninstrumented deliveries. A second perinatal
study, ACTG 185, also reported an increased rate of infectious complications in
HIV-infected women undergoing surgical deliveries: 26% for elective C-sections
and 40% for C-sections performed after rupture of amniotic membranes.[70] Vaginal deliveries had a lower rate
of infectious complications: 13% for spontaneous deliveries and 19% for
assisted vaginal deliveries. Of interest, in this study absolute CD4+ cell
count did not correlate with an increased rate of infectious complications. These
results clearly demonstrate that risks and benefits of surgical procedures must
be taken into account when considering elective C-sections for HIV-infected
women.
Nonetheless, the current data do demonstrate a significant advantage to
elective C-section delivery in HIV-infected mothers. Such a mode of delivery
would theoretically be associated with decreased likelihood of
microtransfusions of infected blood to the fetus during labor. Further,
C-section would result in avoidance of direct fetal contact with infected
maternal sections in the birth canal. Unfortunately, however, elective
C-sections do not prevent against in utero infection. Furthermore, the
current studies were conducted prior to the advent of highly-active
antiretroviral therapy (HAART). Thus, it is unknown whether HIV transmission
rates after maternal use of potent combination antiretroviral therapy would be
further reduced by elective surgical deliveries.
In terms of vaginally delivered infants, rates of transmission are increased
in deliveries in which episiotomy, scalp electrodes, forceps, or vacuum
extractors were used, but only in those centers where these procedures are not
routinely performed.[16]
Factors related to the fetus. A low birth weight of less
than 2500g[51,61,71] and/or
gestational age <34 weeks[16]
or <38 weeks[51,71] have
each been associated with an increased risk of perinatal HIV transmission. This
association between prematurity and transmission may simply be a consequence of
HIV infection in utero, resulting in abnormalities in fetal
development and premature birth. Additionally, women with more advanced HIV
disease, who are more likely to transmit to their infants, are also more likely
to deliver premature infants. It is also possible that infants born prematurely
may have less developed immune systems, and thus be more susceptible to
infection during labor and delivery. One way to address this issue is to
determine the timing of infection. Recent studies of this type in HIV-exposed
infants have suggested that the rate of intrapartum transmission might
be higher among premature babies, implying that acquisition of infection
occurred because they were born prematurely and not vice versa.[72,73]
Aside from prematurity or low birth weight, the birth order of twins has also
been associated with differing risks of infection. Both Goedert and colleagues[25] and Duliege and associates[65] have shown that the majority of twin
pairs are concordant in terms of HIV-1 infection. However, a significantly
increased risk of HIV-1 infection is also apparent among first-born
("A") as opposed to second-born ("B") twins, independent of
mode of delivery. Thus, as shown by Duliege, HIV-1 infection occurred in 35% of
vaginally-delivered "A" twins versus 15% of vaginally-delivered
second-born twins. In twin pairs born after C-section delivery, the risk of HIV
infection was 16% among "A" twins, and 8% among "B" twins.[65] Although the precise mechanisms for
this increased risk in first-born twins are unknown, it is certainly consistent
with the fact that perinatal infection often occurs at the time of delivery.
Table IV: Perinatal HIV Transmission Rates in Twins[65]
|
Mode of delivery |
Perinatal transmission
rates |
|
|
First-born "A"
twins |
Second-born "B"
twins |
|
|
Vaginal delivery |
35% |
15% |
|
C-section delivery |
16% |
8% |
Role of breastfeeding. HIV-1 has been
isolated from cell-free breast milk,[74] and
HIV DNA has been demonstrated in the majority of milk specimens from
HIV-infected mothers. Thus, Ruff and colleagues detected HIV DNA in 70% of milk
specimens collected from 47 HIV-seropositive women from 0 to 4 days postpartum,
and in about 50% of specimens collected from 6 to 12 months postpartum.[75] Evidence of HIV transmission via breastfeeding
has come from reports in which children were exposed to HIV-1 only through
breastfeeding,[76] and from
studies in which breastfed infants had an increased risk of perinatal HIV
transmission, when compared with children who were bottlefed.[9,16,19,77]
While the potential for HIV transmission through maternal milk is clearly
evident from these studies, the actual risk for such transmission has been
uncertain. Studying a group of mothers with primary HIV infection, Van de Perre
and colleagues found that at least 4 of 11 (36%) infants became infected with
HIV through breastfeeding.[34]
Plasma viral load is known to be high during primary HIV infection,[21] making it difficult to assess the
applicability of these data to other stages of HIV infection. In fact, a
meta-analysis of five different studies of postnatal transmission reported an
excess transmission risk by breastfeeding of 14% for women with established HIV
infection, and an excess risk of 29% among women who developed primary
infection during the postpartum period.[78]
De Martino and coworkers studied a group of 168 breast-fed and 793 bottlefed
children born to seropositive mothers in Italy.[79] Breastfeeding was shown to increase the risk of HIV-1
transmission, with an estimated adjusted odds ratio for 1 day of breastfeeding
versus bottlefeeding of 1.19 (95% CI, 1.10-1.28). The odds ratio of
transmission increased with the duration of breastfeeding, a finding also
reported by Nagelkerke and colleagues.[80]
Recent work from Malawi in Africa has demonstrated a clear relationship
between duration of breastfeeding and the likelihood of HIV transmission to the
infant. During months 2 to 6 postpartum, the incidence of transmission through
breastfeeding was 0.7% per month. During later months, the risk of transmission
decreased slightly but was still present, at 0.6% per month from 6 to 11
months, and 0.3% per month from 12 to 18 months. Thus, the cumulative risk of
HIV transmission was 3.5% at 5 months, 7.0% at 11 months, 8.9% at 17 months,
and 10.3% at 23 months of breastfeeding.[81]
|
Key Points
|
|
Case Study (continued) In January 1997, the patient is seen for nausea and vomiting of
approximately 3 weeks' duration. Physical examination and laboratory analysis
subsequently confirm that the patient is pregnant. After discussing the
pregnancy with her family and boyfriend, the patient decides to keep the
child. The patient is subsequently educated and counseled regarding her
options for use of antiretroviral therapy during the pregnancy and delivery.
Since very little information is available regarding use of antiretroviral
agents during the first trimester of pregnancy, and since the patient's viral
load has remained nondetectable, she decides to stop all antiretroviral drugs
until week 14. She is advised to stop cigarette smoking, at least during the
remainder of the pregnancy. |