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Mandelbrot L, Le Chenadec J, Berrebi A, et al. Perinatal HIV-1 Transmission: Interaction Between Zidovudine Prophylaxis and Mode of Delivery in the French Perinatal Cohort. JAMA. 1998;280(1):55–60. doi:10.1001/jama.280.1.55
From the Service de Gynécologie-Obstétrique I, Hôpital Cochin-Port Royal and the Institut National de la Santé et de la Recherche Médicale (INSERM) U149, Paris, France (Dr Mandelbrot); INSERM U292, Kremlin-Bicêtre, France (Mr Le Chenadec and Ms Mayaux); Service de Gynécologie-Obstétrique, Hôpital de La Grave, Toulouse, France (Dr Berrebi); Service de Gynécologie-Obstétrique, Hôpital de L'Archet 2, Nice, France (Dr Bongain); Service de Gynécologie-Obstétrique, Hôpital Bichat, Paris (Dr Bénifla); Service de Médecine Interne, Hôpital de Kremlin-Bicêtre (Dr Delfraissy); and the Service de Pédiatrie, Hôpital Necker, Paris (Dr Blanche).
Context.— It is unclear whether elective cesarean delivery may have a protective
effect against the transmission of human immunodeficiency virus 1 (HIV-1).
Objective.— To investigate whether mode of delivery has an impact on perinatal HIV-1
transmission in the presence of zidovudine prophylaxis.
Design.— A prospective cohort study.
Setting.— The 85 perinatal centers in the French Perinatal Cohort, from 1985 to
Patients.— A total of 2834 singleton children born to mothers with HIV-1 infection.
Main Outcome Measure.— Human immunodeficiency virus 1 infection of the infant.
Results.— No zidovudine was used in 1917 pregnancies and zidovudine prophylaxis
was used in 902 pregnancies. Cesarean deliveries were performed in 10.9% on
an emergent basis and in 8.3% electively, prior to labor or membrane rupture.
In 1917 mothers who did not receive zidovudine, of 1877 with information on
mode of delivery, 17.2% transmitted HIV-1 to their child. Risk factors statistically
significantly associated with transmission were maternal p24 antigenemia,
cervicovaginal infections during pregnancy, amniotic fluid color, and rupture
of membranes 4 hours or more before delivery. Mode of delivery was not related
to transmission. In 902 mothers receiving zidovudine, transmission was 6.4%
in 872 with information on mode of delivery, and elective cesarean delivery
(n=133) was associated with a lower transmission rate than emergent cesarean
or vaginal delivery (0.8%, 11.4%, and 6.6%, respectively; P=.002). In a multivariate analysis of all mother-child pairs, including
obstetrical risk factors, maternal p24 antigenemia, and zidovudine prophylaxis,
interaction between mode of delivery and zidovudine prophylaxis was significant
(P=.007). In the multivariate analysis of pregnancies
with zidovudine prophylaxis, factors related to transmission rate were maternal
p24 antigenemia, amniotic fluid color, and mode of delivery. Adjusted odds
ratios (95% confidence intervals) were 1.6 (0.7-3.6) for emergent cesarean
delivery and 0.2 (0.0-0.9) for elective cesarean delivery (P=.04) in comparison with vaginal delivery.
Conclusions.— We observed an interaction between zidovudine prophylaxis and elective
cesarean delivery in decreasing transmission of HIV-1 from mother to child.
This observation may have clinical implications for prevention.
THE IMPORTANCE of labor and delivery in mother-to-child transmission
of human immunodeficiency virus 1 (HIV-1) has been suspected for years. A
large body of data indicates that transmission occurs predominantly late in
pregnancy and intrapartum.1-4
However, the role of obstetrical management remains unclear. An increased
risk of transmission was observed in several studies in association with rupture
of membranes before the onset of labor5 or
more than 4 hours before delivery,6 and in
a few studies with events such as hemorrhage and bacterial infection.5,7,8 Conversely, conditions
of delivery itself, such as length of labor, instrumental delivery, or episiotomy,
had little relation to transmission.5,6,9
The impact of mode of delivery is still controversial.10
Transmission risk was decreased following cesarean delivery in some studies,11-13 but not in others.5,6,14-17
Elective cesarean delivery is a potential strategy for reducing perinatal
HIV transmission. Elective cesarean delivery must be distinguished from emergent
cesarean delivery, which is performed because of obstetrical complications.
Surprisingly, in the European Collaborative Study11
transmission rate was actually lower following emergent cesarean delivery
compared with elective cesarean delivery. In the French Perinatal Cohort,5 neither elective nor emergent cesarean delivery was
observed to be associated with a lower transmission rate than with vaginal
delivery in the cohort prior to 1993.
Since introduction of zidovudine prophylaxis,18
mother-to-child transmission rates have decreased by about two thirds in various
clinical settings.19,20 We previously
reported no difference in transmission rates in the presence of zidovudine
prophylaxis between children delivered vaginally or by cesarean20;
however, we lacked statistical power to distinguish rates with emergent and
elective cesarean delivery compared with vaginal delivery. The goal of this
study was to investigate whether use of zidovudine changed the relationship
between obstetrical factors and HIV-1 transmission.
The French Perinatal Cohort is a study of HIV transmission resulting
from fusion of the French Pediatric Cohort, established in September 1985,
and the SÉROGEST Cohort, established in 1989. The study was approved
by the institutional review board of the Hôpital Necker, Paris, France,
and by the French computer database watchdog commission (Commission Nationale
de l'Informatique et Libertés), Paris. Follow-up from birth of all
children born to consenting mothers with HIV was done in 85 obstetrical services.
Protocols for enrollment, data collection, and anonymous data transmission
to the coordinating center were reported previously.5,21
Maternal data included age, geographic origin, suspected route of HIV transmission,
clinical symptoms, lymphocyte subsets, viral load markers (p24 antigenemia
until mid-1996 and routine plasma HIV RNA levels thereafter22),
and detail regarding antiretroviral prescriptions. Cervicovaginal infections
were defined as any lower genital tract infection diagnosed by clinical examination
and vaginal or endocervical sampling with wet mount and culture as appropriate.
Genital herpes, gonorrhea, chlamydial endocervicitis, condyloma, gardnerella
vaginosis, and trichomoniasis were classified as sexually transmitted diseases.
Detailed obstetrical information was recorded as previously described.5 In particular, cesarean delivery was defined as elective
when performed before the onset of labor and with intact membranes, and defined
as emergent in all other cases. Neonatal bathing (mostly with benzalkonium
chloride) and breast-feeding were also recorded.
The HIV infection status was determined for children born at least 3
months prior to April 1, 1997. A child was considered infected at 18 months
if HIV-1 antibodies persisted or in the case of death from HIV-related disease,
and considered uninfected if the findings of 2 HIV antibody tests were negative.
Antibody testing was carried out with both of 2 commercial enzyme-linked immunosorbent
assays, and positive results were confirmed by immunoblot. Immunoblot findings
were considered negative when no antibody was detected directed against the
HIV envelope glycoproteins. For children aged 3 to 18 months, infection status
was determined using DNA-polymerase chain reaction and/or HIV culture.20,23 The child was considered infected
when 2 different sample test findings were concordantly positive, and was
considered uninfected when 2 different sample test findings were concordantly
negative (at least 1 of which was administered at or beyond age 3 months).
Because of the 3-fold decrease in transmission rate for mothers receiving
zidovudine,20 obstetrical factors were considered
separately for these mothers and mothers not treated. Transmission rates were
compared using the χ2 test or the Fisher exact test when necessary.
A logistic regression was performed on the overall cohort, which included
in the model zidovudine prophylaxis and maternal p24 antigenemia,24 as well as all obstetrical variables found to be
statistically significant in either of the univariate analyses, except duration
of membrane rupture. Because by definition there was no membrane rupture in
elective cesarean delivery, these 2 variables could not be included in the
same model. Interactions between zidovudine use and each obstetrical factor
were tested. Only the interaction between zidovudine use and the mode of delivery
was statistically significant. Logistic regressions were then performed separately
for the untreated and treated groups. Analysis was performed with SAS, Version
6.12 (SAS Institute Inc, Cary, NC).
From September 1, 1985, through December 31, 1996, the participating
sites reported 3474 deliveries of HIV-seropositive women. The study group
comprised 2834 mother-child pairs after excluding 174 mothers infected with
HIV-2, 44 breast-fed children, 114 twins, 43 children who died before HIV
status could be determined, 61 children not enrolled because of lack of parental
consent, 84 children lost to follow-up, and 120 children with indeterminate
status at the time of analysis. The nonevaluable children did not differ statistically
significantly from the study group for any of the variables investigated.
All deliveries occurring through 1993 (n=1632) were included in a previous
publication5 and 354 pregnancies with prophylaxis
in 1994 and 1995 were included in another publication.20
Mother's mean age at delivery was 28 years, 31% were past or present intravenous
drug users, and 40% were born in sub-Saharan Africa or the Caribbean. Undissociated
p24 antigenemia at delivery, available in 83.6% of treated mothers and 76.7%
of untreated mothers, was found in 7%. Median maternal CD4 cell count at delivery
was 0.47×109/L (474/µL), and 13% of mothers had counts
under 0.20×109/L. Infected children were followed up for
a mean duration of 51 months and a median of 48 months.
Zidovudine use increased sharply as of March 1994, when an official
policy was issued following the French-American AIDS Clinical Trials Group
076 results.20,25 The proportion
of women treated was 15% in 1993, reaching 90% by mid-1994, and was stable
thereafter. Data on zidovudine use were missing for 15 mother-child pairs.
Transmission occurred in 58 (6.4%) of 902 treated mothers and 329 (17.2%)
of 1917 untreated mothers, a 3-fold decrease as previously reported.20
In the 1917 children not exposed to zidovudine, transmission rate was
higher (Table 1) in the case of
cervicovaginal infections during pregnancy, membrane rupture more than 4 hours
before delivery, preterm delivery, and bloody or meconium-stained vs clear
amniotic fluid, as reported.5 In 35 cases with
bloody amniotic fluid, 6 were caused by placental abruption or placenta previa.
We also observed a higher transmission rate in the case of maternal temperature
higher than 38°C during labor (28.3% vs 16.6%, P
=.003). As previously reported, none of the other obstetrical factors were
related to transmission risk. Transmission rates did not differ by mode of
delivery. Human immunodeficiency virus 1 was transmitted from mother to child
in 17 (17.5%) of 97 elective cesarean deliveries (95% confidence interval
[CI], 9.9%-25.1%), 31 (15.6%) of 186 emergent cesarean deliveries (95% CI,
10.4%-20.8%), and 279 (17.5%) of 1594 vaginal deliveries (95% CI, 15.6%-19.4%).
Transmission rates were significantly higher in the case of p24 antigenemia
(40.0% vs 15.9% when negative, P =.001).
A total of 902 children had mothers who received zidovudine prophylaxis.
Contrary to the findings in the absence of zidovudine, mode of delivery was
related to the rate of transmission (Table
1), which was 6.6% (95% CI, 4.7%-8.8%) with vaginal delivery (41
of 625), 11.4% (95% CI, 6.2%-18.7%) with emergent cesarean delivery (13 of
114), and 0.8% (95% CI, 0.2%-4.0%) with elective cesarean delivery (1 of 133).
For a global test for the 3 categories, P was .002.
The only other obstetrical factor that was statistically significantly
associated with transmission risk in treated women was the color of the amniotic
Similar to findings in subjects without zidovudine use, the proportion
of children with HIV infection was higher in the case of p24 antigenemia (16.7%
vs 5.3% for women whose test findings were negative for the antigen, P=.003).
Of deliveries with detailed data available, cesarean deliveries were
performed in 283 (15.2%) of 1877 cases in the untreated group, of which 10%
were emergent and 5.2% were elective, and in 247 (28.3%) of 872 cases in the
zidovudine-treated group, of which 13% were emergent and 15.3% were elective.
Repeat section, fetal indications (principally anomalous fetal heart rate
tracings or intrauterine growth retardation), maternal indications (such as
diabetes mellitus, thrombocytopenia, or cervical intraepithelial neoplasia),
fetopelvic disproportion, and breech presentation were the principal obstetrical
indications for elective cesarean delivery in both groups. The proportion
of elective cesarean deliveries performed without classic obstetrical indications,
as prevention for HIV transmission, was higher in the zidovudine-treated group
than in the untreated group (30% and 12%, respectively).
Median duration of gestation did not differ between treated and untreated
groups. However, gestational age at delivery in both groups was 1 week less
for elective cesarean delivery (37.8 weeks) than for emergent cesarean delivery
(39 weeks) or vaginal delivery (39 weeks).
Durations of labor and membrane rupture were longer for emergent cesarean
delivery than for vaginal delivery. Median length of active labor was 390
minutes for emergent cesarean delivery and 300 minutes for vaginal delivery
in the untreated group and 410 minutes and 315 minutes, respectively, in the
treated group. Median duration of membrane rupture was 405 minutes for emergent
cesarean delivery and 190 minutes for vaginal delivery in the untreated group,
and 330 minutes and 180 minutes, respectively, in women receiving zidovudine.
The proportion of deliveries with intravenous zidovudine infusion during
delivery did not differ significantly by mode of delivery (85.4% for vaginal
delivery, 81.8% for emergent cesarean delivery, and 90.8% for elective cesarean
delivery, P =.12). The proportion of children receiving
zidovudine postnatally also did not differ significantly by mode of delivery
(98.1% for vaginal delivery, 98.0% for emergent cesarean delivery, and 98.4%
for elective cesarean delivery, P=1.00). Mean duration
of zidovudine prophylaxis during pregnancy was also similar for all modes
of delivery (4.2 months, 4.4 months, and 4.3 months, respectively). In 30
(3.3%) of 902 pregnancies with prophylaxis, antiretroviral drugs were prescribed
in addition to zidovudine. The proportion of those receiving combination therapy
did not differ statistically significantly by mode of delivery.
We first tested the interactions between each obstetrical variable and
zidovudine prophylaxis in a logistic regression model including the factors
statistically significantly linked to transmission risk in either of the univariate
analyses, as well as zidovudine prophylaxis. Only the interaction between
mode of delivery and zidovudine prophylaxis was significant (P=.007).
Multivariate analyses were performed separately for mothers receiving
zidovudine and for those not treated (Table
2). To adjust for unknown confounders that may be involved in decrease
in transmission rate over time, we added a variable for the child's year of
Because untreated women showed decreased transmission risk, from 20%
from 1986 through 1991 to 15% from 1992 through 1996, we also tested in the
model interaction between period of birth and mode of delivery. This interaction
term was not significant (P=.97). In the final multivariate
analysis for the untreated group, 4 variables remained significantly related
to transmission rate: p24 antigenemia (P<.001),
cervicovaginal infections (P=.008), amniotic fluid
appearance (P<.001), and birth year (P=.008).
In the treated group, only 3 variables remained significantly associated
with transmission: p24 antigenemia (P=.02), amniotic
fluid color (P=.04), and mode of delivery (P=.04). To assess the impact of membrane rupture on difference
between elective cesarean and other deliveries, we constructed a new 3-class
variable for the logistic regression: elective cesarean delivery, other modes
of delivery with membrane rupture 4 hours or less before delivery, and other
modes of delivery with membrane rupture more than 4 hours before delivery.
Transmission rate remained significantly lower following elective cesarean
delivery vs other deliveries with membrane rupture 4 hours or less before
delivery (adjusted odds ratio, 0.16; 95% CI, 0.01-0.84).
In the presence of zidovudine prophylaxis, we observed only 1 child
infected with HIV-1 in 133 delivered by elective cesarean. In a multivariate
analysis, transmission risk remained 5-fold lower following elective cesarean
delivery than in vaginal or emergent cesarean delivery.
These findings contrast with those observed in our cohort in the absence
of zidovudine prophylaxis, in which case the transmission rate was the same
irrespective of the mode of delivery, as reported.5
Similarly, several studies performed prior to the introduction of zidovudine
prophylaxis showed no relationship between mode of delivery and transmission.5,6,14-17
However, data from other cohort studies had suggested a protective effect
for cesarean delivery.11-13
Observational studies may show divergent results because of differences in
populations or because they lack statistical power to differentiate between
elective and emergent cesarean delivery. Whereas both types of cesarean delivery
may have an impact on intrapartum transmission,26
planned cesarean delivery may avoid physiologic and pathologic processes related
to labor, thereby decreasing late in utero transmission as well. Whether cesarean
delivery has a protective effect independent of zidovudine prophylaxis can
be further investigated by a large, international, individual patient data
meta-analysis of observational studies. However, a definitive answer to the
question will require a randomized clinical trial,27
which is the only method to ensure that women who undergo an elective cesarean
delivery do not differ from those with other types of delivery for any known
or unknown confounding factor.
The mother-to-child HIV transmission rate started to decrease in France
before the introduction of zidovudine prophylaxis.20
A decrease in transmission independent of zidovudine prophylaxis has also
been reported in the United States.14 Changes
in clinical management over a decade may have played a role, possibly regarding
risk factors such as cervicovaginal infections during pregnancy,28
chorioamnionitis,7,8 fever in
labor, preterm delivery,9 and above all, prolonged
membrane rupture,5,6 all of which
may involve subclinical bacterial infection.29
Improved management of these complications cannot, however, account for the
protective efficacy of elective cesarean delivery, which was by definition
performed with intact membranes, whereas emergent cesarean delivery had longer
duration of membrane rupture than vaginal delivery. When a variable combining
mode of delivery and membrane rupture duration was introduced into a multivariate
analysis, elective cesarean delivery remained significantly associated with
lower transmission rates. We must raise the possibility that cesarean deliveries
became more protective over time because of changes in indications for cesarean
delivery as well as changes in the operative procedure itself. The proportion
of elective cesarean deliveries tripled over a decade, largely because obstetricians
increasingly performed "prophylactic" cesarean deliveries in low-risk cases
with the hope that they might be protective.30
Although none of the centers reported implementing "bloodless cesarean" techniques,
obstetricians may also have taken increasing care to prevent contact between
the fetus and maternal blood. However, in the multivariate analysis, we found
no significant interaction between the mode of delivery and the time period
in reducing transmission risk.
The only significant interaction was between elective cesarean delivery
and zidovudine use. Our findings were based on a large cohort, but require
confirmation from other studies, since only 133 of the women received zidovudine
and were delivered by elective cesarean. In a smaller study, zidovudine and
elective cesarean delivery appeared to have cumulative protective effects.31 Several hypotheses may be advanced to suggest why
zidovudine prophylaxis would be more effective regarding elective cesarean
delivery. First, we checked that women who had planned cesarean deliveries
did not receive intravenous zidovudine infusions more frequently than those
who were delivered vaginally or by emergent cesarean. Nonetheless, according
to the published guidelines,25 zidovudine infusion
is started 4 hours before a planned cesarean delivery, whereas in other deliveries
it is started later, when active labor is diagnosed.
A second hypothesis is that zidovudine is less preventive in the case
of vaginal delivery than cesarean delivery because it has less effect on cervicovaginal
excretion of HIV than on systemic viral load. Contrary to this hypothesis,
zidovudine has been reported to decrease cervicovaginal HIV excretion.32 Furthermore, the efficacy of zidovudine prophylaxis
is due only partially to a reduction in plasma viral load.33
Finally, the transmission rate was actually higher with emergent cesarean
delivery compared with vaginal delivery, indicating that transmission occurred
up to and during labor, rather than during exposure of the fetus during the
passage through the birth canal.
The impact of zidovudine prophylaxis may differ according to timing
and mechanism of exposure. Although relative contributions of each possible
mechanism to overall transmission rate are not known, they are likely to differ
by mode of delivery. For instance, incidence of maternal-fetal microtransfusions
has been reported to be 5-fold lower during elective cesarean delivery vs
emergent cesarean or vaginal delivery.34 Conversely,
the procedure itself may expose the fetus to maternal blood, leading to transmission
via the oropharynx or the digestive tract, as has been suggested for postnatal
transmission via breast-feeding.35 Prevalence
of the presence of HIV RNA in neonatal gastric aspirates has been found to
be higher in the case of exposure to maternal blood.36
We speculate that zidovudine may be more effective as preexposure and postexposure
prophylaxis regarding oral route exposure than regarding parenteral exposure,
such as transplacental microtransfusions. If zidovudine is effective regarding
oral exposure, it may also reduce transmission via the ascending route. It
may also be more effective in the case of placental transfer of small amounts
of virus or infected cells, as may occur with inflammatory placental changes
in late gestation, than in the case of maternal-fetal microtransfusions.
The role of elective cesarean delivery in the prevention of mother-to-child
HIV-1 transmission remains to be defined for clinical practice. Its preventive
impact may differ in women who receive various combination antiretroviral
therapies.37 Most importantly, the risk-benefit
ratio may differ according to the baseline transmission rate. Assuming that
a planned cesarean delivery with zidovudine monotherapy can decrease the risk
of transmission from 6% to 1%, 20 operations would be necessary to prevent
1 case of transmission. Maternal mortality with cesarean delivery is increased
5-fold (from 7 to 40 per 100000 deliveries in Sweden38)
compared with vaginal delivery, and postoperative complications have been
reported in 31% of HIV-infected women, 3 times more than in HIV-negative subjects.39 In most of the developing world, where preventive
measures are desperately needed, the mortality associated with cesarean delivery
is much higher.40
Investigation of the mechanisms whereby obstetrical factors and antiretroviral
therapy are protective, as well as their interaction, may offer insights into
the pathophysiology of perinatal HIV transmission, which should be useful
for developing new strategies for prevention worldwide.
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