D RUG TH ER A PY

Review Article

Drug Therapy

TABLE 1. CARE, IN ADDITION TO ROUTINE OBSTETRICAL CARE,

OF HIV-INFECTED PREGNANT WOMEN AND THEIR INFANTS.*

A L A S T A I R J . J . W O O D , M. D. , Editor

M ANAGEMENT OF H UMAN
I MMUNODEFICIENCY V IRUS
I NFECTION IN P REGNANCY
D. HEATHER WATTS, M.D.

N estimated 16.4 million women worldwide

are living with human immunodeficiency virus (HIV) infection; 600,000 children are
infected annually, most of them by mother-to-child
transmission.1 Interventions designed to reduce perinatal transmission of HIV in the developing world
have been described elsewhere.2 This article focuses
on the management of HIV infection in pregnant
women in developed countries where antiretroviral
therapy, scheduled cesarean delivery, and alternatives
to breast-feeding are available (Table 1). Standards of
care for HIV change rapidly, and up-to-date recommendations are available on the Web (e.g., at http://
www.hivatis.org). Clinicians who care for HIV-infected women of reproductive age should provide familyplanning services and counseling to optimize the use
of medications and health status, including updating
immunizations, before a pregnancy occurs.
INTERACTION BETWEEN HIV INFECTION
AND PREGNANCY

Studies in the United States and Europe have

shown no effect of pregnancy on the progression of
HIV disease.3-5 The largest study included women
with a known date of seroconversion and reported
that the adjusted relative risk of progression from
HIV infection to the acquired immunodeficiency syndrome (AIDS) associated with pregnancy was 0.7
(95 percent confidence interval, 0.4 to 1.2).3 Reports from developing countries suggest that progression accelerates with pregnancy, but it is difficult
to interpret such reports because the samples are small
From the Pediatric, Adolescent, and Maternal AIDS Branch, Center for
Research on Mothers and Children, National Institute of Child Health and
Human Development, Bethesda, Md. Address reprint requests to Dr. Watts
at the Pediatric, Adolescent, and Maternal AIDS Branch, National Institute
of Child Health and Human Development, 6100 Executive Blvd., Rm.
4B11, Bethesda, MD 20892, or at hw59i@nih.gov.

Antepartum care
History: symptoms; duration of HIV infection; hospitalizations for therapy; immunizations
Physical examination: ophthalmologic examination if <50 CD4+ lymphocytes/mm3
Additional laboratory testing: TB skin testing; Toxoplasma gondii, cytomegalovirus, and hepatitis C antibody status if unknown; renal- and
liver-function testing; lymphocyte subgroups; plasma HIV RNA level
Counseling: effect of pregnancy on HIV; effect of HIV on pregnancy
perinatal transmission, therapy, mode of delivery
Intrapartum care
Therapy: intravenous zidovudine; continuation of other antiretroviral
agents
Obstetrical management: avoidance of invasive monitoring, use of instruments to assist delivery, and a prolonged interval between rupture
of membranes and delivery
Postpartum care
Woman: continuation or discontinuation of therapy; psychosocial support; no breast-feeding; contraception
Infant: zidovudine for 6 wk with or without other antiretroviral agents;
initiation of PCP prophylaxis at 46 wk; determination of HIV-infection status with testing at 12 days, 2 wk, 12 mo, and 36 mo of age
*TB denotes tuberculosis, and PCP Pneumocystis carinii pneumonia.

and the studies are subject to selection bias related

to the presence of indications for testing.6,7
Are outcomes of pregnancy affected by HIV infection? Studies conducted in industrialized countries
before antiretroviral agents became available did not
show an increase in the frequency of prematurity, low
birth weight, or intrauterine growth restriction associated with HIV infection. In these studies, the rates
of adverse events in the control groups were relatively high, probably because of coexisting conditions
such as substance abuse, although it is difficult to interpret the data.8,9 Studies in developing countries
have shown greater frequencies of preterm birth, low
birth weight, intrauterine growth restriction, and
stillbirth among the infants of HIV-infected women
than among those of similar groups of women who
were HIV-negative.8,10 Higher rates of adverse outcomes were seen among women with more advanced
HIV infection.8,10 Increased mortality, primarily related to HIV infection in the infant, has been reported
among infants born to HIV-infected women in developing countries.8 No studies have indicated that
there is an increase in the frequency of birth defects
related to HIV infection, and the theory that there
is a syndrome of malformation related to HIV infection has been disproved.8,11 The rates of factors relat-

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

ed to preterm birth and low birth weight are similar

among HIV-infected and HIV-negative pregnant
women; these factors include previous adverse outcomes, hypertension, multiple gestation, smoking,
bleeding during pregnancy, and Trichomonas vaginalis infection.12,13 In the absence of antiretroviral therapy, a low percentage of CD4+ cells was an additional
risk factor for adverse outcomes12; but with zidovudine therapy, maternal HIV RNA levels and CD4+
cell counts were not directly correlated with adverse
outcomes.13
It has been suggested that antiretroviral therapy
may increase the rate of adverse outcomes of pregnancy, but one randomized trial as well as cohort
analyses found that zidovudine monotherapy had no
negative effect on the outcomes of pregnancy (Table
2).14-16 A 1998 study suggested that combination therapy may increase the rate of preterm birth15; subsequent data from cohorts in the United States have

TABLE 2. HIV THERAPY

NO. OF
WOMEN

MATERNAL REGIMEN

PACTG 076 study

Placebo
Zidovudine regimen

AND

not shown an increase in the rate of preterm birth

with the use of dual-nucleoside or protease-inhibitor
therapy,17 but data from the European Collaborative
Study and the Swiss Mother and Child HIV Cohort
Study have shown higher rates of preterm birth as the
number of antiretroviral agents used has increased.16
Thus, clinicians should be aware of the potentially increased risk of preterm delivery among HIV-infected
women who are receiving combination antiretroviral
therapy but should not withhold indicated therapy.
DATA ON ANTIRETROVIRAL DRUGS
DURING PREGNANCY

Information about currently approved antiretroviral

drugs is summarized in Table 3.18-22 Clinicians should
report cases of exposure to antiretroviral drugs during
pregnancy to the Antiretroviral Pregnancy Registry (at
1-800-258-4263 or http://www.apregistry.com) to
assist in monitoring patients for teratogenic effects.

OUTCOMES

BIRTH WEIGHT
<2500 g

GESTATIONAL
AGE

mean

16
12

39 wk
40 wk

OF

PREGNANCY.*

COMMENTS

14

230
232

No significant differences between treatment groups

<37 wk (%)

Swiss HIV Cohort Study

No therapy
Zidovudine only
Combination without PI
Combination with PI

452
112
17
13

NA
NA
NA
NA

14
17
35
31

OR for preterm birth, 2.7 (95% CI, 1.4

6.9) for combination without PI and 2.3
(95% CI, 1.27.2) for combination with
PI, as compared with no therapy

PACTG 185 study13

Monotherapy
Combination therapy

427
70

14
11

17
19

No significant differences between treatment groups

15

European Collaborative Study and Swiss Mother and Child HIV Cohort Study16
No therapy
2819
NA
16
OR for preterm birth, 1.8 (95% CI, 1.1
Monotherapy
555
NA
17
2.9) for combination without PI and 2.6
Combination without PI
188
NA
22
(95% CI, 1.44.8) for combination with
Combination with PI
101
NA
29
PI, as compared with no therapy
Women and Infants Transmission Study17
Zidovudine only
685
Combination without PI
184
Combination with PI
247

19
15
17

17
19
17

No significant differences among treatment

groups

*Combination therapy without a protease inhibitor (PI) included two or more nucleoside reverse-transcriptase inhibitors with or without a nonnucleoside reverse-transcriptase inhibitor. Combination therapy with protease inhibitor included two or more nucleoside reverse-transcriptase inhibitors with one or more protease inhibitors. PACTG denotes
Pediatric AIDS Clinical Trials Group, OR odds ratio, and CI confidence interval.
Regimen included oral zidovudine during pregnancy, intravenous zidovudine during labor, and a six-week regimen
of oral zidovudine for the infant.
Odds ratios were adjusted for use or nonuse of opiates, clinical stage of HIV disease, and use or nonuse of cesarean
section.
Odds ratios were adjusted for the CD4+ count and use or nonuse of illicit drugs.

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D R UG TH ER A PY

TABLE 3. USE

DRUG

FDA PREGNANCY
CATEGORY

OF

ANTIRETROVIRAL DRUGS

ISSUES OF CONCERN
HUMAN PREGNANCY

Well-tolerated; pharmacokinetic study shows no

need for dose modification; resistance develops
rapidly if not used as part of fully suppressive
regimen
Didanosine
B
Pharmacokinetic study shows no need for dose
modification; possible increased risk of lactic acidosis during pregnancy with long-term use of
didanosinestavudine
Stavudine
C
Phase 12 study in progress; no pharmacokinetic
changes in primates; possible increased risk of
lactic acidosis during pregnancy with long-term
use of didanosinestavudine
Zalcitabine
C
No studies in humans; hydrocephalus in rats at
1000 human dose, skeletal defects at moderate doses
Abacavir
C
No studies in humans; anasarca, skeletal abnormalities at 35 human dose in rodents, not in
rabbits
Nonnucleoside reverse-transcriptase inhibitors
Nevirapine
C
Phase 1 and phase 3 studies in late pregnancy,
well-tolerated; incidence of hepatotoxicity and
rash possibly increased in women
Delavirdine
C
No studies in humans; embryotoxicity in rabbits;
atrial and ventricular septal defects in rats, developmental delay, decreased pup survival
Efavirenz
C
No studies in humans; pregnancy should be
avoided because of primate teratogenicity; anencephaly, microophthalmia, and cleft palate in
cynomolgus monkeys at doses similar to those
used in humans
Protease inhibitors
Indinavir
C
Low serum levels with a dose of 800 mg three
times daily; study of higher dose or boost with
ritonavir planned
Ritonavir
B
Phase 12 study ended; full results pending
Saquinavir

Nelfinavir

Amprenavir

Lopinavir

Other
Hydroxyurea

PREGNANCY.*
RECOMMENDED USE
DURING PREGNANCY

IN

Nucleoside reverse-transcriptase inhibitors

Zidovudine
C
Safe for short-term use; possible mitochondrial
toxic effects; tumors in rodents
Lamivudine

DURING

Serum levels inadequate with a dose of 1200 mg

three times daily during pregnancy; phase 12
study in progress with 800 mg of saquinavir
and 100 mg of ritonavir twice daily
Phase 12 study in progress; dose changed from
750 mg three times daily to 1250 mg twice daily because of low levels
No studies in humans; oral solution contraindicated in pregnant women and children <4 yr old
because of high propylene glycol levels
No studies in humans

13 Infants with first-trimester exposure reported

to have no anomalies, but teratogenicity not
ruled out; teratogenic with multiple defects in
rats, rabbits, hamsters, cats, monkeys

Should be included as part of antiretroviral regimen during

pregnancy unless there are serious toxic effects of stavudine
use
First-line agent with zidovudine and another drug for
HAART during pregnancy
Alternative NRTI for HAART regimen during pregnancy

Alternative NRTI for HAART regimen; may be antagonistic

to zidovudine should not be used together
Rarely indicated
Alternative agent for HAART regimen; use with caution and
intensive patient education about symptoms of hypersensitivity
Can be component of HAART during pregnancy or used
with or without zidovudine during labor and in neonate for
women without other antiretroviral use during pregnancy
Not recommended because of findings in animals, lack of data
on use in human pregnancy
Not generally recommended; may be considered for use after
first trimester for women with intolerance or resistance to
alternative drugs

Can be used as part of HAART regimen during pregnancy,

although potentially more side effects than other PIs
Best used in low dose to enhance levels of second PI in
HAART regimens
Can be used as part of HAART regimen during pregnancy,
with ritonavir boost
Can be used as part of HAART regimen during pregnancy
Capsule can be used as part of HAART regimen during pregnancy, though no published data on use during human
pregnancy
Can be used with ritonavir in HAART regimen during
pregnancy, though no published data on use during human
pregnancy
Avoid use during pregnancy; unclear efficacy as therapy of
HIV in nonpregnant persons

*Information is from the Centers for Disease Control and Prevention,18,19 the Physicians Desk Reference,20 Bersoff-Matcha et al.,21 and the interim report
of the Antiretroviral Pregnancy Registry.22 The Food and Drug Administration (FDA) categories are as follows: A, adequate and well-controlled studies
involving pregnant women failed to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of risk during the later
trimesters); B, reproduction studies in animals failed to demonstrate a risk to the fetus, and adequate and well-controlled studies involving pregnant women
have not been conducted; C, safety in human pregnancy has not been determined, studies in animals are either positive for fetal risk or have not been
conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus; D, there is positive evidence of human
fetal risk in the form of data regarding adverse reactions from investigational or marketing experiences, but the potential benefits from the use of the drug
in pregnant women may be acceptable despite its potential risks; X, studies in animals or reports of adverse reactions have indicated that the risk associated
with the use of the drug for pregnant women clearly outweighs any possible benefit. HAART denotes highly active antiretroviral therapy, NRTI nucleoside
reverse transcriptase inhibitor, and PI protease inhibitor.

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

A number of studies have examined the use of antiretroviral drugs during the perinatal period. These
studies are described in the Appendix, and their designs and results are summarized in Table 4.5,14-17,23-26
The results of additional trials of short courses of antiretroviral drugs for the prevention of perinatal transmission of HIV-1 are summarized in Figure 1.
Nucleoside Reverse-Transcriptase Inhibitors

The nucleoside reverse-transcriptase inhibitors are

generally well tolerated and cross the placenta. These
agents have not been shown to be teratogenic in animals in concentrations similar to those used in humans. The rate of birth defects among the infants
born to the more than 400 women whose exposure
to zidovudine or lamivudine during the first trimester of pregnancy was reported to the Antiretroviral
Pregnancy Registry has been no higher than the rates
among infants born to women who were exposed after the first trimester or infants in the Metropolitan
Atlanta Congenital Defects Program of the Centers
for Disease Control and Prevention.22
Nucleoside reverse-transcriptase inhibitors bind to

TABLE 4. SELECTED STUDIES

STUDY

PACTG 076

14

PACTG 185

13

OF

PERINATAL TRANSMISSION

mitochondrial DNA polymerase gamma and can cause

mitochondrial dysfunction,33 which may be manifested
as myopathy, cardiomyopathy, neuropathy, lactic acidosis, or fatty liver. Hepatomegaly and steatosis occurred at a rate of 1.3 cases per 1000 person-years
among women who received nucleoside therapy,34
and symptomatic hyperlactatemia occurred at a rate
of 8 cases per 1000 person-years among those who
received any antiretroviral drugs.35
Toxic effects of long-term therapy with nucleoside
reverse-transcriptase inhibitors may be enhanced in
pregnant women. Three deaths and additional cases
of lactic acidosis and hepatic failure have been described among pregnant women who began receiving stavudine and didanosine along with other drugs
before pregnancy.36 Clinical findings are similar to
those in acute fatty liver of pregnancy, a syndrome
that is more frequent among women with heterozygous defects of mitochondrial fatty-acid metabolism
who are carrying fetuses that are homozygous for
the same defect.37 The enhancement of mitochondrial toxic effects during pregnancy is similar to that
seen in mice that have significant reductions in mito-

OF

HIV

AND

ANTIRETROVIRAL USE

DESIGN

STUDY QUESTION

Randomized, double-blind,
placebo-controlled
Randomized, double-blind,
placebo-controlled

Can zidovudine reduce perinatal transmission of HIV-1?

Can HIV hyperimmune globulin added
to zidovudine reduce perinatal transmission of HIV-1 compared to
immune globulin placebo?
Can nevirapine given intrapartum and to
the neonate in addition to established
antiretroviral therapy reduce perinatal
transmission of HIV-1?
What clinical and virologic factors are associated with a reduced or increased risk of
perinatal transmission of HIV-1?
What clinical and virologic factors are associated with a reduced or increased risk of
perinatal transmission of HIV-1?
What clinical and virologic factors are associated with a reduced or increased risk of
perinatal transmission of HIV-1?

PACTG 31624

Randomized, double-blind,
placebo-controlled

Perinatal AIDS Collaborative

Transmission Study25

Observational cohort

Women and Infants

Transmission Study17

Observational cohort

Swiss HIV Cohort Study5

Observational cohort

European Collaborative Study

and Swiss Mother and Child
HIV Cohort Study16

Observational cohort

What clinical and virologic factors are associated with a reduced or increased risk of
perinatal transmission of HIV-1?

PETRA26

Four-group, randomized,
double-blind, placebocontrolled

Can zidovudinelamivudine given during

labor only, during labor and after delivery (to mother and infant), or as a short
course during pregnancy as well as during labor and after delivery reduce perinatal transmission of HIV-1?

DURING

PREGNANCY.*
OUTCOME

Yes, 67% reduction with zidovudine

No, similar transmission rates (4.6%) in
each group
No, similar transmission rates (approximately 1.5%) in nevirapine and placebo
groups
Reduced transmission with zidovudine;
antiretroviral resistance not associated
with increased risk of transmission
HAART associated with lowest transmission rate; no increase in preterm birth
with combination therapy
Zidovudine resistance not associated
with increased risk of transmission;
possible increase in rate of preterm
birth with protease-inhibitor therapy
HIV RNA level important predictor of
transmission; possible increase in rate
of preterm birth with combination
antiretroviral therapy
Transmission reduced with therapy during labor and after delivery and with
therapy during pregnancy and labor
and after delivery, but not with therapy
during labor alone

*PACTG denotes Pediatric AIDS Clinical Trials Group, HIV-1 human immunodeficiency virus type 1, HAART highly active antiretroviral therapy, and
PETRA Perinatal Transmission trial.

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D RUG TH ER A PY

Duration of
Antiretroviral Therapy
PACTG 076

HIV Transmission Rates at First Analysis

Zidovudine, 8.3%; placebo, 25.5% at 18 mo; P<0.001

Thai Short

Zidovudine, 9.4%; placebo, 18.9% at 6 mo; P=0.006

Shortshort, 10.5%; shortlong, 8.6%; longshort, 4.7%;
longlong, 6.5%; no significant differences among last
3 groups at 6 mo

Thai 4-Group
PACTG 316

Nevirapine, 1.5%; placebo, 1.4%; not significantly different at 6 mo

Ivory CoastBurkina Faso

Zidovudine, 18.0%; placebo, 27.5% at 6 mo; P=0.03

Ivory Coast

Zidovudine, 12.2%; placebo, 21.7% at 4 wk; P=0.05

Before delivery
During labor
After delivery

PETRA

Zidovudinelamivudine before delivery, during labor, and after

delivery, 8.6% (P=0.001); during labor and after delivery only,
10.8% (P=0.02); intrapartum only, 17.7%; placebo, 17.2% at 6 wk

HIVNET 012

Nevirapine, 13.1%; zidovudine, 25.1% at 1416 wk; P<0.001

SAINT

Nevirapine, 13.3%; zidovudinelamivudine, 10.9% at 8 wk;

not significantly different

Figure 1. Duration of Antiretroviral Therapy and Perinatal Transmission of HIV-1.

The bars show the longest duration of antiretroviral therapy during pregnancy, labor, and delivery and in the newborn in a given
study. Transmission rates listed are for the first analysis point reported. The first four studies listed involved women who were not
breast-feeding; most of the women in the remaining studies were breast-feeding. The Pediatric AIDS Clinical Trials Group (PACTG)
Protocol 076 study14 compared placebo with oral zidovudine starting at 14 to 34 weeks of gestation, intravenous zidovudine during
labor, and oral zidovudine for 6 weeks in the infant. A short-course zidovudine study in Thailand (Thai Short)27 compared placebo
with oral zidovudine starting at 36 weeks of gestation, oral zidovudine intrapartum, and no neonatal therapy. The Perinatal HIV
Prevention Trial in Thailand (Thai 4-Group)28 had a factorial design and included four groups, all of which received oral intrapartum
zidovudine; the short antepartum course of zidovudine started at 36 weeks of gestation, and the long course started at 28 weeks
of gestation; the short course of oral zidovudine for the infant was 3 days and the long course was 6 weeks. PACTG 31624 compared
placebo with a single dose of nevirapine in the woman during labor and a single dose in the infant at 48 hours of age; both groups
of women had been receiving ongoing antiretroviral therapy during pregnancy, including at least zidovudine. A short-course zidovudine trial in the Ivory Coast and Burkina Faso29 compared placebo with zidovudine beginning at 36 weeks of gestation, oral zidovudine during labor, and zidovudine for 1 week in the infant. Another short-course zidovudine trial in the Ivory Coast30 compared
placebo with oral zidovudine beginning at 36 weeks of gestation and oral zidovudine during labor. The Perinatal Transmission
(PETRA) trial26 involved four groups: in one, oral zidovudinelamivudine treatment was started at 36 weeks of gestation, and was
given during labor and for 1 week after delivery in mother and infant; in the second, oral zidovudinelamivudine was given during
labor and for 1 week after delivery in mother and infant; in the third, oral zidovudinelamivudine was given during labor only; and
the fourth group received placebo. The HIV Network for Prevention Trials (HIVNET) 012 Trial31 compared a single dose of nevirapine
during labor and a single dose in the infant with oral zidovudine given during labor and in the infant for one week. The South
African Intrapartum Nevirapine Trial (SAINT)32 compared a single dose of nevirapine during labor and a single dose in the infant at
48 hours with oral zidovudinelamivudine given during labor and for one week in the infant.

chondrial fatty-acid oxidation during the late phases

of pregnancy or when they are given high doses of estrogen and progesterone.38,39 Although lactic acidosis
and hepatic failure have been noted most commonly
with long-term use of stavudine and didanosine, the
potential exists with all nucleoside reverse-transcriptase inhibitors (the binding affinity with polymerase
gamma is greatest for zalcitabine, followed in descending order by didanosine, stavudine, lamivudine,
zidovudine, and abacavir).33
Both clinicians and their pregnant patients should
be aware of the nonspecific symptoms of liver dys-

function and lactic acidosis. Routine measurement

of blood lactate is not recommended because it is
difficult to obtain accurate samples and because normal levels in pregnant women have not been established. However, lactate testing during pregnancy may
be helpful if suggestive symptoms are present and
levels are in the range that would be considered elevated in persons who were not pregnant.
It has also been suggested that mitochondrial dysfunction might develop in infants who are exposed
to nucleoside reverse-transcriptase inhibitors. Eight
cases of possible mitochondrial dysfunction, includ-

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ing two deaths, were reported in a cohort of 1754

infants exposed to zidovudine or zidovudinelamivudine during pregnancy and the neonatal period.40,41
In a review covering more than 16,000 children in
cohorts in the United States, no increase in the rate
of death was reported among children exposed to nucleoside reverse-transcriptase inhibitors as compared
with children with no such exposure, and no deaths
were found to be definitely related to mitochondrial
toxicity.42 Monitoring for symptoms among living
children is ongoing. Among the 1798 infants in the
Perinatal Transmission trial, which included a placebo group and three zidovudinelamivudine groups,
the rate of symptoms potentially related to mitochondrial toxic effects (present in a total of 5 infants
[0.28 percent]) did not differ significantly among
the treatment groups.43 Thus, the risk of mitochondrial toxic effects in an infant that are related to therapy with nucleoside reverse-transcriptase inhibitors
during pregnancy appears to be small and must be
balanced against the benefit in terms of a reduction
in the rate of perinatal transmission.
Transplacental carcinogenesis is another issue of
concern related to exposure in utero to nucleoside reverse-transcriptase inhibitors. An increase in the incidence of tumors of the liver, lungs, and reproductive
system was reported in rodents exposed in utero to
zidovudine at 30 times the dose used in humans,44
but no increase was found in a similar study using
lower doses.45 Data from studies in humans do not
suggest an increase in the incidence of tumors in
children with prenatal exposure to antiretroviral drugs.
Among 727 children exposed to zidovudine in utero
and followed for up to six years, no tumors or deaths
from cancer occurred.46
Nonnucleoside Reverse-Transcriptase Inhibitors

Data on use of nonnucleoside reverse-transcriptase inhibitors during pregnancy are limited, but nevirapine and efavirenz readily cross the placenta in
primates.18 Use of efavirenz in the early stages of
pregnancy is not recommended because birth defects
(anencephaly, anophthalmia, or cleft palate) occurred
in 3 of 20 monkeys (15 percent) born after exposure
during the first trimester of pregnancy.18 However,
use during the later stages of pregnancy may be considered for women in whom other regimens have
failed. Delavirdine at high doses has been associated
with heart defects in rodents and should therefore,
like efavirenz, be used only during the later stages of
pregnancy. Nevirapine is the nonnucleoside reversetranscriptase inhibitor that has been used most commonly during pregnancy, primarily close to the time
of delivery.24,31
The most common toxic effect of nonnucleoside
reverse-transcriptase inhibitors is rash. Nevirapine-

related rash occurs in 17 percent of users and requires

an interruption of treatment in 5 to 6 percent.20 Hepatitis develops in about 1 percent of those who receive nevirapine and may be fatal.
Protease Inhibitors

Protease inhibitors are increasingly being used during pregnancy.17,47 There appears to be minimal transplacental passage in humans.48 No specific teratogenic
effects have been noted in animals. Optimal dosing of
protease inhibitors during pregnancy remains under
study. Lower serum concentrations of protease inhibitors have been observed in pregnant patients than
in nonpregnant patients, although in most cases, the
HIV RNA levels in pregnant women have been suppressed.49,50 The toxic effects among pregnant women appear to be similar to those among nonpregnant
women. There are insufficient data to support the recommendation of a specific protease inhibitor during
pregnancy, although nelfinavir has been used most
commonly.22
INDICATIONS FOR ANTIRETROVIRAL
THERAPY DURING PREGNANCY

Guidelines for the treatment of HIV infection during pregnancy have increasingly diverged from the
general guidelines for HIV treatment: a less aggressive
strategy has evolved for the management of HIV infection in pregnant women, although it is important to
reduce maternal HIV RNA levels in order to decrease
the risk of perinatal transmission. Although therapy is
recommended for nonpregnant persons with a CD4+
lymphocyte count below 350 per cubic millimeter or
an HIV RNA level above 55,000 copies per millimeter,51 antiretroviral therapy should be offered to all
HIV-infected pregnant women in order to reduce
the risk of perinatal transmission.18 This recommendation is based on the consistent findings that the risk
of perinatal transmission increases with increasing maternal HIV RNA levels,52,53 that transmission rates
are below 2 percent among women receiving highly
active antiretroviral therapy,17,54 and that the use of
multiple agents minimizes the potential for the development of resistance.51 Scheduled cesarean delivery is recommended for HIV-infected women with
HIV RNA levels above 1000 copies per milliliter,55
but highly active antiretroviral therapy may decrease
the need for cesarean delivery.
Zidovudine monotherapy was the first regimen
shown to reduce the rate of perinatal transmission of
HIV type 1 (HIV-1).14 Subsequent trials have documented reductions in transmission with shorter courses of zidovudine, intrapartum and neonatal treatment
with nevirapine, and treatment with zidovudine
lamivudine (Fig. 1).24,26,27-32,56-58 However, the lowest
transmission rates have been observed in cohorts re-

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D RUG TH ER A PY

ceiving highly active antiretroviral regimens 1.2

percent among the 250 women in the Women and
Infants Transmission Study and 1.2 percent among
the 494 women in the Pediatric AIDS Clinical Trials
Group Protocol 316 study (PACTG 316).17,24
Women with a new diagnosis of HIV infection during pregnancy should be fully evaluated to determine
the stage of the HIV infection and to identify any coexisting conditions. If therapy is indicated for maternal
health (CD4+ lymphocyte count, <350 cells per cubic millimeter; or HIV RNA level, >55,000 copies
per milliliter), the clinician and the patient should
discuss these indications, potential regimens, and the
need for strict adherence in order to prevent the development of resistance. Even without maternal indications for therapy, initiation of highly active antiretroviral therapy should be considered for the prevention of
HIV transmission when the HIV RNA level is above
1000 copies per milliliter.18 Whenever possible, zidovudine should be used, as in the PACTG 076 study
(Table 4), because of its documented reduction of the
risk of perinatal transmission, which is independent
of its effect on viral load.59 The options of continuing therapy during the postpartum period or stopping therapy at the time of delivery should be discussed. The potential risks of short courses of highly
active antiretroviral therapy for the prevention of transmission have not been studied. However, the risk of
the development of resistant viral strains should be
minimized by choosing maximally suppressive regimens and by starting and stopping all agents simultaneously.
The option of zidovudine monotherapy or highly
active antiretroviral therapy for the reduction of transmission can be considered for pregnant women with
HIV RNA levels below 1000 copies per milliliter. At
such RNA levels, the transmission rate was 9.8 percent
among 368 untreated women and 1 percent among
834 women receiving zidovudine (P<0.001), indicating a beneficial effect even with low HIV RNA levels.60 Zidovudine monotherapy for the prevention of
transmission was not associated with an increased
risk of maternal death or disease progression in follow-up to PACTG 076.61 No mutations causing highlevel resistance were detected in a subgroup of 61
women in PACTG 076 who were selected because
of an increased potential for resistance; a mutation
causing low-level resistance developed between base
line and delivery in 1 of 39 women with paired specimens.62 Given limited viral replication, resistance is
unlikely to develop with monotherapy. No data are
available to permit the comparison of women with
low pretreatment HIV RNA levels who receive zidovudine with those who receive highly active antiretroviral therapy in terms of transmission rates and longterm outcomes in the mothers and their infants.

Drug Resistance

Whether pregnancy is a specific indication for resistance testing remains controversial. The guidelines
of the Public Health Service for perinatal treatment
recommend that resistance testing be performed for
the same indications in pregnant women as in nonpregnant adults specifically, acute infection, viral
rebound, or persistent viremia in a patient receiving
a highly active antiretroviral regimen.18 Other groups
recommend that resistance testing be performed in
all pregnant women with detectable HIV RNA levels,
even if they have not been treated, in order to maximize the response to antiretroviral drugs, although
there are no data available to demonstrate that resistance testing leads to improvement in outcomes for
mothers or infants.63,64
The prevalence of resistance mutations in pregnant women varies. No resistance to zidovudine was
detected at base line among women in PACTG 076,
all of whom had CD4+ lymphocyte counts above
200 per cubic millimeter and most of whom had not
received antiretroviral drugs.62 Conversely, a zidovudine-resistance mutation developed in 25 percent of
the women in the Women and Infants Transmission
Study who were receiving zidovudine for their own
health, and high-level resistance to zidovudine was
detected in 10 percent of 142 isolates.65 Mutations
in codon 215, which are associated with high-level
resistance to zidovudine, were detected in 9.6 percent
of 62 consecutive women in the Swiss Collaborative
HIV and Pregnancy Study.66 No such mutations developed in the 33 women in a New York cohort who
delivered before 1997, but such mutations did develop in 9.7 percent of the 31 women in the cohort
who delivered between 1997 and 1999; these mutations were detected only in women with previous
exposure to zidovudine.67
Of 220 pregnant women chosen because of previous exposure to zidovudine, 21.8 percent had a
mutation associated with resistance to nucleoside reverse-transcriptase inhibitors, and 17.7 percent had a
primary mutation associated with such resistance. A
total of 2.3 percent of the 220 had a mutation associated with resistance to nonnucleoside reverse-transcriptase inhibitors, but none had a primary mutation
associated with such resistance. A total of 0.5 percent had a primary mutation associated with protease-inhibitor resistance.25
In all of these studies, the women who were evaluated for resistance mutations represented a subgroup
with detectable HIV RNA and clinical characteristics suggesting an increased risk of resistance. Thus,
the rate of resistance mutations in the entire study
populations was probably lower.
The detection of mutations associated with resistance to zidovudine or other drugs was not associat-

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

ed with an increased risk of perinatal transmission in

PACTG 076, PACTG 185, the Swiss Collaborative
HIV and Pregnancy Study, or the Perinatal AIDS
Collaborative Transmission Study.25,62,66,68 In a substudy of the Women and Infants Transmission Study,
detection of zidovudine resistance was not significantly associated with transmission according to univariate analysis, but when the data were adjusted for the
duration of ruptured membranes and the total lymphocyte count, resistance mutations were found to
confer an increased risk of transmission.65 Women in
this cohort (who were studied before 1994) were receiving zidovudine during pregnancy for their own
health, and zidovudine was generally not given intravenously during labor or to the infants. Although
perinatal transmission of resistant virus has been reported,69 it is not clear that the presence of mutations increases the risk of transmission. Until further
data are available, resistance testing should be performed in HIV-infected pregnant women for the
same indications as in nonpregnant patients.51
Ongoing Therapy

Management of HIV infection in pregnant women who are already receiving antiretroviral therapy
depends on the gestational age of the fetus, clinical
findings, and the regimen being used. If the pregnancy is discovered after the first trimester, therapy
should be continued. A detailed ultrasonographic
examination should be performed at 18 to 20 weeks
of gestation to confirm the gestational age of the fetus and to screen for detectable anomalies. Options
during the first trimester include continuing the regimen; changing the regimen if it includes specific
drugs that carry an increased risk, such as efavirenz or
delavirdine; or discontinuing all antiretroviral drugs
and reinstituting them after the first trimester. This
last strategy has the potential to cause viral rebound
and might increase the risk of transmission. Decisions should depend on the clinical circumstances
and the treatment history. Hydroxyurea should be
discontinued during pregnancy, since it is teratogenic
in animals and its value in the treatment of HIV is unclear.18 If antiretroviral therapy must be interrupted
during the first trimester, all agents should be discontinued and reinstated simultaneously in order to
prevent the development of resistance.
Several options are available for treatment during
labor in HIV-infected women who have had no previous antiretroviral therapy. Observational studies
found that the use of intravenous zidovudine during
labor plus a six-week regimen of oral zidovudine in
the infant reduced the rate of transmission: 27 to 31
percent of infants in the untreated group became infected, as compared with 10 percent of those in the
treated group.70,71 Other studies demonstrated re-

ductions in the rate of transmission with intrapartum

and neonatal zidovudinelamivudine therapy or maternal and neonatal nevirapine therapy (Fig. 1).26,31,32,58
Current guidelines include the combination of zidovudine and nevirapine as an option for such intrapartum and neonatal treatment, although there are no
data available to permit an assessment of the efficacy
of this regimen in the prevention of transmission.18
The addition of intrapartum and neonatal nevirapine to an established antiretroviral regimen during
pregnancy did not result in an additional reduction
in the rate of perinatal transmission of HIV in the
PACTG 316 trial.24 Furthermore, in a subgroup
with detectable HIV RNA levels at the time of delivery, resistance to nevirapine developed in 11 percent of the women.72 Thus, despite its efficacy in reducing the rate of transmission among previously
untreated women, the addition of peripartum nevirapine to the regimens of women who are already receiving antiretroviral therapy is not recommended.
The optimal therapy for infants born to HIVinfected women who have received no antiretroviral
therapy has not been determined. Observational data
suggest that zidovudine therapy initiated within 48
hours after birth is beneficial.70 Whether the use of
additional agents would further reduce the risk of
transmission is unknown, although some clinicians
would choose to use combination regimens in such
infants a strategy analogous to that used for postexposure prophylaxis in adults.
MODE OF DELIVERY

Among women who have not received antiretroviral therapy, more than half the cases of perinatal
transmission occur late in pregnancy or during delivery; focused efforts are needed to interrupt transmission in such cases.73 Early studies suggested that
cesarean delivery before labor began or the membranes ruptured was effective in reducing the rate of
transmission.74-76 Two large studies have confirmed
that such a reduction occurred among women who
were receiving either zidovudine monotherapy or no
antiretroviral drugs. In a meta-analysis of 15 cohorts,
the adjusted odds ratio for HIV infection was 0.43 (95
percent confidence interval, 0.33 to 0.56) among
infants delivered by cesarean section without labor
or membrane rupture, as compared with those born
by other modes of delivery, with a similar benefit in
the subgroup receiving zidovudine.77 HIV was transmitted to 1.8 percent of the infants of 178 women
who were randomly assigned to cesarean delivery
but to 10.5 percent of 200 infants who were delivered vaginally (P<0.001).78 These studies antedated
the use of highly active antiretroviral therapy and the
measurement of maternal HIV RNA levels in pregnancy. It would be difficult to assess the benefit of

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D RUG TH ER A PY

scheduled cesarean section among women with HIV

RNA levels below 1000 copies per milliliter who are
receiving zidovudine or potent antiretroviral therapy, because the transmission rate among such women is only 1 to 2 percent.17,24,54,60
It is also difficult to assess the potential benefit of
cesarean section shortly after the rupture of the membranes or the onset of labor. In most studies, transmission rates among women who delivered by cesarean section after labor or membrane rupture have
been similar to those among women who delivered
vaginally. However, among women receiving zidovudine or no therapy, transmission rates increase with
the interval between the rupture of the membranes
and delivery.79,80 In women who are near term and
for whom a scheduled cesarean delivery is planned
but who present with ruptured membranes, management must be individualized on the basis of recent HIV RNA levels, the time that has elapsed since
rupture, the progress of labor, and the preferences of
the patient. If the membranes rupture before 32 weeks
of gestation, expectant management with continued
antiretroviral therapy, including consideration of the
initiation of intravenous zidovudine, should be offered
in an attempt to prolong gestation and reduce the risk
of complications of prematurity. Women with preterm labor should receive tocolytic therapy for the
same indications as HIV-negative women, and when
delivery is inevitable, selection of the delivery mode
should be based on obstetrical considerations and recent HIV RNA levels.
The potential benefit of cesarean delivery must be
weighed against the risks. In HIV-negative women,
cesarean delivery is associated with a risk of complications and death that is five to seven times as high
as the risk with vaginal delivery.81,82 Early casecontrol studies suggested an increased risk of maternal
complications of cesarean section associated with HIV
infection.83-86 More recent data from cohort studies
suggest that the increased risk associated with cesarean delivery in HIV-infected women is similar to that
in comparable HIV-negative populations.87-89
Current guidelines recommend that scheduled cesarean delivery be offered to women with HIV RNA
levels above 1000 copies per milliliter in the late stages
of pregnancy and that the benefits and risks should
be discussed thoroughly.18,55 The option of scheduled cesarean delivery should also be discussed with
women with lower HIV RNA levels, but in such cases, the benefit is less clear. Cesarean delivery can be
scheduled at 38 weeks of gestation rather than the
usual 39 weeks, to minimize the chances that membrane rupture or labor will occur,55 although delivery
at 38 weeks confers a small but significant increase in
the risk of respiratory distress in the neonate.90 Amniocentesis to assess fetal-lung maturity is not rec-

ommended because it carries a risk of transmission.

Treatment of genital infections such as bacterial vaginosis before delivery and the prophylactic use of antibiotics may reduce the risk of postoperative infection,
although these interventions have not been evaluated
in patients with HIV infection.
PREVENTION AND TREATMENT
OF OPPORTUNISTIC INFECTIONS
DURING PREGNANCY

Recommendations for prophylaxis against and treatment of opportunistic infections in nonpregnant

adults should be followed with slight modification
during pregnancy (Table 5).19 Prophylaxis against and
treatment of Mycobacterium tuberculosis, Pneumocystis
carinii, M. avium complex, and Toxoplasma gondii
infections during pregnancy are similar to prophylaxis
and treatment in nonpregnant adults. Primary prophylaxis against cytomegalovirus infection, mucosal
candida infections, and invasive fungal infections is
not recommended routinely for nonpregnant persons because of drug toxicity. Treatment of serious
infections should not be withheld because of pregnancy; regimens should be chosen in consultation between the obstetrician and a specialist in infectious
diseases. Hepatitis B, influenza, and pneumococcal
vaccines may be given during pregnancy for the usual indications but should be administered after HIV
RNA has been suppressed to undetectable levels with
antiretroviral therapy, in order to prevent the increase
in the risk of transmission that theoretically accompanies the transient increase in HIV RNA after immunization.
OTHER ASPECTS OF CARE
FOR HIV-INFECTED PREGNANT WOMEN
Antepartum Care

Aspects of evaluation and care that are specific to

pregnant women with HIV infection are summarized
in Table 1. For women receiving protease-inhibitor
therapy, 50-g glucose-load testing may be considered early in pregnancy to screen for glucose intolerance, with a second test at 24 to 28 weeks of gestation if the initial result is normal. Pregnant women
receiving methadone in whom regimens containing
nevirapine, efavirenz, or any protease inhibitor except
indinavir are initiated should be monitored for signs
and symptoms of drug withdrawal, since these agents
have the potential to decrease methadone levels.51
The schedule of testing for toxic effects of antiretroviral drugs depends on which drugs are chosen. In
general, frequent evaluation (every two to four weeks)
for new symptoms and laboratory abnormalities is
indicated during the first one to two months of therapy, with less frequent testing thereafter. The optimal
schedule of testing for the early diagnosis of antiret-

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

TABLE 5. MANAGEMENT OF OPPORTUNISTIC INFECTIONS

DURING PREGNANCY IN HIV-INFECTED WOMEN.
INFECTIOUS AGENT

Pneumocystis carinii
Toxoplasma gondii

Mycobacterium avium
complex
Mycobacterium
tuberculosis
Candida species

Cryptococcus neoformans

Histoplasma capsulatum

Coccidioides immitis

Cytomegalovirus
Herpes simplex virus

COMMENTS

Prophylaxis and therapy same as for nonpregnant patients; notify neonates health care
provider of maternal sulfa therapy
Therapy and secondary prophylaxis (maintenance therapy) same as for nonpregnant patients; primary prophylaxis with trimethoprimsulfamethoxazole only
Azithromycin first choice for primary prophylaxis during pregnancy; clarithromycin teratogenic in animals; for maintenance therapy,
azithromycin plus ethambutol
Isoniazid preferred for prophylaxis during pregnancy; for multidrug-resistant tuberculosis
during pregnancy, consult an expert
Prophylaxis not indicated during pregnancy;
craniofacial and skeletal abnormalities reported in 4 infants after prolonged exposure to
fluconazole in utero
Primary prophylaxis not recommended; anomalies as noted above after prolonged fluconazole exposure; consider switching to amphotericin B during first trimester for long-term
suppression
Primary prophylaxis not recommended; because
of concern about anomalies with fluconazole
exposure and uncertain safety of chronic itraconazole during pregnancy, consider switching to amphotericin B during first trimester if
continued long-term suppression indicated
Primary prophylaxis not recommended; anomalies as noted above after prolonged fluconazole exposure; consider switching to amphotericin B during first trimester if continued
long-term suppression indicated
Primary prophylaxis not recommended; manage
long-term suppression or therapy during
pregnancy in consultation with experts
Prophylaxis and therapy same as for nonpregnant patients

roviral-induced hepatic toxicity or lactic acidosis has

not been determined, but one approach would be to
evaluate hepatic function and electrolytes monthly
during the third trimester and whenever new symptoms occur. HIV RNA levels should be monitored
as in nonpregnant adults that is, 4 weeks after a
change or initiation of therapy, then monthly until
undetectable, then every 3 months while therapy remains stable, and at 34 to 36 weeks of gestation for
the planning of delivery.51 CD4+ lymphocyte counts
should be evaluated every three months. Although the
percentage of CD4+ lymphocytes is less subject to
variation during pregnancy than the absolute count,91
most clinicians use treatment guidelines that are based
on absolute counts; thus, absolute counts may be
used in pregnant women as in nonpregnant adults.
Counseling with regard to the options for prenatal

diagnosis is required for HIV-infected pregnant women. Although screening for serum markers or ultrasonographic examination may enhance the risk assessment, only invasive testing with fetal karyotyping can
rule out chromosomal abnormalities.92 It is unclear
whether invasive procedures for prenatal diagnosis
carry a risk of HIV transmission. An increase by a
factor of two to four in the risk of HIV transmission
related to amniocentesis or other invasive procedures
has been reported among untreated women.93,94 Invasive testing has not been identified as a specific risk
factor for transmission in cohort studies performed
since antiretroviral therapy has become standard, but
the use of amniocentesis among HIV-infected women is uncommon, and the use of chorionic-villus
sampling is rare. If a pregnant woman would not undergo amniocentesis after a positive result on serum
or nuchal translucency screening, then such screening
may be more anxiety-provoking than helpful. If an
invasive prenatal procedure is planned for an HIVinfected woman, she should be receiving optimal antiretroviral therapy and have undetectable HIV RNA
before the procedure.
Intrapartum Care

The potential mode of delivery should be discussed throughout the pregnancy, and the final decision should be based on the HIV RNA level at 34 to
36 weeks of gestation. Infusion of zidovudine should
be begun as soon as possible after the onset of labor
or the rupture of the membranes (or at least three
hours before a scheduled cesarean delivery), at a dose
of 2 mg per kilogram of body weight given over the
course of one hour, followed by a continuous infusion of 1 mg per kilogram per hour until delivery.14
The use of other antiretroviral medications should
be continued on schedule during labor or preoperatively. Stavudine may antagonize the effects of zidovudine and should therefore be given orally without zidovudine or discontinued before intravenous
zidovudine is administered.
Artificially induced rupture of the membranes
should be avoided, and the interval between rupture
and delivery should be minimized by augmenting labor as needed after spontaneous rupture has occurred.
Fetal-scalp electrodes, scalp blood sampling, the use of
instruments to assist delivery, and other procedures
that might be traumatic to the infant should be avoided. Avoidance of episiotomy may decrease the exposure of the infant to maternal blood. Midazolam and
ergot preparations should not be used in women receiving protease inhibitors, efavirenz, or delavirdine,
because their metabolism may be delayed by such
antiretroviral drugs.51 The infant should be washed
before any blood is drawn or any injections or other
invasive procedures are performed.

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D RUG TH ER A PY

Postpartum Care

HIV-infected women require additional counseling and support during the postpartum period. In industrialized countries, breast-feeding by HIV-infected
women is not recommended because it is associated
with an additional 15 to 20 percent risk of transmission of HIV.95,96 Among women in whom antiretroviral therapy is continued after delivery, measures to
enhance adherence to the regimen may be needed
because of the demands of newborn care, the loss of
the incentive of preventing transmission, and postpartum depression. Adherence may be improved by
simplifying the regimen, explaining again the consequences of nonadherence, using aids such as daily
pill boxes or pagers, recruiting family and friends for
support, and using support groups. Additional psychosocial support is needed while the infants HIV
status is being determined and afterward if the infant
is found to be infected with HIV.
Options for contraceptive methods should be discussed during pregnancy and the need for condom
use should be emphasized. If a woman elects to use
additional methods, interactions with other therapies
must be considered. Estradiol levels from oral contraceptives are reduced by nevirapine, ritonavir, nelfinavir, rifampin, rifabutin, and possibly amprenavir, which
may reduce the contraceptive efficacy.51 Interactions
between medroxyprogesterone acetate and antiretroviral drugs are under study, but this agent is a reasonable choice. Intrauterine contraceptive devices may
be offered to HIV-infected women who have a low
risk of sexually transmitted infections and do not
have severe immune suppression.97 The appropriate
care for infants born to HIV-infected women is described in Table 1.98 Although the provision of early
access to prenatal care for all women and universal
voluntary HIV testing during pregnancy would allow
for interventions that can improve maternal health
and reduce HIV transmission, the ultimate goal must
be primary prevention of HIV infection in women.
APPENDIX. STUDIES OF
ANTIRETROVIRAL THERAPY
DURING THE PERINATAL PERIOD
The Pediatric AIDS Clinical Trials Group (PACTG) Protocol
076 study, a randomized, double-blind, placebo-controlled trial,
demonstrated that antepartum, intrapartum, and neonatal treatment with zidovudine could prevent perinatal transmission of
HIV type 1 (HIV-1).14 PACTG 185 evaluated whether zidovudine combined with infusions of HIV-1 hyperimmune globulin
administered monthly during pregnancy and to the neonate at
birth would result in lower rates of perinatal HIV transmission
than treatment with zidovudine and intravenous immune globulin without antibodies against HIV-1.23 PACTG 316, a phase 3,
randomized, double-blind, placebo-controlled trial, evaluated the
safety and efficacy of intrapartum and neonatal treatment with
nevirapine in addition to established antiretroviral treatment for
the prevention of maternalfetal HIV transmission. 24 The Perina-

tal AIDS Collaborative Transmission Study enrolled HIV-infected

women during pregnancy or within 60 days after delivery in four
cities Atlanta, Baltimore, New York, and Newark, New Jersey
and examined risk factors for perinatal transmission in the absence of therapy and with the use of zidovudine during the antenatal, intrapartum, and neonatal periods.25 The Women and Infants Transmission Study is a longitudinal study of the natural
history of perinatal HIV-1 infection conducted at six sites in the
continental United States and Puerto Rico.17 The European Collaborative Study is a longitudinal study of the natural history of perinatal HIV infection conducted at 22 centers in eight European
countries.16 The Swiss HIV Cohort Study is an ongoing multicenter
research project involving HIV-infected adults that has a subgroup
of mothers and infants.5 The Perinatal Transmission (PETRA) trial
was a randomized, double-blind, placebo-controlled trial that evaluated three oral regimens of zidovudine and lamivudine for the
prevention of perinatal transmission of HIV-1.26

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