Extended antenatal use of triple antiretroviral therapy for prevention of mother-to-child transmission of HIV-1 correlates with favorable pregnancy outcomes

Abstract

To evaluate pregnancy outcomes in a cohort of HIV-infected women receiving triple antiretroviral therapy (ART) for prevention of mother-to-child-transmission.
A retrospective cohort study with review of records of 3273 HIV-positive women receiving prenatal care in Malawi and Mozambique from July 2005 to December 2009 was conducted in Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) centers. Patients were offered nevirapine-based triple ART initiated in pregnancy until 6 months postpartum. Main outcome measures were maternal mortality, abortion/stillbirth, prematurity, and low birth weight.
Maternal mortality was 1.2% (42/3273): 7.4% in 68 women with no antenatal ART and 0.7% in 1370 with at least 90 days of antenatal ART [P < 0.001; odds ratio (OR) 0.29 (95% confidence interval [CI] 0.14-0.96]. Abortion/stillbirth was 5.2% (169/3273): 26.5% in 68 women with no ART and 5.0% in 1370 women with at least 90 days of antenatal ART [P < 0.001; OR 0.39 (95% CI 0.27-0.57)]. Prematurity was 19.1%: 70% in 10 women with no antenatal ART and 8.5% in 1330 women with at least 90 days of antenatal ART [P < 0.001; OR 0.15 (95% CI 0.14-0.19)]. Low birth weight was 11.5% (57/496) and not associated with ART duration. The protective effect of antenatal ART against mortality, fetal demise, and prematurity was independent of CD4 strata. Multivariate analysis for BMI, CD4 cell count, virus load, days in care, predelivery length of ART, and hemoglobin demonstrated an independent association between predelivery length of ART and CD4 with maternal mortality, abortion/stillbirth, and prematurity. ART toxicities were infrequent (5.2%).
Antenatal triple ART reduces adverse pregnancy outcomes in HIV-infected women.

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Extended antenatal use of triple antiretroviral therapy
for prevention of HIV-1 mother-to-child transmission
correlates with favourable pregnancy outcomes.
Maria Cristina Marazzi
a
, Leonardo Palombi
b
, Karin Nielsen-Saines
c
,
Jere Haswell
d
, Ines Zimba
e
, Nurja Abdul Magid
e
, Ersilia Buonomo
f
,
Paola Scarcella
f
, Susanna Ceffa
f
, Giovanna Paturzo
e
, Pasquale Narciso
g
and Giuseppe Liotta
f
Objective: To evaluate pregnancy outcomes in a cohort of HIV-infected women
receiving triple antiretrovirals (ART) for prevention of mother-to-child-transmission.
Methods: A retrospective cohort study with review of records of 3273 HIVþwomen
receiving prenatal care in Malawi and Mozambique from 7/05 –12/09 was conducted in
Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) centers. Patients
were offered nevirapine-based triple ART initiated in pregnancy until 6 months post-
partum. Main outcome measures were maternal mortality, abortion/stillbirth, prema-
turity, and low birth weight.
Results: Maternal mortality was 1.2% (42/3273): 7.4% in 68 women with no antenatal
ART and 0.7% in 1370 with 90 days of antenatal ART, p <0.001; OR: 0.29
(95%CI:0.14–0.96). Abortion/stillbirth was 5.2% (169/3273): 26.5% in 68 women
with no ART and 5.0% in 1370 women with 90 days of antenatal ART, p <0.001; OR:
0.39 (95%CI:0.27–0.57). Prematurity was 19.1%: 70% in 10 women with no antenatal
ART and 8.5% in 1330 women with 90 days of antenatal ART, p <0.001; OR: 0.15
(95%CI:0.14–0.19). Low birth weight was 11.5% (57/496), and not associated with
ART duration. The protective effect of antenatal ART against mortality, fetal demise and
prematurity was independent of CD4 strata. Multivariate analysis for body mass index
(BMI), CD4 count, virus load, days in care, pre-delivery length of ART and hemoglobin
demonstrated an independent association between pre-delivery length of ART and CD4
with maternal mortality, abortion/stillbirth and prematurity. ART toxicities were infre-
quent (5.2%).
Conclusions: Antenatal triple ART reduces adverse pregnancy outcomes in HIV-
infected women. ß2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
AIDS 2011, 25:000–000
Keywords: HIV in pregnancy, PMTCT, pregnancy and ART, pregnancy outcomes
a
Lumsa University, Rome, Italy,
b
Department of Public Health, University of Tor Vergata, Rome, Italy,
c
Division of Infectious
Diseases, David Geffen UCLA School of Medicine, MDCC 22 442 10833 LeConte Ave, Los Angeles, CA 90095,
d
Blantyre DREAM
Medical Center, Blantyre, Malawi,
e
Maputo DREAM Medical Center, Maputo, Mozambique,
f
University of Tor Vergata, Rome,
Italy, and
g
National Institute of Infectious Diseases, Rome, Italy.
Correspondence to Karin Nielsen-Saines, MD, MPH, Division of Infectious Diseases, David Geffen UCLA School of Medicine,
MDCC 22-442 10833 LeConte Ave, Los Angeles, CA 90095.
Tel: +310 206 6640; fax: +310 825 9175; e-mail: knielsen@mednet.ucla.edu
Received: 23 March 2011; revised: 20 May 2011; accepted: 27 May 2011.; accepted: 27 May 2011.
DOI:10.1097/QAD.0b013e3283493ed0
ISSN 0269-9370 Q2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 1

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Introduction
There is significant variability in the approach to
Prevention of HIV-1 Mother-To-Child-Transmission
(PMTCT) in resource-limited settings despite the well
established prophylactic advantage of triple antiretrovirals
(ART) for PMTCT purposes [1–6]. Reports on
pregnancy outcomes following tr iple ARTadministration
to pregnant women have been conflicting. Some studies
have suggested triple ART may be associated with low
birth weight or prematurity [7 – 9] while others have not
found an association between adverse pregnancy out-
comes and treatment, but with advanced maternal disease
[10]. HIV infection undoubtedly has been shown to be a
relevant risk factor for maternal mortality in the African
continent [11,12]. The Drug Resource Enhancement
Against AIDS and Malnutrition (DREAM) program uses
triple ART for the purposes of HIV PMTCT at all 31
DREAM centers throughout ten African countries since
its inception in 2002. A dramatic decline in HIV MTCT
has been observed, accompanied by a significant decline
in maternal and infant mortality resulting in infant HIV-
free survival exceeding 92% at 12 months of age [3–5,13].
In order to evaluate the impact of maternal triple ART on
maternal mortality and pregnancy outcomes, a detailed
review of all mother-infant pairs enrolled in a public
health PMTCT program in Mozambique and Malawi
was conducted. Pregnancy outcomes included rates of
miscarriage, stillbirth and prematurity, and maternal
outcomes included maternal mortality and antiretroviral
toxicities.
Materials and Methods
Study Design
Retrospective observational cohort study.
Study Population
HIV-1-infected women followed at DREAM centers for
prenatal care Inclusion criteria: (1) prenatal care at
DREAM centers; (2) availability of pregnancy outcome
data: miscarriage, stillbirth or delivery of a live-born
infant; (3) intent to follow-up at DREAM centers
postpartum; (4) maternal informed consent to participate
in the program; and (5) intent to breast-feed. Data were
analyzed in a blinded fashion with removal of patient
identifiers. The study was approved by institutional
review boards and regulatory institutions in Italy,
Mozambique and Malawi.
Methods
Data were pooled from DREAM centers in Mozambique
and Malawi. All files available for mother-infant pairs
followed in PMTCT programs from July 2005 to June
2009 were reviewed. Data were collected on maternal
demographics, obstetrical and medical history, gestational
age, body mass index, laboratory parameters including
HIV-1 virus load, T cell subsets, hemoglobin and
transaminases, antiretroviral history, duration, and
mortality data. Clinical centers used electronic medical
records linked to medical, nutritional, and laboratory
data.
Study outcomes
Pregnancy outcomes included spontaneous abortion or
stillbirth, prematurity, and low birth weight. Abortion
was defined as fetal death occurring at less than 32 weeks
of gestation, and stillbirth as greater than 32 weeks of
gestation (determines fetal viability in resource-limited
settings). Prematurity was defined as delivery of a live
infant at less than 37 weeks gestation. Prematurity rates
were determined only for women who accessed program
centers before 37 weeks of gestation. Gestational age was
estimated by clinical exam and date of last menstrual
period. Birth weight data were obtained when infants
presented to centers within a week of birth or had birth
weights recorded on health cards. Low birth weight was
defined as less than 2.5 kg. Maternal outcomes included
Maternal Mortality (MMR) defined as death during
pregnancy, at delivery or within 42 days after delivery.
Statistical Analysis
SPSS v. Win 16.0.1 was used for data analysis. Data were
censored at the time of death, or at the last patient visit
before loss to follow-up, or on 6/30/2009. Ninety-five
percent confidence intervals for incidence of adverse
pregnancy events were calculated and Pearson X
2
test was
used for assessment of potential differences in pregnancy
and maternal outcomes according to length of pre-
delivery ART. To assess the impact of ARTon pregnancy
outcomes and mortality, data were dichotomized
according to baseline CD4 counts and viral load in
order to generate univariate Odds Ratio (OR) for each
strata and adjusted Mantel-Haenszel OR for the entire
sample and multivariate risk analysis. Duration of pre-
delivery ART and gestational age at ART initiation were
continuous variables in the model. Binary logistic
regression forward stepwise model was performed for
the main outcomes.
Results
Medical records for 3,273 pregnant women followed
from July 2005 to June 2009 were reviewed. Ninety-four
percent of pregnancies (n ¼3071) resulted in 3148 live
births. Infant 12 month HIV-free survival was 92.5%,
with a corresponding infant mortality rate of 6.7%, and a
cumulative HIV-transmission rate of 2% at 12 months of
age [13]. Baseline characteristics of the population, details
of antiretroviral administration and pregnancy outcomes
are outlined in Table 1. Maternal mortality was 1.2% (42/
3273) with 9/42 deaths (21%) occurring in the
2 AIDS 2011, Vol 00 No 00

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immediate postpartum period. The abortion/ stillbirth
rate was 5.2% (169/3273), with 3.1% stillbirths (101/
3273) and 2.1% spontaneous abortions (68/3273).
Premature deliveries occurred in 19.1% (564/2955) of
pregnancies. The prevalence of low birth weight was
11.5% in a subset of patients (57/496) as this parameter
was available for 19% (496/2584) of evaluable infants.
Fifty percent of women had baseline CD4 counts lower
than 350 cells/mm
3
, while the median time of obser-
vation in prenatal care and antenatal treatment duration
with triple ARTwas 3 months. Twelve percent of women
received less than one month of triple ART before
delivery and 3% less than one week.
Maternal Mortality
Maternal mortality strongly correlated with the length of
antenatal ART. It was ten-fold higher in women with no
treatment before delivery as compared to women with 90
days or greater of triple ART prior to birth (Table 2).
MMR adjusted for observation time was 13-fold lower in
women with greater than 90 days of triple antenatal ART,
as seen in Table 2. A CD4 stratified analysis demonstrated
that the impact of ART on maternal mortality was also
present in women with CD4 counts higher than
350 cells/mm
3
(Table 3). The Mantel-Haenszel OR
demonstrated a 70% reduction in the risk of maternal
death in women receiving more than 30 days of triple
ART before delivery. The multivariate logistic regression
analysis demonstrated an independent association
between baseline CD4 counts, hemoglobin, Body Mass
Index (BMI), and pre-delivery length of maternal ART
with maternal mortality (Table 4).
Abortion and Stillbirth
The impact of antenatal ART on cumulative abortion-
stillbirth rates was significant. As seen in Table 2, fetal
demise rates fell from 26.5% to 5% when stratified by
duration of maternal triple ART, p <0.001. When rates
were adjusted for days of patient observation, the fetal
demise rate declined from 3.3 for women with no
treatment to 0.13 for women receiving 90 days of
antenatal ART, a 25-fold decrease, p <0.001. The
Antenatal HAART and Pregnancy Outcomes Marazzi et al. 3
Table 1. Baseline parameters and overall pregnancy outcomes.
Baseline maternal values prior to ART initiation Median IQR 25– 75
Age (years) 26.4 23.1 – 30.4
Hemoglobin (gm/100 ml) 9.9 8.9 – 10.9
ALT (IU) 20 16 – 27
AST (IU) 10 7 – 15
CD4 cell count (cell/mm
3
) 357 234 – 518
Viral Load (c/ml) 4.0 3.36 – 4.51
Pregnancy and ART parameters Median IQR 25– 75
Length of pregnancy (weeks) 39.1 36.7 – 40.8
Observation time along pregnancy (days) 103 64 – 145
Week of pregnancy at beginning of ART 26.4 24.7 – 30.7
Length of pre-delivery ART (days) 83.0 53 – 108
ART Regimen details: N %
Lifelong stavudine (D4T) based triple ART 751 22.9
Lifelong zidovudine (ZDV) based triple ART 948 29.0
ZDV-based triple ART stopped 6 mo. postpartum 1,434 43.8
D4T-based triple ART stopped 6 mo. postpartum 140 4.3
Pregnancy Outcomes N %
Maternal Mortality Rate 42/3,273 1.2
Abortion-Stillbirth Rate 169/3,273 5.2
Prematurity RateM564/2,955 19.1
Low Birth Weight^ 57/496 11.5
M332 pregnancies were excluded from this analysis because patients accessed the program after 37 weeks of gestation. ^ Calculated only for term
newborns for whom weight measures in the first week of life were available.
Table 2. Pregnancy outcomes and duration of antenatal triple ART.
Maternal Mortality Abortion – Stillbirth Prematurity
Maternal Mortality
Rate
MMR/100 days
of observation
Abortion –stillbirth
Rate
Abortion –stillbirth
Rate /100 days of
observation
Prematurity
RateM
Prematurity
Rate/100 days
of observationM
Days of
pre-delivery
triple ART N % Mean (SD) N % Mean (SD) N % Mean (SD)
No triple ART 5/68 7.4 0.250 (1.195) 18/68 26.5 3.277 (13.182) 7/10 70.0 30.409 (38.368)
0 – 30 10/365 2.7 0.060 (0.395) 26/365 7.1 0.274 (1.226) 121/215 56.3 3.287 (6.081)
31 – 90 17/1,470 1.2 0.013 (0.129) 57/1,470 3.9 0.053 (0.286) 319/1,386 23.0 0.314 (0.695)
>90 10/1,370 0.7 0.004 (0.046) 68/1,370 5.0 0.030 (0.141) 113/1,330 8.5 0.046 (0.202)
TOTAL 42/3,231 1.3 0.019 (0.238) 169/3,273 5.2 0.130 (1.933) 560/2,941 19.0 0.511 (3.340)
p<0.001 <0.001 <0.001 <0.001 <0.001 <0.001

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incidence of abortion/stillbirth in women who conceived
while on triple ART and maintained ART throughout
pregnancy was 6.8% (22/323). The incidence of this
outcome in women who received no ART throughout
pregnancy was 26.5% (18/68), a relative risk of 4.24
(95%CL: 1.79–10.07). Fetal demise was highly associated
with duration of maternal ART (Table 3). Fetal demise
occurred in 6.5% of women with lower CD4 counts and
3.7% of women with CD4 cells greater than 350 cells/
mm
3
. This outcome doubled (from 5.8% to 11.6%) in
women with lower CD4 cells if ART duration was less
than a month during pregnancy and tripled (from 2.9% to
8.7%) in women in the higher CD4 strata who received
less than a month of ART. Figure 1 demonstrates the rate
of fetal demise by baseline maternal CD4 cells and
duration of ART in pregnancy. Women with the highest
4 AIDS 2011, Vol 00 No 00
Table 3. Pregnancy outcomes stratified by maternal CD4 cell count.
Baseline
CD4 count
Pre delivery length
of triple ART N % OR (CL 95%)
Mantel Haenszel OR
(CL 95%) Missing
Maternal Mortality <350 <30 days 8/185 4.3 0.30 (0.13 – 0.69) 0.29 (0.14 – 0.96) 93
30 days 18/1,163 1.3
TOTAL 26/1,548 1.7
>350 <30 days 4/226 1.8 0.28 (0.08 – 0.96)
30 days 7/1,399 0.5
TOTAL 11/1,632 0.7
Abortion – Stillbirth <350 <30 days 22/1889 11.6 0.47 (0.28 – 0.77) 0.39 (0.27 – 0.57) 18
30 days 81/1,394 5.8
TOTAL 103/1,583 6.5
>350 <30 days 20/230 8.7 0.31 (0.18 – 0.55)
30 days 42/1,442 2.9
TOTAL 62/1,672 3.7
PrematurityM<350 <30 days 55/95 57.9 0.14 (0.09 – 0.22) 0.15 (0.11 – 0.19) 78
30 days 209/1,276 16.4
TOTAL 264/1,371 19.3
>350 <30 days 66/119 55.5 0.15 (0.10 – 0.22)
30 days 215/1,373 15.7
TOTAL 281/1,492 18.8
Table 4. Multivariate logistic regression analysis.
Maternal Mortality OR 95,0% C.I
Lower Upper
Baseline Viral Load 1.457 0.916 2.318
Baseline CD4 count 1.557 1.042 2.328
Baseline Haemoglobin 2.055 1.232 3.428
Baseline Body Mass INdex 0.105 0.041 0.268
Pre-delivery days in care 0.988 0.639 1.526
Gestational age at the beginning of HAART 0.984 0.916 1.057
Pre-delivery length of triple ART 0.977 0.956 0.998
Prematurity OR 95,0% C.I
(2749 subjects who accessed care before 37 weeks of pregnancy) Lower Upper
Baseline Viral Load 1.028 0.904 1.168
Baseline CD4 count 0.860 0.773 0.957
Baseline Haemoglobin 1.008 0.861 1.182
Baseline Body Mass INdex 1.295 0.697 2.405
Pre-delivery days in care 0.248 0.208 0.294
Gestational age at the beginning of HAART 0.749 0.725 0.774
Pre-delivery length of triple ART 0.931 0.919 0.943
Abortion/stillbirth OR 95,0% C.I
Lower Upper
Baseline Viral Load 1.039 0.854 1.264
Baseline CD4 count 1.315 1.107 1.561
Baseline Haemoglobin 0.842 0.652 1.087
Baseline Body Mass INdex 0.659 0.332 1.307
Pre-delivery days in care 0.632 0.514 0.778
Gestational age at the beginning of HAART 0.899 0.871 0.928
Pre-delivery length of triple ART 0.976 0.964 0.989
Continuous variables. Weeks of pre delivery length of triple ART. Gestational age at the beginning of triple ART. Categorical Variables. Baseline
Viral Load: 0 1,000 c/ml; 1 ¼1,000 –10,000; 2 ¼10,000 –100,000; 3 100,000. Baseline CD4 count: 0 500; 1 ¼350 –500; 2 ¼200–350;
3200. Baseline Hemoglobin: 0 10.0 gm/100 ml; 1 ¼8.0– 10.0; 2 8.0. Baseline Body Mass Index: 0 18.5; 1 18.5. Pre delivery days in
care: 1 70; 2 ¼71– 110; 3 ¼111– 150; 4 150. (229 cases were excluded because of one or more missing values).

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rate of immune suppression (less than 200 CD4 cells/
mm
3
) had the highest rate of abortion/stillbirth events.
Regardless of maternal CD4 cell strata, women with little
to no ART treatment during pregnancy had a 2 to 4-fold
increase in the rate of fetal demise. Table 4 demonstrates a
multivariate analysis with an independent protective
effect of longer triple ART duration and higher maternal
CD4 cell counts on abortion-stillbirth risk.
Prematurity
There was a significant association between prematurity
and duration of maternal triple ART. As seen in Table 2,
both crude and adjusted prematurity rates per 100
observation days demonstrated a significant statistical
association with duration of maternal ART, p <0.001.
An association between prematurity risk and reduced
exposure to triple ART in pregnancy was present
regardless of CD4 strata. Proportions were similar, 58%
and 56% of women with lower or higher CD4 counts
respectively had premature deliveries if triple ART were
used in pregnancy for less than a month. The protective
effect of triple ARTwas similar across CD4 categories with
reduction of the risk of prematurity by 85% according to
Mantel-Hanszel OR (Table 3). The association between
triple ART and prematurity was confirmed in the
multivariate analysis where a protective effect of longer
treatment courses was noted. A protective effect associated
with higher CD4 cell counts was also noted.
Low Birth Weight
Birth weight measures were available for 496 infants.
Infants born before 37 weeks gestation (n ¼564) were
excluded as the attempt was to evaluate low birth weight
independent of prematurity. Birth weight analyses
exploring potential associations with maternal baseline
and treatment parameters were not performed due to the
small proportion of patients. Low birth weight (less than
2.5 kg) was present in 11.5% of infants, a finding not
inferior to country-wide statistics for the general
population of Malawi and Mozambique. Growth
parameters to 18 months of age for children in this
cohort were previously reported [15].
Adverse reactions
Anemia defined as hemoglobin lower than 8.0 gm/
100 ml up to six months postpartum from ART initiation
(in patients with baseline pre-ART hemoglobin higher
than 8.0 gm/100 ml) was present in 226 of 2670 women
(7.8%). The difference in anemia between patients
receiving ZDV-based triple ART and D4T-based triple
ART was 1% (3.99% in ZDV arm versus 3.0% in D4T
arm) in the first six weeks postpartum and 2.7% in the first
six months postpartum (8.3% vs, 5.6% respectively,
p¼0.03). Grade 3 or 4 liver toxicities were observed in
69 of 3273 women (2.1%). Grade 3 or 4 skin rashes were
present in 80 of 3273 women (2.4%) and Steven-Johnsons
Syndrome diagnosed in 39 (1.2%). A high number of
adverse reactions (109/3273 women, 3.5%) was due to
peripheral neuropathy which developed late in the
postpartum period. Cases of toxicity concurrent with
antiretroviral use were low considering the high back-
ground morbidity. No toxicity-related deaths occurred.
The number of women who required a change to
alternate ART treatment due to toxicities was 367
(11.2%), of which 171 (5.2%) had severe adverse
reactions. Approximately one-third of patients who
switched ART after several months of therapy did so
due to the development of peripheral neuropathy. The
remaining 258 women, (7.9%) switched ART because of
the development of liver toxicities, skin rash, Steven-
Johnson Syndrome or anemia.
Discussion
HIV-1 infection has been shown to be associated with
adverse pregnancy outcomes in prior studies conducted
Antenatal HAART and Pregnancy Outcomes Marazzi et al. 5
Fig. 1. ??.

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in Sub-Saharan Africa [16 – 19]. Wherever cohorts of
HIV-infected and uninfected pregnant women were
compared in resource-limited settings, pregnant women
with HIV-infection fared worse. Besides a significantly
higher mortality risk, HIV-infected women have
consistently higher rates of problems throughout
gestation including prematurity, low birth weight, fetal
demise, and perinatal mortality [6 – 19]. A South African
study demonstrated that HIV was strongly associated with
adverse pregnancy outcomes in a prospective cohort of
3465 women where 1449 were HIV-infected [11].
Similar findings were reported in Tanzania where HIV
infected women had a much higher likelihood of small for
gestational age infants, preterm births and perinatal death
[12]. Among patients with HIV, the ones with most
advanced disease are at higher risk of dying, regardless of
pregnancy status [20]. Pregnant patients with AIDS,
anemia and poor nutrition have worse fetal outcomes, as
measured by the same parameters [19]. Patients with
advanced disease are most likely to receive triple ART. As
a consequence, a number of studies have linked triple
ART to worse pregnancy outcomes [21 –23] although in
many settings, receipt of ART is a marker for advanced
disease which in itself is linked to an adverse endpoint. In
early large scale studies [10] it was demonstrated that the
pivotal variable for an adverse outcome is AIDS, while the
use of triple ART can often represent a surrogate marker
for this condition.
Maternal death is the worst possible pregnancy outcome.
In our cohort, women who received antenatal triple ART
for 90 days or longer were 13 times less likely to die than
women with no treatment. This was a progressive trend,
directly proportional to duration of treatment and present
at all CD4 levels, not only in women with advanced
disease. Although women with lower CD4 counts had a
higher maternal mortality rate, duration of prenatal
treatment showed a 70% protective effect in both groups
of patients. The assumption that women with higher
CD4 counts are not at risk of dying during or
immediately following pregnancy in Sub-Saharan Africa
is inaccurate. Pregnant women with higher CD4 cell
counts have been found to have a higher mortality risk
especially in the immediate postpartum period [18,24].
Pregnancy-associated complications such as anemia and
nutritional deficiencies (highly prevalent in resource
limited settings) contr ibute to worsening HIV disease [25]
and can render a more vulnerable immunologic state.
Coupled to the increased surrounding co-morbidity of
TB, malaria, anemia and malnutrition of the resource -
limited setting environment, the risk of death is
magnified. Anemia in our cohort was independently
associated with mortality. The excessive mortality of
HIV-infected pregnant women in Sub-Saharan Africa,
particularly in face of high virus loads (not necessarily in
women with lowest CD4 counts) is documented in large
cohort studies [17]. Our data underscores the beneficial
impact of triple ART in reducing maternal mortality at all
CD4 count levels. Nevertheless, in Sub-Saharan Africa,
women with higher CD4 counts are not typically offered
triple ART during pregnancy as it is generally assumed
that treatment can be deferred and that the risk for HIV
MTCT is considerably lower. Our data demonstrates
otherwise as in this same cohort, 50% of perinatal
transmissions occurred in women with higher CD4 cell
counts [13].
The relative risk of abortion and stillbirth in women who
received no ART was 4.24. Women who received less
than 30 days of treatment were 2 to 3-fold more likely to
develop fetal demise. This finding, although more
prevalent in women with advanced disease, was
consistently associated with duration of treatment. Low
CD4 cell counts were also found to be significantly
associated with adverse pregnancy outcomes, including
abortion or stillbirth, mortality and prematurity.
Untreated maternal HIV infection has been found to
be associated with fetal death [11]. Studies of the
pathogenesis of HIV transmission suggest that early fetal
infection may lead to a higher miscarriage rate with
female fetuses being more susceptible to infection [26]. A
higher fragility of male fetuses following in utero HIV
infection has been postulated as the mechanism behind a
gender predilection for female infants in a case series in
Malawi [27]. Regardless of the mechanism of fetal
demise, extended antenatal triple ART clearly correlated
with a lower abortion-stillbirth rate.
The correlation between prematurity and use of triple
ART is often debated. An association between poor
nutrition, low BMI and prematurity is well established
and has been documented in several nutritional studies of
pregnant HIV-infected women in Tanzania and Zambia
[14,19,28]. A strong association between maternal AIDS
and prematurity has been demonstrated in a large series
[10]. Advanced maternal HIV disease has been clearly
associated with an increased risk of prematurity, as high as
27% in a Swiss cohort of treated women [29]. In African
cohorts, prematurity rates are reported at 19% according
to nutritional studies in Tanzania where subjects had a
median CD4 cell count of 500 cells/mm3 [28]. In our
cohort, prematurity was the parameter which most
closely correlated with duration of triple ART, ranging
from 70% in a small subset of women with no treatment
to 8.5% in women with at least three months of antenatal
ART. Prematurity rates were extremely high in women
who had less than 30 days of ART (56 to 58%). Our
analyses for prematurity were adjusted per 100 days of
observation time, in order to eliminate confounding by
duration of observation. In addition, all patients who
were late presenters at or beyond 37 weeks of gestation
were excluded from this specific analysis in order to avoid
selection bias. One limitation was the absence of
ultrasound data to confirm gestational age which was
assessed on physical exam (measure of the uterine fundus)
and history of last menstrual period. Nevertheless reliance
6 AIDS 2011, Vol 00 No 00

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CE: ; QAD/202674; Total nos of Pages: 8;
QAD 202674
on physical examination for determination of gestational
age is the norm in most African settings.
One limitation of our study was that adherence data was
not collected in this cohort. However, our program
focuses heavily on adherence through the community
activist initiative, which has prompted adherence rates
higher than 95% in patients who continue in the program
[30]. Another limitation was that we did not have data on
incident HIV infections. Because most subjects initiated
medical care within the first trimester of pregnancy we
presume most infections anteceded pregnancy. MTCT
rates were very low, which corroborates this assumption.
Maternal toxicities due to antiretroviral treatment were
relatively uncommon and within the range of adverse
reactions reported for women in similar cohorts such as
women receiving triple ART in the BAN study, a
randomized control study in a similar population in
Malawi [31]. In our cohort, anemia and peripheral
neuropathy occurred most frequently, and despite the
wide use of nevirapine, adverse reactions due to skin
rashes and alterations in liver function tests were
infrequent, an observation consistent with prior studies
by our group [31 – 35].
In summary, extended triple ART was highly protective
against adverse pregnancy outcomes including maternal
mortality in a large cohort of pregnant women followed
in a public health program in Malawi and Mozambique.
The level of protection against mortality, fetal demise and
prematurity conferred by longer courses of antenatal
triple ART surpassed CD4 cell count thresholds and
benefitted patients at all stages of HIV disease. Pregnant
HIV-infected women in resource-limited settings,
regardless of disease stage, are at higher risk for a series
of significant complications including fetal and maternal
death as compared to uninfected counterparts. Early
triple ART should be provided, whenever possible, to all
HIV-infected pregnant women in resource-limited
settings for reduction of maternal mortality and improved
pregnancy outcomes.
Acknowledgments
Authorship: Each individual author fully contributed to
the preparation of this manuscript: J.H, I.Z., and N.A.M.
obtained the original patient data set in Malawi and
Mozambique. E.B. and P.S. obtained, plotted and
analyzed all maternal clinical parameters and participated
in the data analysis. A.M.D.A, P.N.. and S.M. coordinated
all data collection efforts from DREAM health clinics in
Mozambique and Malawi and performed preliminary
data analysis. G.P. and S.C. were responsible for the
performance of all laboratory studies and coordinated the
laboratory data for the project. K.N.-S., G. L. and L. P.
performed the final data analysis and wrote the manu-
script in conjunction with M.C.M. who was also
responsible for supervision of health center activities
and data base coordination. L.P. is the Principal
Investigator and the Medical Director of the DREAM
program who coordinated all research efforts for the
present article.
This manuscript represents valid work and has not been
previously published nor is being considered for
publication elsewhere. Preliminary findings were pre-
sented at the 5
th
International AIDS Society Meeting on
HIV Pathogenesis, Treatment and Prevention in Cape
Town, South Africa as an oral presentation, July 19 - 22
2009, Abstract TUAC102.
Disclosures: The authors do not have any conflicts of
interest including financial interests, activities, relation-
ships or affiliations to disclose.
The authors would like to acknowledge the multiple
members of the DREAM program who participated in
the conduct of this study and all study participants.
Sources of Funding: The DREAM (Drug Resource
Enhancement Against AIDS and Malnutrition) Pro-
gram, of the Sant’Egidio Community, a faith-based
NGO in Rome, Italy is sponsored by multiple
organizations including the World Bank Treatment
Acceleration Program, several Italian private banks,
several governmental cooperations including the Ger-
man Agency for Technical Cooperation, the Agence
Francaise de De?veloppement, the Catalan Agency for
Development Cooperation, the Belgium Development
Cooperation, and the United States President Emer-
gency Plan for AIDS Relief among others. DREAM
Program–Project Malawi was funded in Malawi by
Intesa Sanpaolo, Italy and the CARIPLO Foundation,
Italy. The present study was not funded by a specific
award.
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