Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 103(4): 351-357, June 2008
online | memorias.ioc.fiocruz.br
Determinants and trends in perinatal human immunodeficiency virus
type 1 (HIV-1) transmission in the metropolitan area of
Belo Horizonte, Brazil: 1998 - 2005
Fabiana Maria Kakehasi, Jorge A Pinto/1/+, Roberta Maia de Castro Romanelli,
Mariângela Carneiro/2, Carolina Silva Cardoso, Maria do Carmo Teatini Tavares/3,
Victor Hugo Melo/4, Regina Amélia Lopes Pessoa de Aguiar/4
Grupo de Aids Materno-Infantil 1Departamento de Pediatria 4Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina,
2Epidemiologia de Doenças Infecciosas e Parasitárias, Departamento de Parasitologia, Instituto de Ciências Biológicas Universidade
Federal de Minas Gerais, Av. Alfredo Balena 190, s/ 161, 30130-100 Belo Horizonte, MG, Brasil 3Centro de Treinamento e Referência em
Doenças Infecciosas e Parasitárias Orestes Diniz, Secretaria de Saúde da Prefeitura Municipal de Belo Horizonte, MG Brasil
Significant decrease in human immunodeficiency virus type 1 (HIV-1) vertical transmission has been observed
worldwide in centers where interventions such as antiretroviral therapy (ART), elective cesarean section, and avoid-
ance of breastfeeding have been implemented. This prospective cohort study aimed to assess the determinants of and
the temporal trends in HIV-1 vertical transmission in the metropolitan area of Belo Horizonte, Brazil from January
1998 to December 2005. The rate of HIV-1 vertical transmission decreased from 20% in 1998 to 3% in 2005. This
decline was associated with increased use of more complex ART regimens during pregnancy. Multivariate analysis
restricted to clinical variables demonstrated that non ART, neonatal respiratory distress/sepsis and breastfeeding
were independently associated with HIV-1 vertical transmission. When laboratory parameters were included in the
model, high maternal viral load and non maternal ART were associated with HIV-1 vertical transmission. The re-
sults from this study confirm the impact of ART in the reduction of HIV-1 vertical transmission and indicate the need
for improvement in the care and monitoring of mother and infant pairs affected by HIV-1.
Key words: HIV-1 - vertical transmission - pregnant women - antiretroviral therapy
By the end of 2006, it was estimated that almost 39.5
(CI95%: 34.1-47.1) million adults and children were in-
fected with the human immunodeficiency virus (HIV-1)
worldwide, with 1.7 million (CI95%: 1.3-2.5) HIV-1-
positive individuals living in Latin America (UNAIDS
2007). The vertical transmission of HIV-1 is the major
route for HIV-1 acquisition in children, and 13,012 cases
of pediatric acquired immunodeficiency syndrome
(AIDS) cases have been reported in Brazil (MS 2007a).
In the absence of interventions, the reported HIV-1 ver-
tical transmission rate varies from 15 to 25% in Europe
and the USA and extending to 40% in under-developed
countries (WGMCT 1995). In Brazil, initial studies
demonstrated a transmission rate of 16% (CI 95%: 13-20)
(Tess et al. 1998), but a significant decrease has been ob-
served in recent years; a nation-wide study reported a
transmission rate of 7.1% in 2001, but centers in Rio de
Janeiro and São Paulo have described lower rates (3.57%
between 1996 to 2001 and 2.4% in 2002, for each city
respectively) (João et al. 2003, Matida et al. 2005, Succi
2007). Brazilian data reflect the progress achieved in
the reduction of HIV-1 vertical transmission reported
worldwide in centers where maternal antiretroviral ther-
apy (ART) and breast milk replacement are available
Financial Support: CNPq
+ Corresponding author: email@example.com
Received: 30 January 2008
Accepted: 5 June 2008
(Dorenbaum et al. 2002, Wade et al. 2004, Magder et al.
2005, Newell et al. 2007).
The Pediatric AIDS Clinical Trials Group Protocol
076, a multicenter study published in 1994 (Connor et
al. 1994) demonstrated a decrease of 67.5% in the HIV-1
vertical transmission rate when zidovudine (ZDV) was
offered prophylactically to HIV-1 pregnant women and
to their newborns. Following this landmark study, differ-
ent ART regimens have demonstrated variable impact in
the reduction of HIV-1 vertical transmission rates (Dabis
et al. 1999, Guay et al. 1999, Shaffer et al. 1999, Wiktor
et al. 1999, PST 2002, Lallemant et al. 2004, Read et
al. 2007). In addition to ART, other interventions have
contributed to the reduction of HIV-1 vertical trans-
mission, such as elective cesarean section (C-section)
(IPHIVG 1999, EMDC 1999), vaginal cleaning during
the intrapartum period (Taha et al. 1997), vitamin A
supplementation (Semba 1997), and avoidance of breast-
feeding (Nduati et al. 2001, RoUsseau et al. 2004).
The objective of this prospective study was to evaluate
the determinants associated with HIV-1 transmission and
to describe the temporal trends in HIV-1 vertical trans-
mission rates in the metropolitan area of Belo Horizonte
(BH), Brazil, from January 1998 to December 2005.
PATIENTS, MATERIALS AND METHODS
Population - This prospective observational study
was carried out at the main referral center for HIV-1/
AIDS care and treatment in BH (Centro de Referência
em Doenças Infecciosas e Parasitárias Orestes Diniz –
UFMG/PBH). Eligible cases included HIV-1 infected
Determinats of perinatal HIV-1 transmission • Fabiana M Kakehasi et al.
pregnant women and/or mothers and their exposed ba-
bies who were admitted before three months of age to
the outpatient clinic. The participants were enrolled
from January 1998 to December 2005.
Data collection - Clinical and laboratory data were
collected using standardized forms. Maternal data in-
cluded HIV-1 route of acquisition, date of diagnosis,
pregnancy and delivery history, ART during pregnancy,
and disease classification (revised by CDC 1992). Re-
sults from maternal CD4+ lymphocyte count and viral
load closest to delivery were also collected for analysis.
Results from tests performed between three months pri-
or to to three months post delivery date were considered.
Infants were evaluated monthly for the first six months
of life and every three months thereafter until defini-
tion of HIV-1 status was determined. CD4+ lymphocyte
count and plasma viral load were performed in infected
infants every three months.
Definitions - Mode of delivery was categorized as
elective C-section or other. ART regimens were de-
scribed as ZDV monotherapy, dual nucleoside reverse
transcriptase inhibitor therapy (NRTI; ZDV plus an-
other NRTI), highly active ART therapy (HAART; 2
NRTIs plus 1 protease inhibitor or 1 non-NNRTI), or no
therapy at any stage of gestation. Duration of ruptured
membranes was considered prolonged if it occurred pri-
or to 4 h of delivery.
Infants were classified as low birth weight if they
weighed less than 2.500 g and classified as premature if
they were born at less than 37 weeks of gestational age as-
sessed by Capurro et al. (1978) method. HIV-1 infection
was defined in infants who presented: (i) a plasma viral
load greater than 10,000 copies per ml in two samples
collected after four weeks of life; (ii) any class C diagno-
sis according to CDC (1994) pediatric HIV-1/AIDS case
definition; or (iii) a persistent positive HIV-1 antibody
exam (enzyme-linked immunoassay and western blot)
after 18 months of age. Uninfected infants were defined as
those who presented with two negative plasma viral load
exams after four weeks of life or those who seroreverted
(a negative serologic test performed after 12 months of
age). All mothers were counseled to not breastfeed.
Statistical analysis - The relationships between ma-
ternal factors and HIV-1 status of the infants were first
analyzed by univariate analysis using the chi-square
test, Fisher’s exact test, chi square for trend test, Mann-
Whitney test, estimative of odds ratio (OR), and 95% CI.
Following univariate analysis, the independent contribu-
tion from risk factors was assessed using stepwise logistic
regression. The initial model included all variables with
p-values less than 0.25 or those variables known to have
biological plausibility for perinatal HIV-1 transmission.
New models were built using a backward process with
statistical significance determined by the likelihood ratio
test (Hosmer & Hjort 2002). Interactions between vari-
ables selected for the final multivariate model were also
considered if they remained significantly associated with
the transmission risk. Statistical analyses were performed
using SPSS version 12.0 (SPSS Inc. Chicago IL USA).
The study was approved by the Ethical Comitee from
Universidade Federal de Minas Gerais (ETIC 008/97) and
all participants provided writen informed consent.
During the period from January 1998 to December
2005, 939 mother-infant pairs were evaluated. Analyses
were performed with 900 pairs; data from 39 (4.2%) pairs
were either lost to follow-up or reported no infection
status at time of analysis. HIV-1 vertical transmission
occurred in 56 infants, with an overall rate of transmis-
sion of 6.2% (95% CI: 4.8-8.1). A significant decrease in
transmission was observed throughout the study period
(Fig. 1) (p < 0.05). The relative reduction in HIV-1 verti-
cal transmission rate from 1998 to 2005 was 85%.
Maternal characteristics - No maternal demographic
characteristics were associated with HIV-1 vertical
transmission: Overall, 46.6% of mothers had mixed eth-
nic origin (“mulata”), 63.8% had a stable marital status,
and 62.8% had less than eight years of formal education.
Transmitting and non-transmitting mothers had simi-
lar median ages (26.0 and 27.9 years, respectively; p =
0.30). Illicit drug use was not associated with transmis-
sion (OR 1.0, 95% CI: 0.4-2.5). Information on route of
HIV-1 acquisition was available for 93.1% of the women
and sexual contact with HIV-1-positive partner was re-
ported by 96.9% of the women. The majority of mothers
were asymptomatic or had mild manifestations (CDC
1992, class A = 60%). CD4+ lymphocyte counts and
plasma viral load were available for 49.4% and 55.4%,
respectively, of the HIV-1-infected mothers (Table I).
Median time of these blood tests from delivery (pre to
post) was 6.4 weeks for CD4+ count (interquartile range:
IQR25%-75%: 2.0-6.4) and six weeks for viral load as-
sessment (IQR25%-75%: 2.1-13.7). Transmitting mothers
were significantly more immunossupressed and demon-
strated higher plasma viremia than non-transmitting
Fig. 1: HIV vertical transmission rate among HIV-infected women
per study year, from 1998 to 2005.
Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 103(4), June 2008
mothers. Maternal viral load greater than 1,000 copies/ml
was significantly associated with vertical transmission
(OR 13.0, 95%CI: 2.9-80.6); however, we were not able
to establish a plasma viral load threshold that predicted
Obstetric history - Neither rupture of membranes
prior to 4 h of delivery, complications during pregnancy,
nor maternal death were associated with an increased
risk of HIV-1 vertical transmission. Rates for mode of
delivery varied throughout the study period: Elective C-
section rates rose until 2001 and then declined; rates for
vaginal deliveries increased since 2001 (Fig. 2). Rates of
non-elective C-section deliveries remained stable during
the study years, accounting for less than 7% of deliver-
ies. Vaginal deliveries were associated with increased
risk of transmission (OR 3.33, 95% CI: 1.82-5.88).
In this cohort, ART during pregnancy has shown to
increase from 66.7% in 1998 to 89.9% in 2005 (p = NS).
In the first three years of this study, ZDV monotherapy
and dual therapy (2 NRTI drugs, including ZDV) were
the most common ART regimens used by pregnant
women (Fig. 3). HAART increased from 11.1% in 1998
to 76.1% in 2005 (chi-square for trend = 134.67, p < 0.05)
and it was inversely correlated with HIV-1 vertical trans-
Infant follow-up - Mean birth weights for infected
and uninfected infants was 2,890 g and 2,910 g, respec-
tively (p = 0.25). Numbers of low birth weight (infected:
25.5% vs. uninfected: 20.5%, p = 0.39) and premature
(infected: 20% vs. uninfected: 11.7%, p = 0.07) infants
Characteristics of women and infants in the study population, according to HIV vertical transmission (n = 900)
Characteristics HIV Transmission: Yes (n = 56) HIV Transmission: No (n = 844) Statistic
Median age (years)
None (%) 34/48 (70.8%)
ZDV monotherapy (%) 7/48 (14.6%)
Dual therapy (%) 4/48 (8.3%)
HAART (%) 3/48 (6.3%)
Prolonged rupture of membranes (%)b
Mode of delivery (%)b
Elective C-section 21/56 (37.5%)
Emergence C-section 02/56 (3.6%)
Vaginal delivery 33/56 (58.9%)
Median CD4 count (cells/mm3)
Median Plasma Viral Load (log)
Viral load > 1,000 copies/ml (%) 23/25 (92%)
26.0 27.9 0.30a
Birth Weight (grams)
(IQR 25%-75%) (2,875-3,443)
Low birth weight (%)b
Neonatal Morbidity (%)b
Median CD4 count (cells/mm3)
(IQR 25%-75%) (1,040-2,325)
2,890 2,910 0.25a
a: Mann Whitney Test; b: Qui –square; c: Odds ratio (CI 95%); IQR: interquartile range.
Fig. 2: rate of elective C-section and vaginal deliveries among HIV
infected pregnant women, from 1998 to 2005.
Determinats of perinatal HIV-1 transmission • Fabiana M Kakehasi et al.
occurred equally between infected and uninfected.
Breastfeeding was significantly higher among infected
compared to uninfected infants (infected: 4.3% vs. un-
infected: 33.9%) and represented an important risk fac-
tor for HIV-1 vertical transmission (OR = 11.5, 95% CI:
7.8-23.1, p < 0.05) as shown in Table II. Neonatal mor-
bidities due to sepsis and respiratory discomfort were
associated with HIV-1 vertical transmission (OR 3.6,
95%CI: 2.0-6.3). Although still in the normal range, in-
fected presented decreased CD4+ lymphocyte counts in
the first trimester of life when compared with uninfected
(median values: infected: 1,792 cells/ml vs. uninfected:
2.555, p < 0.05, median age of collection = 1.9 months).
Multivariate analysis - Two models were analyzed
in this cohort: one model included only clinical data
(Model 1) and a second model included both clinical and
laboratory data (CD4+ lymphocyte count and viral load;
Model 2). Among the available 900 mother-infant pairs,
the clinical-only model included 748 (83.1%) pairs and
the clinical and laboratory model comprised 339 (37.7%)
pairs. The initial step in both models included the logis-
tic modeling of all variables that demonstrated known
biological plausibility for HIV-1 vertical transmission
or demonstrated statistical importance in the initial uni-
variate analysis (Table II). Model 1 included delivery
type (elective C-section vs other), timing of amniotic
membrane rupture (< or > 4 h prior to delivery), ART
use (ZDV, ZDV + NRTI, HAART, or no therapy), pre-
maturity (< 37 weeks gestational age), birth weight (g),
neonatal disease and breastfeeding as variables. Model
2 included all clinical variables listed above and added
absolute CD4+ lymphocyte count and plasma viral load
in log scale (Table II). Absence of maternal ART was
the major independent risk factor associated with an
increased risk in both models. Despite that prematurity
was not a significant independent risk factor in the clini-
cal model, neonatal disease was associated with HIV-1
vertical transmission. Multiplicative interactions between
breast feeding or prematurity and neonatal disease were
not statistically significant (p = 0.08 and p = 0.918, re-
spectively). In Model 2, higher maternal viral load was as-
sociated with a two-fold increased risk of HIV-1 vertical
transmission. There was no interaction between maternal
viral load and ART during pregnancy (p = 0.49)
The rate of HIV-1 vertical transmission declined from
20% to 3% during the seven-year period (1998-2005)
of this prospective observational study carried out at a
HIV-1/AIDS referral center in BH: The relative reduc-
tion was 85%. This decline is similar to what has been
reported in other studies both in-country and internation-
ally (João et al. 2003, Wade et al. 2004, Matida et al. 2005,
Succi 2007), demonstrating the effectiveness of strategies
aimed at reducing mother to child transmission. Results
from a multicenter observational study conducted in
Latin America and Caribbean countries that included 770
mother-infant exposed to different ART regimens (Read
et al. 2007) also demonstrated a low (0.91%, 95%CI: 0.37
- 1.86) HIV-1 mother to child transmission rate. The Na-
tional AIDS Brazilian Program (NAP) has been provid-
ing routine HIV-1 testing for all pregnant women during
prenatal care and for all HIV-1 exposed babies at birth.
In addition NAP has been providing infant formula,
ART drugs, and laboratory monitoring universally and
free of charge. The NAP strategy focuses on all steps to
block HIV-1 vertical transmission (MS 2007b).
The conclusions drawn from our study could have
been affected by selection bias or our studied cohort
might not be representative of all HIV-1-infected preg-
nant women from metropolitan BH. However, this po-
Multivariate analyses of factors associated with HIV vertical
transmission performed in two models
Models and variables Adjusted OR 95% CI p-value
Model 1: clinical dataa
Absence of maternal ART use
Model 2: clinical and laboratory datab
Maternal viral load by log
Absence of maternal ART use
a: variables included in a full model were time of membrane
rupture, prematurity, birth weight, breastfeeding, maternal
antiretroviral use, neonatal diseases and C-section (n = 748);
b: variables included in a full model were membrane rupture,
prematurity, birth weight, breastfeeding, neonatal diseases, an-
tiretroviral use, C-section, maternal viral load by log and mater-
nal absolute CD4 count (n = 339).
Fig. 3: antiretroviral schema used among HIV-infected pregnant
women, from 1998 to 2005.
Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 103(4), June 2008
tential bias is attenuated by the fact that we are the only
referral center for the care of HIV-1 exposed and infected
children in the area.
In this observational study there were no differences
in the transmission rates between mothers who had pro-
longed rupture of membranes (> 4 h prior to delivery) or
any reported complication during pregnancy. In a meta-
analysis conducted by the IPHIVG (2001) the probability
of HIV-1 vertical transmission rate increased from 8%
(for rupture 2 h prior to delivery) to 32% (for rupture
24 h prior to delivery) among HIV-1-infected women.
Other studies have also described associations between
premature labor, intrapartum transmission, and timing
of rupture of membranes among HIV-1-infected women
(Magder et al. 2005). However, the contribution of com-
plex ART regimens was not addressed in this study, in
which the majority of women were exposed to ZDV
monotherapy or less complex regimens.
The C-section pattern described in this current study
is similar to the increasing proportion of C-section rates
among HIV-1-infected women performed in the US.
Dominguez et al. (2003) observed that the proportion of
deliveries conducted by C-section increased from 24%
before June 1998 to 58% after June 1998. Similarly, an in-
crease in C-section rates was detected by the ECS (2005)
from 1985 to 2004. It was recommended that all HIV-1-
infected pregnant women be offered elective C-sections
to reduce HIV-1 vertical transmission, including women
receiving ART (ECS 2005). A recent publication com-
paring characteristics of HIV-1-infected pregnant wom-
en from Europe and the USA demonstrated a greater
elective C-section delivery rate in Europe (61% vs 22%,
Europe vs. USA, respectively), but an earlier initiation
of ART and HAART in the USA (Newell et al. 2007). It
is likely that the release of the results from EMDC study
(1999) was an important determinant for the increment in
C-section rates, especially in Brazil and European coun-
tries. It is important to emphasize that the HIV-1 vertical
transmission rates continued to decline, even when the
elective C-section rates reached a plateau around 2002.
This trend was probably associated with the increased use
of HAART regimens as depicted in Fig. 3.
The importance of maternal viremia was confirmed
in the second model of the multivariate analysis. This
factor was associated with an increased risk of HIV-1
vertical transmission (OR 2.3, 95% CI: 1.2-4.4) consis-
tent with results from international studies including
the women infant transmission study (WITS) (OR 2.4,
95% CI: 1.69-2.34), an African study (OR 2.66, 95% CI:
1.95-3.63), and the NICHD International Site Develop-
ment Initiative study (OR3.3, 95% CI: 2.0-5.4) (Cooper
et al. 2002, Taha et al. 2004, Read et al. 2007). However,
the quality of prenatal care remains a key issue: The
large numbers of mothers without assessment of CD4+
lymphocyte count and viral load are an indirect marker
of missed opportunities in prenatal care. Additionally,
the extended interval between laboratory assessment
and delivery time is a limitation that may potentially
compromise our findings and conclusions. Despite
the significant difference between mean viral load in
mother to child transmission and non- mother to child
transmission, a threshold for predicting mother to child
transmission was not established, similar to other stud-
ies (Mayaux et al. 1997, Garcia et al. 1999, ECS 2005,
Read et al 2007).
The maternal use of combined ART regimens has in-
creased significantly throughout the study period. This
finding is consistent to what has been reported in a large
American cohort of HIV-1 infected women (Tuomala
et al. 2002) that demonstrated a significant increase in
HAART use with and without protease inhibitor from
the early 90s to 1998. In the WITS study, HIV-1 verti-
cal transmission rate was 20% for women not receiving
prenatal ART 10.4% for those receiving ZDV monother-
apy, 3.8% for multi-ART, and 1.2% for HAART (Cooper
et al. 2002). Unfortunately, our study did not measure
the duration of therapy during pregnancy or assess the
suppression of viral replication. The benefit of ART was
confirmed and this was independently associated with a
reduction in the HIV-1 vertical transmission in both sce-
narios described in the multivariate analyses as is histori-
cally demonstrated in maternal-to-child transmission.
In our study, low birth weight and prematurity were ob-
served equally among infected and exposed/uninfected.
However, other studies have reported low birth weight
(LBW) and prematurity to be associated with mother
to child transmission, and a possible explanation for the
discrepancy could be the higher frequency of LBW and
prematurity described in other populations (Nogueira et
al. 2001, João et al. 2003, Magder et al. 2005, Szyld et al.
2006). However, neonatal diseases such as respiratory
distress syndrome, sepsis, and neonatal jaundice were
associated with HIV-1 vertical transmission indicating
that others factors are associated with the newborn in-
fection. In addition, the administration of ART to moth-
ers and ZDV to infants that is associated with elective
C-section could also have contributed to the prevention
of mother to child transmission of HIV-1 in most of our
preterm and LBW infants. Also, the current study did
not demonstrate a demographic difference among in-
fected and non-infected newborns; it was not possible to
demonstrate the timing of HIV-1 infection, whether in-
tra or peripartum (Bryson et al. 1992, Kalish et al. 1997).
A significant issue to be addressed is the high frequency
of breastfeeding in a country where formula is available.
This statistic could reflect a subgroup of HIV-1 infected
women that had not been diagnosed during pregnancy or
at labor. Unfortunately, time of maternal diagnosis was
not addressed in our study. The opportunity to advise
against breastfeeding was missed in this subpopulation
and thus, a number of HIV-1 transmissions were not
avoided. Neonatal disease can predict if an exposed baby
is HIV-1-infected, but prematurity does not influence
this factor. A lower CD4+ lymphocyte count was present
in HIV-1 infected children. However this finding is nor-
mal for children of this age, and thus additional studies
must be done to establish the value of this measure for
predicting risk of infection and disease.
This current study reports a decrease in HIV-1 verti-
cal transmission rates for metropolitan BH and also re-
ports the impact of ART on the reduction of infection
rates in this population. The real scenario in impover-
Determinats of perinatal HIV-1 transmission • Fabiana M Kakehasi et al.
ished communities is as is expressed in Model 1, where
only clinical data are available to predict the risk of
HIV-1 vertical transmission. It has clearly been observed
that two interventions must be implemented: avoidance of
breastfeeding, and maternal/neonatal ART. The effective-
ness of high quality, multidisciplinary prenatal care can
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