1. No category

Neurodevelopment in Children Born to HIV-Infected Mothers by Infection and
Treatment Status
Kirsty Le Doaré, Ruth Bland and Marie-Louise Newell
Pediatrics; originally published online October 1, 2012;
DOI: 10.1542/peds.2012-0405
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/early/2012/09/26/peds.2012-0405
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
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of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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REVIEW ARTICLE
Neurodevelopment in Children Born to HIV-Infected
Mothers by Infection and Treatment Status
AUTHORS: Kirsty Le Doaré, BA(Hons), MBBS, MRCPCH,a,b
Ruth Bland, BSc, MB ChB, DCH, FRPCH, MD,c,d and MarieLouise Newell, MB, MSc, PhDc,e
aCentre
for International Health and Development, and eMRC
Centre of Epidemiology for Child Health, University College
London, Institute of Child Health, London, United Kingdom;
bCroydon University Hospital, London, United Kingdom; cAfrica
Centre for Health and Population Studies, University of KwaZuluNatal, Mtubatuba, South Africa; and dGlasgow University Medical
Faculty, Glasgow, United Kingdom
KEY WORDS
neurodevelopment, HIV, childhood development, antiretroviral
therapy, HAART
ABBREVIATIONS
ARV—antiretroviral drug
HAART—highly active antiretroviral therapy
Dr Le Doaré prepared and undertook the literature review and
was responsible for writing the first draft of this article.
Professor Newell and Dr Bland reviewed the data and provided
comments during writing, and substantially contributed to, and
approved, the final manuscript.
www.pediatrics.org/cgi/doi/10.1542/peds.2012-0405
doi:10.1542/peds.2012-0405
Accepted for publication Jun 26, 2012
Address correspondence to: Kirsty Le Doaré, MBBS, MRCPCH, c/o
Paediatric Department, Croydon University Hospital, London
Road, Croydon CR7 7YE, UK. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
FUNDING: The Africa Centre for Health and Population Studies is
funded by a core grant from the Wellcome Trust (grant number
082384/Z/07/Z).
abstract
BACKGROUND: We reviewed the impact of HIV, HIV exposure, and
antiretroviral therapy/prophylaxis on neurodevelopmental outcomes
of HIV-infected and HIV-exposed-uninfected infants and children.
METHODS: A literature search of Medline, Embase, PsychINFO, Web of
Science, PubMed, and conference Web sites (1990–March 2011) using
the search terms, infant, child, HIV, neurodevelopment, cognition, language, and antiretroviral therapy, identified 31 studies of HIV/
antiretroviral exposure using standardized tools to evaluate infant/
child development as the main outcome. Articles were included if
results were reported in children ,16 years of age who were
exposed to HIV and antiretrovirals in fetal/early life, and excluded if
children did not acquire HIV from their mothers or were not exposed
to antiretrovirals in fetal/early life.
RESULTS: Infants who acquired HIV during fetal and early life tended to
display poorer mean developmental scores than HIV-unexposed
children. Mean motor and cognitive scores were consistently 1 to 2
SDs below the population mean. Mean scores improved if the infant
received treatment before 12 weeks and/or a more complex
antiretroviral regimen. Older HIV-infected children treated with
highly active antiretroviral therapy demonstrated near normal
global mean neurocognitive scores; subtle differences in language,
memory, and behavior remained. HIV-exposed-uninfected children
treated with antiretrovirals demonstrated subtle speech and
language delay, although not universally.
CONCLUSIONS: In comparison with resource-rich settings, HIV-infected
and HIV-exposed-uninfected infants/children in resource-poor settings
demonstrated greater neurodevelopmental delay compared with HIVunexposed infants. The effects on neurodevelopment in older HIVinfected children commenced on antiretroviral therapy from an
early age and HIV-exposed-uninfected children particularly in
resource-poor settings remain unclear. Pediatrics 2012;130:1–19
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1
Mother-to-child transmission during
pregnancy, delivery, or breastfeeding is
the dominant mode of acquisition of
HIV infection in children.1 Without prophylaxis, ∼15% to 30% of babies born
to HIV-infected women will acquire HIV
in utero or during delivery and a further
5% to 20% through breastfeeding.2–4
Maternal HIV has been associated with
an increased risk of low birth weight
(,2500 g)5–7 and small-for-gestationalage infants,6,8,9 both of which are
independently associated with an increased risk of mortality and of developmental delay.10–12
HIV-1 is thought to enter the central
nervous system days to weeks after
primary infection,13–15 causing neuronal damage and cell death.16,17 This
infective process manifests in childhood as a progressive encephalopathy,
and previously affected 8% to 50% of
children diagnosed with HIV infection
in the United States and Europe.18–21
Symptoms can vary greatly, with motor
manifestations predominating.19,22 Microcephaly can be seen as a result of
brain atrophy22,23 and radiologic studies demonstrate periventricular and
basal ganglia calcifications and cerebral matter attenuation.24,25
Studies of cerebrospinal fluid from
children with progressive encephalopathy found active and persistent brain
infection, highlighting the need for
antiretroviral drugs (ARVs) that cross
the blood-brain barrier. This information has recently been developed
into a ranking system to aid clinicians’
ARV prescribing.26 Highly active antiretroviral therapy (HAART), containing
ARVs that cross the blood-brain barrier, has been found to reduce the incidence of progressive encephalopathy
by 50% compared with non-HAART
regimens.27 With the routine use of
ARVs in childhood in the United States
and Europe, cumulative incidence of
progressive encephalopathy in HIVinfected children aged 6 months to 16
2
years has fallen from more than 30%
to less than 2%.28–30 Prevention of
mother-to-child transmission through
maternal ARV prophylaxis and treatment has successfully reduced transmission rates since the 1990s,31,32 and
in countries offering a combination of
ARV prophylaxis, elective cesarean delivery, and avoidance of breastfeeding,
transmission rates of ,2% have been
reported.33
HAART has been associated with severe
prematurity (twofold increased risk of
being born at ,32 weeks’ gestation)34,35
in Europe and the United States. Similar reports from Africa, where most
women with HIV infection live, indicated
that women on a HAART regimen containing a protease inhibitor were twice
as likely to deliver prematurely (before
37 weeks) than those on a regimen not
containing a protease inhibitor,36,37 and
were 50% more likely to deliver extremely premature infants (before 28
weeks).37 An increased risk has also
been reported in regimen containing
efavirenz and nevirapine.38,39 Severe
prematurity increases the risk of cerebral events, such as hypoxic brain
injury and cerebral hemorrhage, which
will affect future neurodevelopmental
potential.11,12
Interventions to improve development
in the first 3 years of life, including nutritional supplementation, developmental stimulation, dedicated
health and community-based development centers, have demonstrated
sustained improvement in later cognition and schooling in developing
countries40,41 but this has not been
specifically investigated in children affected by HIV.
Assessing neurodevelopmental outcomes is a difficult task owing to potential confounders, such as maternal
health, mood, infant-mother bonding
and attachment, early years stimulation, maternal substance misuse, poverty, illiteracy, malnutrition, and
disease.41 The past 10 years have seen
a large investment in prevention of
mother-to-child transmission programs and the treatment of HIVinfected children at an earlier disease
stage with more aggressive therapy.42
With earlier detection and improved
treatment, HIV has become a chronic
disease rather than a fatal illness.
Therefore, improving the quality of life
for infants and children affected by HIV,
including interventions to improve
neurodevelopmental outcomes and
maximize school achievement are vital.
This review aims to summarize what
has been learned about neurodevelopmental outcomes in HIV-infected and
HIV-exposed-uninfected infants and
children and discusses the effects of
different antiretroviral regimens on
neurodevelopmental outcomes. We discuss the implications of these findings
to improve the care of children infected
and affected by HIV.
METHODS
We searched the online databases
Medline, Embase, PsychINFO, Web of
Science, and PubMed for studies published in English between 1990 and
March 1, 2011, with the following search
terms: “infant,” “child,” “HIV,” “neurodevelopment,” “cognitive impairment,”
“motor impairment,” “language impairment,” “antiretroviral therapy.” The
search identified 210 studies in Medline; subsequent searches identified
additional studies: 16 in Embase, 7 in
PsychINFO, and 12 in PubMed. The
results of this review have been
reported using the checklist described
for writing systematic reviews by Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA).43
The current focus of HIV programs
globally is on prevention of mother-tochild transmission and early detection
of childhood infection with immediate
treatment. Therefore, to determine the
effect on neurodevelopment of maternal
LE DOARÉ et al
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REVIEW ARTICLE
HIV and possible ARV exposure in utero
or early life, and of childhood exposure
to ARVs, studies were included if they
met the following criteria:
1. The study concerned HIV-infected
and HIV-exposed-uninfected infants
and children ,16 years of age who
were exposed to ARVs in fetal and/
or early life
2. The study used a standardized tool
to evaluate infant/child development
3. A developmental variable was the
main outcome
4. English language articles/abstracts
Studies of special groups, such as
patients with hemophilia, orphans, or
HIV-infected children who had not acquired HIV infection via mother-to-child
transmission, were excluded, as these
groups would either not have been
exposed to HIV/ARVs in utero or have
other potential confounders that are
known to affect development, independent of child health status.15
In addition, a manual search of the references from selected articles and
recent conferences of interest (international AIDS conferences, Conference
on Retroviruses and Opportunistic
Infections from 2002–2010) was carried out to ensure all relevant articles
were identified. This yielded an additional 8 studies that met the inclusion
criteria; 31 studies fulfilled the inclusion criteria and were reviewed
(Fig 1).
CHARACTERISTICS OF STUDIES
Three-quarters of the studies reviewed
(75%) emanated from the United States
or Canada (n = 18)44–61 and Europe
(n = 5),62–66 whereas studies from
resource-poor settings accounted for
25%: Africa (n = 6),67–72 South/Central
America and the Caribbean (n = 1),73
and Asia (n = 1).74 The characteristics
of the studies included in this review
are outlined in Tables 1, 2, and 3.
FIGURE 1
Flowchart of study selection process (based on PRISMA flowchart).
The prevalence of infants born before
37 weeks’ gestation ranged from 6%
to 29%50,52,55 in HIV-infected children
and 2.8% to 17.3% in HIV-exposeduninfected children.48,53,54 The prevalence of low birth weight (,2500 g)
among HIV-infected children ranged
from 13% to 33%50,55 and 12% to 16% in
HIV-exposed-uninfected children.53,54
Only 1 study commented on mean duration of ARVs in pregnancy (17.7
weeks).54
Additional exposure to maternal alcohol and drug abuse, including cocaine,
cannabis, and heroine was reported in
31 studies with a prevalence of between
9% and 67%.44,45,48,50–55,57,60–61 All these
studies were from the United States or
Europe.
HIV-INFECTED INFANTS AND
CHILDREN EXPOSED TO ARVS IN
RESOURCE-RICH SETTINGS
HIV-Infected Infants
HIV-infected infants examined using the
Bayley Scales of Infant Development
(I and II, Psychomotor Developmental
Index, and Mental Developmental Index,
mean score of 100, SD 15)75 displayed
mean neurodevelopmental scores
more than 1 SD below the population
mean. Compared with HIV-exposeduninfected infants, HIV-infected infants
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1995
1996
1999
1999
Pollack (44)
Culnane (48)
Raskino (49)
1994
Year
Chase (46)
Nozyce (45)
First Author
(Reference
No.)
US
US and
France
US
US
US
Location
Cohort
Cohort
Cohort
Cohort
Cohort
Study
Type
831
332
91
51
274
n
All HIV-infected
HIV-exposeduninfected
HIV-unexposed = 27
HIV-infected = 22
HIV-exposeduninfected = 42
HIV-infected = 24
HIV-exposeduninfected = 27
All HIV-infected
Groups
Studied
Mean age 3.8 y
2 mo–18 y
0–3 y
0-2 y
4–70 mo
3–24 mo
Age at
Entry
TABLE 1 Infants Exposed to HIV/ARVS In Utero and Early Life in Resource-Rich Settings
BSID, MSCA,
WIT
BSID
MSCA
BSID
BSID
BSID
Development
Scale
Not stated if antenatally.
Infants randomized
to receive zidovudine
or didanosine
monotherapy or
combination
zidovudine and
didanosine therapy
Not stated if antenatally.
Infants received –
zidovudine
Not stated if antenatally.
11/18 zidovudine
postnatally at mean
age of 4.5 mo.
Yes, not stated when.
ARVS not stated.
Not antenatally.
On therapy depending
on disease stage.
ARVs not stated.
Exposure to ARVs
No SDs in groups for
BSID or MSCA.
Developmental results
improved with
combination
zidovudine and
didanosine.
Yes- not stated
how many
Low birth weight
Growth, immunologic
parameters, birth
weight and gestation
Growth failure
Mean MDI and PDI
predictive of
scores comparable
neurocognitive
at birth but declined
scores.
versus controls by 12
mo if HIV-infected
(83.5 vs 112 vs 116,
P = .01). HIV-infected
10.5 times more
likely to have mean
MDI score .1 SD
lower and 4.4 times
more likely PDI mean
score ,85 (,1 SD)
below population
mean.
Not stated
Yes – not stated
Not stated
Additional
Outcome
Measures
Not stated
Early motor delay and
mental decline if HIVinfected versus HIVexposed-uninfected.
Mean scores
decelerate over time.
Variable outcomes,
even if HIV-infected.
Those with worse
disease stage at
higher risk of lower
neurodevelopmental
scores than the
population mean.
Yes – not stated
Not stated
Developmental
Outcomes
Additional In
Utero Exposure
to Drugs (Cocaine,
Heroin, Other)
Smith (50)
Chase (47)
First Author
(Reference
No.)
2000
2000
Year
TABLE 1 Continued
US
US
Location
Cohort
Cohort
Study
Type
114
595
n
All HIV-infected
HIV-infected = 114
HIV-exposeduninfected = 481
Groups
Studied
0–3 y
0–36 mo
Age at
Entry
BSID
BSID
Development
Scale
Not stated if antenatally.
All infants treated
with zidovudine.
ARVS not stated.
Yes, not stated when.
Exposure to ARVs
Yes 48%
Yes – 38.7% to 55.8%
in all mothers
Additional In
Utero Exposure
to Drugs (Cocaine,
Heroin, Other)
Additional
Outcome
Measures
Prematurity,
At 4 mo no significant
birth weighta
difference except in
mean scores. Mean
score ,1 SD from
the population mean
by 24 mo for both MDI
and PDI, P = .05. Early
HIV-1 infection was
associated with
a decline in
estimated mean
motor scores of 1
standard score point
per mo compared
with 0.28 point in the
late infected group (P
, .02). Estimated
mean mental scores
of the early-infected
group declined 0.72
point/mo, whereas
the average decline
of the late-infected
group was 0.30
point/mo (P , .13).
HIV-infected RR of .1 SD Prematurity, maternal
education assoc. with
below population
lower mean
mean for
neurocognitive
neurodevelopment:
scores
1.5 CI (1.03–2.18) P =
.034; RR .2 SDs
below population
mean for
neurodevelopment:
2.40; 95% CI: 1.27–
4.56; P = .007. RR of
PDI .1 SD below
population mean:
1.66, CI (1.12-2.45) P =
.011; RR .2 SDs
below population
mean: 3.81; 95% CI:
1.93–7.54; P = .0001.
Developmental
Outcomes
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2003
2006
Foster (64)
UK
US
Canada
Blanchette (51) 2001
Llorente (52)
Location
Year
First Author
(Reference
No.)
TABLE 1 Continued
Cohort
Cohort
Crosssectional
Study
Type
62
157
50
n
HIV-infected
All HIV infected
HIV-infected = 25
HIV-exposeduninfected = 25
Groups
Studied
7–33 mo
0–36 mo
6–37 mo
Age at
Entry
BSID, GMDI
BSID
BSID
Development
Scale
Additional In
Utero Exposure
to Drugs (Cocaine,
Heroin, Other)
Not stated if antenatally.
Category C disease: all
received ARVs; 12/31
mono/dual therapy
before HAART,
median number of
drugs =5 (range 3–
12).
Category A/B disease:
23/31 HAART, 9
received mono/dual
therapy before
HAART. Median
number of drugs = 4
(range 2–11).
Not stated if antenatally.
Either zidovudine
monotherapy, dual
therapy without
protease inhibitor or
HAART.
Not stated
38% to 63%
Not stated when.
Yes – 20% in
3 had therapy including
HIV-infected mothers
a protease inhibitor
and reverse
transcriptase
inhibitors.
Others had combination
therapy with
nucleoside analogs
only.
Exposure to ARVs
Additional
Outcome
Measures
Lower scores if low
birth weight or
premature and
increased risk of
mortality
Disease stage,
Lower verbal scores
worse stage = lower
than population
scores
mean. Children with
worse disease stage
have scores .2 SDs
below the population
mean, not improved
by HAART.
Children with worse
disease had scores
.2 SDs below the
population mean.
Increased risk of
mortality per 10point decrement in
initial MDI and PDI
scores versus
population mean,
even after adjusted
for treatment. 1.32
(CI 1.07–1.63).
Mean MDI lower in HIV- CT abnormalities –
scores worse in HIVinfected group (P ,
infected if also had
.001 [71.4 CI 62.4–
CT abnormalities.
80.4]) versus 92.3 [CI
84.5–99.9]). Mean PDI
lower in HIV-infected
group (61.9 [CI 55.3–
68.6] vs 90.9 [CI 80.1–
98.1] P , .001); HIVexposed-uninfected
normal scores in all
domains.
Developmental
Outcomes
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2008
2010
Caplo (63)
Williams (53)
US
Italy
US
US
Location
Cohort
Crosssectional
Cohort
Crosssectional
Study
Type
HIV-exposeduninfected = 39
HIV-unexposed = 24
Groups
Studied
HIV-infected = 15
HIV-exposeduninfected = 14
1840 All HIV-exposeduninfected
29
1211 HIV-infected = 152
HIV-exposeduninfected = 1059
63
n
0–2 y
2 wk–36 mo
0–2 y
18–36 mo
Age at
Entry
BSID
DDST
BSID
BSID
Development
Scale
Excluded
Yes -17%
Yes – 1694 exposed to
any ARVS antenatally.
11% to 25%
Prematurity, low
birth weight
Additional
Outcome
Measures
Not stated
MDI 94.8 vs 92.2, PDI 93.9 Infants with low
= near normal.
birth weight had
Improved MDI scores
better scores if ARV
with increased
exposed.
duration of maternal
therapy (92 for 0 wk
versus 95.9 for .26
wk exposure). MDI
scores also improved
with maternal
zidovudine and
lamivudine therapy
in second and third
trimesters.
HIV-infected infants
62.5% abnormal
scores vs 14% if HIVexposed-uninfected.
Treatment before 12
wk of age improved
scores versus those
treated later.
Low birth weight,
In pre-protease
gestational age
inhibitor era, HIVinfected lower MDI
and PDI versus HIVexposed-uninfected
by 1 y of age and
remained lower at
age 2 y. Limited
improvement in MDI
and PDI with addition
of PI-based HAART.
Percentage MDI scores
.1 SD below the
population mean
54% vs 25% P = .025;
not significant when
adjusted for
maternal substance
misuse.
Yes – 51%
HIV-exposeduninfected
versus 12% HIVunexposed
Developmental
Outcomes
Additional In
Utero Exposure
to Drugs (Cocaine,
Heroin, Other)
Yes, not stated when.
ARVS not stated.
79% antenatally. Infants
on HAART 6 protease
inhibitor
All HAART exposed: at
least 3 ARVs for at
least 1 wk during
pregnancy and
zidovudine at delivery
and postnatal period
(mean 17.7 wk of
exposure).
Exposure to ARVs
BSID, Bayley Scales of Infant Development; CI, confidence interval; MDI, Mental Developmental Index; MSCA, McCarthy Scale of Childhood Abilities; PDI, Psychomotor Developmental Index; PI, protease inhibitor; RR, relative risk; WIT, Wechsler Intelligence Tests.
a Children followed until 5 y of age.
2007
2006
Alimenti (54)
Lindsey (55)
Year
First Author
(Reference
No.)
TABLE 1 Continued
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2000
2000
2001
Fishkin (57)
Blanchette (61)
1992
Year
Bisiacchi (62)
Levenson (56)
First Author
(Reference No.)
Canada
US
Italy
US
Location
80
42
49
n
Cross- sectional 25
Cross-sectional
Cross-sectional
Cross-sectional
Study Type
Groups Studied
HIV-infected = 14
HIV-exposeduninfected = 11
HIV-infected = 40
HIV-unexposed = 40
HIV-infected = 29
HIV-exposeduninfected = 13
HIV-infected = 41
HIV-exposeduninfected = 8
TABLE 2 Children Exposed to ARVS in Resource-Rich Settings
5–12 y
Mean 9.4 y
3–5 y
6–15 y
School-age
Age at Entry
WIT
WIT
Own tests
MSCA
Development Scale
Developmental
Outcomes
Additional Outcome
Measures
Not stated
Not stated
Executive function
scores lower in
HIV-infected than
HIV-exposeduninfected;
language and
memory scores
only poorer with
worse disease.
HIV-exposed
scores normal
for age.
Yes, not stated how All neurocognitive
many
scores lower in
HIV-infected
group but not
significant, only
significant
difference
executive
function: block
design 6.08 vs
7.53 P = .002
Not stated
Yes, not stated how 44% scored .2 SDs Not stated
many
below the
population mean.
Poor verbal and
memory scores if
HIV-infected and
symptomatic.
Additional In Utero
Exposure to Drugs
(Cocaine, Heroin,
Other)
CT changes
Not stated when.
Yes – 20% in HIVNo differences in
4 children on ARVs +
associated with
infected mothers
cognition. Subtle
PI; 8 children
visuospatial and
fine and gross
ARVs without PI;
visuomotor
motor strength
Average no. of
difficulties.
differences.
drugs = 2 (range
Significant
0–4)
differences in
mean scores in
HIV-infected with
worse disease
stage.
Not stated when.
ARVs not stated
Not stated when.
ARVs not stated
Not stated when.
ARVS not stated
Exposure to ARVs
Smith (60)
Jeremy (59)
First Author
(Reference No.)
TABLE 2 Continued
2006
2005
Year
US
US
Location
Cohort
Cohort
Study Type
Groups Studied
HIV-exposeduninfected = 422
539 HIV-infected = 117
489 All HIV-infected
n
3–7 y
Mean age 6.8 y
24 mo– 17 y
Age at Entry
MSCA
WIT
BSID
Development Scale
Postnatally owing to
infection, not
stated if
antenatally.
Pre-1997:
zidovudine/
lamivudine (100),
stavudine
/ritonavir (97),
zidovudine/
lamivudine/
ritonavir (100).
Post-1997:
stavudine/
nevirapine/
ritonavir (41),
stavudine/
lamivudine/
nelfinavir (63),
stavudine/
nevirapine/
nelfinavir (44), or
the 4-drug (44)
Not stated if
antenatally.
Children treated
with:
35% monotherapy,
17% HAART, 10%
other multidrug
therapy but not
HAART.
Exposure to ARVs
Only children with Lower mean scores
associated with
the class C
viral load,
disease
primary
performed
language and
poorly. All other
maternal
scores
education.
comparable with
norms.
Yes – 41%
Additional Outcome
Measures
Motor, memory, and Low birth weight,
prematurity
language scores
.1 SD below the
population mean
at baseline.
Small
improvement in
verbal score only
with introduction
of PI-based ARVs,
no difference
between the PIcontaining
regimen.
Developmental
Outcomes
Yes, not stated
Additional In Utero
Exposure to Drugs
(Cocaine, Heroin,
Other)
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Location
Study Type
2010
Thomaidis (66)
Greece
US
Cross-sectional
Cross-sectional
All HIV-infected
Groups Studied
60
HIV-infected = 20
HIV-unexposed = 40
HIV-exposeduninfected = 134
325 HIV-infected = 206
22
n
3–18 y
Mean age
11.76 y
9–16 y
9.46 y
Median
6–17 y
Age at Entry
WIT
GMDI
PPVT;WRAT III
SON
Development Scale
All HIV-infected
treated with
HAART not stated
when treatment
started. Not
stated if
antenatal
Not stated if
antenatal
exposure.
84% of youths on
ARVS not stated
which.
18 postnatally
treated with
HAART.
Not stated
antenatally
Exposure to ARVs
Additional Outcome
Measures
33% HIV-infected
Youths on ARVS had
scored below
lower WRAT III
10th centile in
scores than those
both tests.
not taking
PPVT:HIV-infected
medication
mean score 83.9
vs 85.3;
HIV-exposeduninfected: mean
score 87.5
HIV-infected with CT Prematurity and low
birth weight
changes had
lower mean
general, practical
and IQ scores P ,
.001. HIV-infected
without CT
abnormalities had
normal cognitive
scores but
increased
emotional
symptoms and
hyperactivity P ,
.05.
Not stated
Global scores within Higher CD4% at
initiation of
the average range.
therapy and
Differences in
prolonged
executive function
therapy
noted with mean
associated with
scores .1 SD
better mean
below the
scores in pattern
population mean
recognition and
in: verbal scores,
baseline speed.
baseline speed,
pattern
recognition,
shifting set,
visuospatial
memory all P ,
.001.
Developmental
Outcomes
Not stated
Not stated
Additional In Utero
Exposure to Drugs
(Cocaine, Heroin,
Other)
BSID, Bayley Scales of Infant Development; CI, confidence interval; CT, computed tomography; GMDI, Griffiths Mental Developmental Index; MDI, Mental Developmental Index; MSCA, McCarthy Scale of Childhood Abilities; PI, protease inhibitor; PPVT, Peabody
Picture Vocabulary Test; SON, Snijers-Oomen Non-verbal WIT; Wechsler Intelligence Tests; WRAT, Wide-Ranging Ability Test.
2009
2008 Netherlands Cohort
Year
Brackis-Cott (58)
Koekkoek (65)
First Author
(Reference No.)
TABLE 2 Continued
2008
2008
2008
Van Rie (72)
Leartvanangkui
(74)
1995
Year
Smith (71)
Gay (73)
Author
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Thailand
2008
2008
Congo
South
Africa
Haiti
Location
Groups Studied
39
HIV-infected
126 HIV-infected = 28
HIV-exposeduninfected = 98
n
Cross304 HIV-infected = 25
sectional
HIV-exposeduninfected = 279
HIV-exposeduninfected = 35
HIV-unexposed=90
Cross160 HIV-infected = 35
sectional
Cohort
Cohort
Study Type
0–5 y
Mean age
43.7 mo
18–72 mo
Mean age
60 mo
0–24 mo
Age at Entry
TABLE 3 Infants and Children Exposed to HIV/ARVS in Resource-Poor Settings
DDST
BSID, PPVT,
SON
GMDI
BSID
Development
Scale
Yes, not stated when
but part of PMTCT
program
Yes, not stated
when, recruited
from HIV
treatment and
care program so
most ,1 mo of
HAART at
recruitment.
Yes – all started
HAART at
enrollment.
Stavudine,
lamivudine and
ritonavir or
efavirenz.
Not in utero, 13
infants treated
with zidovudine,
mean age at
initiation 14.6 mo
Exposure to ARVs
Additional Outcome
Measures
Gross motor and language delay Stunting and
in HIV-infected children, fine
wasting
motor and language delay in
prevalent in the
HIV-exposed-uninfected.
HIV-infected
group
Motor and cognitive lower in HIV- Stunting and
wasting higher in
infected and HIV-exposedthe HIV-infected
uninfected children (60%
group.
cognitive delay in HIV-infected
versus 40% in HIV-exposeduninfected; 28.6% motor delay
HIV-infected versus 14.3% HIVexposed-uninfected. Delay in
language expression 84.6%,
comprehension 76.7% P ,
.01. HIV-infected children
aged 18–29 mo performed
worse, 91% mental, 82%
motor delay, versus 46% and
4% in HIV-infected children
aged 30–72 mo. Children
presenting before clinically
eligible for HAART had better
cognitive/ motor scores than
those presenting with
requirement for HAART.
No
No
Mean cognitive scores were less Weight-for-height
than the norm at baseline and
at 6 mo despite 6 mo of HAART NB: 86% Xhosa first
language
(mean scores 67–78 pre-and
post-HAART commencement);
33% to 81% subnormal
intelligence quotients, 33%
abnormal motor function.
Mean MDI and PDI scores .1 SD Not stated
below the population mean if
HIV-infected at 3 mo.
Differences between groups
increased over time. 33%
normal cognitive scores, 50%
normal motor scores.
Developmental
Outcomes
No
No
Additional In Utero
Exposure to Drugs
(Cocaine, Heroin,
Other)
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11
12
LE DOARÉ et al
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2011 Zimbabwe
2010
Kandawasvika
(68)
n
HIV-exposeduninfected = 35
HIV-infected = 51
Groups Studied
Cohort
Cohort
593 HIV-infected = 16
HIV-exposeduninfected = 577
122 All HIV-infected
Cross115 HIV-infected = 92
sectional
HIV-exposeduninfected = 28
HIV-unexposed = 34
Cross86
sectional
Study Type
GMDI
BSID
BINS
,2.5 y, mean age
18.5 mo
,12 mo
BSID
Development
Scale
10–15 mo
1–33 mo
Age at Entry
Yes- single dose
nevirapine in
labor, not stated
if postnatally.
Not stated if
antenatally. 18
children
receiving HAART
Yes, not stated when
66.6% of children on
ARVs at
recruitment
39.2% antenatally.
Exposure to ARVs
No
No
No
No
Additional In Utero
Exposure to Drugs
(Cocaine, Heroin,
Other)
NB: Study in Xhosa
through
interpreter
Not stated
Additional Outcome
Measures
HIV-infected most at risk if
discovered HIV-infected
before 3 mo of age
Children on ARVs had lower
developmental scores than
the population mean.
Head
circumference
and low birth
weight
associated with
low BINS scores
Stunting and
wasting common
and associated
with poorer
developmental
scores.
Motor scores lower in HIVGeneral quotient
infected if treatment deferred
higher if treated
until clinically necessary,
with ARVs
versus those on treatment
from diagnosis.
Scores reported as
a percentages:
66.6% HIV-infected had motor
delay versus 5.7% for
controls.
Children exposed to ARVs in
utero had fewer scores .2
SDs below the population
mean than those unexposed
to ARVs in utero.
Developmental
Outcomes
BINS, Bayley Infant Developmental Screener; BSID, Bayley Scales of Infant Development; DDST, Denver Developmental Screening Tool; GMDI, Griffiths Mental Developmental Index; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index; PI,
protease inhibitor; PPVT, Peabody Picture Vocabulary Test; SON, Snijers-Oomen Non-verbal.
2009 South
Africa
2001
Potterton (70)
South
Africa
2008
Location
2009 South
Africa
2009
2009
Year
Laughton (69)
Ferguson (67)
Author
TABLE 3 Continued
REVIEW ARTICLE
demonstrated a greater proportion of
floor scores (scores 3 SD below the
population mean or less; ie, scores of
,49).
Studies that investigated the effects of
other variables known to affect neurodevelopment independent of HIV status reported that prematurity,47,52 low
birth weight,52,55 low weight-for-height
scores,44 and low maternal education46,51 were all associated with poorer
mean neurodevelopmental scores in
HIV-infected infants by the age of 12
months compared with the population
mean. In general, even when adjusting
for these variables, HIV-infected infants
demonstrated mean scores .1 SD below the population mean by the age of 12
months. Those infants with worse disease stage and higher viral loads
appeared to be at greatest risk of neurodevelopmental delay with mean
scores .2 SD from the population
mean, indicating moderate to severe
neurodevelopmental impairment.45,51,64
The prevalence of HIV-infected infants’
exposure to ARVs in utero ranged from
39.2% to 96.6%.50,55 In HIV-infected and
HIV-exposed-uninfected infants exposed
to ARVs in utero, mean mental scores
ranged from 85 to 96 and mean motor
scores from 75.0 to 96.5.50,55 Lindsey
et al55 noted that infants born to mothers treated with ARVs in pregnancy had
improved motor scores compared with
those born to mothers with no ARVs in
pregnancy. They also noted that in the
pre-protease inhibitor era, mean mental and motor scores in HIV-infected
infants ,1 year of age were significantly lower than those among HIVexposed-uninfected
infants
and
remained lower up to 2 years of age and
that these mean scores remained significantly lower than those of HIVexposed-uninfected infants even after
the introduction of a protease inhibitor.
Mean scores declined for both HIVexposed-uninfected infants and HIVinfected infants over time; however,
despite this, there was evidence of limited improvement in the HIV-infected
infants’ overall mean scores after
a protease inhibitor–based treatment
had been instigated.55
Despite the widespread use of ARVs in
pregnancy, infants with early infection
(positive result within 48 hours of life,
presumed in utero infection) had lower
mean mental and motor scores compared with children diagnosed as
infected after 48 hours (presumed
peripartum infection),50 and by 24
months, early HIV-infected infants performed significantly less well in both
mental and motor mean scores than
those infants with later infection.50
There are several limitations to conclusions that can be drawn from this
study, namely that it was conducted at
a time when maternal HAART in pregnancy was not available and initiation
of infants on early treatment was not
indicated. Evidence is emerging that
infants initiated before the age of 12
weeks have improved locomotor
scores compared with those initiated
later.62 With the recently changed
guidelines recommending early diagnosis and initiation of antiretroviral
therapy in infants,42 the impact on the
long-term development of these children remains to be documented.
LONG-SURVIVING HIV-INFECTED
CHILDREN TREATED WITH ARVS IN
RESOURCE-RICH SETTINGS
Early studies of ARV-naive HIV-infected
children .30 months of age at study
enrollment demonstrated slower disease progression and better clinical
outcomes than infants who seemed to
have a more rapidly progressive disease and died early.20,76 These studies
did not collect data on maternal ARV
treatment in pregnancy and describe
characteristics of children who had
never been treated with ARVs.
In the earliest studies of children aged 3
to 18 years treated with dual therapy,
mean global cognitive scores using the
Wechsler Intelligence Tests (mean
score 100, SD 15)77 and McCarthy
Scales of Childhood Abilities (mean
100, SD 15)78 vary from within the
normal range57,61,62 to the neurocognitive impairment range (.2 SDs
below the population mean).49,56 A
proportion of children with severe
disease56,57,62 and high viral loads56,61,62
and those who demonstrated changes,
such as cerebral atrophy on computed
tomography scan,49,61 displayed mean
neurocognitive scores ,70, indicating
moderate-severe neurocognitive impairment.
Differences between scores before and
after treatment instigation are reported by Raskino et al,49 who found that
the mean score improved by 11 to 13
points after 24 weeks of treatment with
combination zidovudine and didanosine therapy but remained in the range
of neurocognitive impairment.
Most early studies of older children
treated with any ARV indicated normal
global cognitive scores, although all
highlighted subtle significant differences in executive function, memory,
and verbal skills. It is important to note
that there was a large attrition rate
because of disease progression, as
most of these studies include children
treated at a time when children were
commenced on ARVs only in advanced
disease, with low numbers of children
followed for prolonged periods, making
generalizability of the results to today’s
situation when ARVs are commenced
early in infants and at an earlier stage
in children problematic.
Recent studies of children treated with
a HAART regimen containing a protease
inhibitor all indicated normal global
cognition mean scores.59,60,65,66 As with
earlier studies, subtle significant differences were noted in executive
function,59,65 verbal skills,58,59,65 behavior,66 and memory.59,65 This is not universal, however, and a large study by
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13
Smith et al60 reported no significant
differences in cognitive scores between groups unless the child had
symptomatic disease.
In a small case-control study from the
Netherlands (2008), Koekkoek et al65
reported higher, but still below average, global neurocognitive scores
among those children with higher CD4
percentage on initiation of HAART and
longer duration of HAART compared
with children with lower CD4 percentage and shorter duration of treatment.
Language skills were the most widely
reported deficit in children older than 3
years. Mean scores from 1 to 2 SD below
the population mean were reported
in overall language ability,56,58 word
recognition,58 receptive vocabulary,61
expressive language,58 and verbal fluency.65 Although language skills continued to develop, this appeared to be
at a slower rate than in HIV-exposeduninfected children, even taking into
account the effect of home circumstances and caregiver arrangements
and irrespective of treatment.58
Jeremy et al59 reported no improvement in overall neurocognitive score
after commencement with protease
inhibitor-based HAART, but noted improvement in verbal scores compared
with pretreatment assessment. It is of
note that a large proportion of children
were tested in a language other than
their mother tongue (range 9% to
75%).58,59,65 The effects of being
assessed in a second language or via an
interpreter on language scores have
been reported in only 1 study.60
HIV-EXPOSED-UNINFECTED
CHILDREN IN RESOURCE-RICH
SETTINGS
Few studies have evaluated the effects
of perinatal exposure to HIVand ARVs on
the neurodevelopment of children
who are HIV-exposed-uninfected. Interpretation of these results was difficult because of the heterogeneity of the
14
study populations in terms of sample
size (range 44–1694 subjects), sociodemographics, and percentage of maternal substance misuse, together with
a lack of clarity surrounding length of
maternal antiretroviral therapy in
pregnancy. Most studies do not consider results compared with a matched
control group, but rather use normative data from the standardization of
the neurodevelopmental instrument as
a comparison. The scales used are not
normed to socioeconomically disadvantaged groups; hence, it is difficult to
interpret whether the results reported
are a result of social disadvantage, HIV
exposure, or ARV exposure.
Studies in early infancy and up to the
age of 2 years have not demonstrated
any global developmental delay in HIVexposed-uninfected children once variables such as maternal substance misuse were allowed for.44,46–48,50,53–55,60,61
However, it appears that subtle deficits
in cognition, motor function, expressive and receptive language, and behavior may be present in older children
manifesting during the preschool
years (ages 3–5 years).58
DEVELOPMENTAL OUTCOMES IN
HIV-INFECTED CHILDREN IN
RESOURCE-POOR SETTINGS
The association between HIV infection
and neurodevelopmental impairment
in infants and children in resource-poor
settings is not well described. In contrast to resource-rich settings, where
prevention of mother-to-child- transmission programs are widespread and
infants are predominantly formula fed,
children in resource-poor settings are,
until very recently, less likely to have
been exposed to ARVs in utero and early
life and are still predominantly
breastfed. In ARV-naive children, neurodevelopmental deficits were reported in 6% to 40% of HIV-infected children
in resource-poor settings, depending
on disease stage.79,80
A direct comparison of studies of children exposed to HIV/ARVs in utero and
early life was limited by the use of different methodological designs and the
variety of developmental screening and
diagnostic tools used: Denver Developmental Scale Test (percentage fail
scores)81; Cognitive Adaptive Test,
Clinical Linguistics and Auditory Milestones (percentage fail scores)82; Bayley Scales of Infant Development;
McCarthy Scales of Childhood Abilities;
and Griffiths Mental Development
Scale83 (all mean 100 SD 15). In addition, comparisons were hampered by
adaptations of these tools, including
nonvalidated translation into local
language and substitution of items
with culturally appropriate alternatives.67,71 As in resource-rich settings, most studies report results
compared with normative data from
the standardization of the instrument
rather than a matched control group.
Further, the effect of ARVs on neurodevelopment is only just emerging, and
several studies had only abstracts
available, meaning an in-depth analysis
of factors that may contribute to neurodevelopmental scores could not be
fully assessed.
In comparison with resource-rich settings, a greater proportion of HIV-infected
infants in resource-poor settings had
scores ,2 SD below the mean (16% to
85% in Africa),70,72 even when adjusting for birth weight and gestational
age.73 Infants demonstrating the most
severe neurodevelopmental delay
were those diagnosed as HIV-infected
before the age of 3 months,68,72 those
with the most advanced disease,69,70
those children who were eligible for
HAART at the time of presentation,67,69,70
and those children with the lowest
weight-for-height scores.70,71
Only one study reported the effect of
prevention of mother-to-child transmission programs on neurodevelopmental outcomes. Kandawasvika et al68
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REVIEW ARTICLE
indicated that maternal treatment with
single-dose nevirapine in labor did not
influence neurodevelopmental outcomes
(adjusted odds ration of high risk of
neurodevelopmental impairment with
single-dose prophylactic nevirapine 0.9;
95% confidence interval 0.99–1.0). The
authors report that background risk of
neurodevelopmental impairment was
9.4% in both HIV-infected and HIVexposed-uninfected infants, probably
owing to survival bias in the HIV-exposeduninfected groups, as the authors speculated that HIV-infected infants with
severe disease would not have survived
to the 12-month analysis.68
As in resource-rich settings, infants
presenting at an earlier disease stage
and those commenced on antiretroviral
therapy at an earlier age demonstrated
some improvement in cognitive and
motor developmental scores once
commenced on antiretroviral therapy
as compared with than those presenting laterand with worse clinical disease
at instigation of ARVs.72
There are few studies with long-term
follow-up of children born to HIVinfected mothers, and such studies
have been hampered by high mortality
rates in HIV-infected and HIV-exposeduninfected children.70,72,74 In resourcepoor settings where new HIV treatment
guidelines recommending early ARV
initiation have not been implemented,
older children who survive early
childhood would tend to have slowly
progressing disease. Young children
who developed encephalopathy, and
those with more advanced disease
generally, would be expected to have
a shorter life expectancy.84 This selective attrition was seen in some of the
earlier studies in resource-poor settings. So the population samples
available may be children who were
less at risk for central nervous system
effects of HIV disease and therefore
function at a higher cognitive level.
Additionally, these children would have
been diagnosed as HIV-infected at
a time when early treatment was not
yet available, hindering extrapolation
to the current situation with early initiation of antiretroviral therapy and
improved survival rates.85
Despite subsequent HAART treatment,
high levels of motor delay are noted
(66.7% to 85%)67,70 and mean motor
scores remained .2 SDs below the
population mean. In common with
resource-rich settings, language delay
was also noted in older HIV-infected
children with scores remaining below
the mean despite 6 months of antiretroviral therapy.71,74 These studies
were limited by their small sample
sizes.
Few studies in resource-poor settings
reportresults forHIV-exposed-uninfected
children. Contrary to studies from United
States and Europe, these HIV-exposeduninfected children in Africa demonstrated cognitive impairment (40%),
motor impairment (14.3%), and language
expression delay compared with HIVunexposed infants.72,74 Evidence from
Thailand indicated that HIV-exposeduninfected children assessed using the
Denver Developmental Screening Test
demonstrated language deficits and fine
motor problems compared with their
HIV-unexposed peers.74 As with studies of
older HIV-infected children in this setting,
conclusions were difficult owing to the
small sample size and cross-sectional
nature of the study.
CONCLUSIONS
All studies identified HIV-infected
infants as having worse mean neurodevelopmental scores than the reference population in infancy with mean
scores consistently more than 1 SD
below the population mean, irrespective of whether they had been exposed to ARVs in utero or not. Infants
presenting with HIV infection before the
age of 3 months had the lowest scores.
Since the advent of prevention of
mother-to-child-transmission
interventions, studies have indicated variable
improvement in mean developmental
scores in HIV-infected infants exposed
to a protease inhibitor–based HAART
regimen in utero. Infants commencing
treatment before the age of 12 weeks
demonstrated better, but still subnormal, mean locomotor scores, than
those with delayed treatment. No studies have yet examined the effect of early antiretroviral therapy on cognitive
scores.
Older HIV-infected children demonstrated near normal global neurocognitive scores, probably as a result of
slower disease progression in this
group. However, there is evidence that
subtle deficits in higher cognitive
functioning (poorer memory, language
development) and behavior exist in
school-aged children with only limited
improvement after initiation of antiretroviral therapy. Evidence suggests
that the subtle differences detected in
older children in the pre-HAARTera may
be improved with more effective HAART
and that language skills may be improved with a protease inhibitor–based
ARV regimen.
The evolution of more effective antiretroviral therapy, from single therapy
to HAART, appears to have had a positive
impact on mean neurodevelopmental
scores in infants and children in the
United States and Europe who are HIVinfected and HIV-exposed-uninfected.
Lately, results appear to highlight improved outcomes for children treated
with ARVs while they are still clinically
well. There is also an indication that
commencing HAARTat an earlier stage of
disease benefits long-surviving children.
This highlights the importance of the
continuing effort to roll out the World
Health Organization recommendations42
in resource-poor settings for early and
more effective antiretroviral therapy to
all eligible pregnant women and their
infants.
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15
The extent to which HIV-exposeduninfected children are affected by in
utero exposure to HIV and ARVs remains
unclear. This group has only recently
become the focus of attention. Although preliminary studies of neurodevelopment from the United States
and Europe are reassuring, these
studies have yet to be replicated in
Africa, where most these children live.
Results of the few small studies from
sub-Saharan Africa and Asia indicate
that in contrast to normal developmental scores seen in populations
from the United States, a larger proportion of HIV-exposed-uninfected
infants and children displayed global
developmental scores 1 to 2 SDs below
the population mean, and children
appeared to show deficits in language
and behavior by the age of 5 years. There
are a number of factors that should be
considered when reviewing these
results. First, access to ARVs in
resource-poor settings in pregnancy
has only recently become widespread.
Although prevention of mother-to-childtransmission programs began to be
established in sub-Saharan Africa from
the early 2000s, UNAIDS estimated that
only 9% of eligible HIV-infected pregnant
women in resource-poor settings received ARVs in pregnancy in 2004, increasing to ∼33% in 2007.86 In addition,
in low- and middle-income countries,
47% of eligible adults now have access
to ARVs.1 So most children in studies
from resource-poor settings included
in this review will have been born to
mothers who are unwell themselves,
with higher viral loads and increased
number of associated conditions, such
as poor nutrition and concurrent illnesses. This will have had a direct effect on transmission of HIV and ability
to care for and stimulate their infants,
but also possible longer-term effects
including impaired attachment between mother and child, which affects
developmental potential, even if the
child is HIV-exposed-uninfected. Added
factors, such as poverty and early infant malnutrition and growth, also
combine to give a more complicated
picture of developmental challenges in
this environment.
tools used, lack of matched control
groups, and the need for modification
and translation into local languages
hinders synthesis and summary of data.
Robust studies that use validated neurodevelopmental assessment tools are
uncommon, and a large number of
studies were excluded from our review
because such tools were lacking. What
is needed is an internationally validated
tool that is easy to adapt culturally and
can be administered quickly by laytrained staff in everyday practice to
screen and identify developmental delay early.
Measures of cognitive, neurologic and
behavioral function serve as an indirect
means of assessing central nervous
system function, along with the more
direct measures, such as computed
tomography/magnetic resonance imaging. The variety of developmental
Interventions to reduce the rate of
mother-to-child transmission have
been successful in resource-rich settings, and the recent scale up of prevention of mother-to-child transmission
programs in resource-poor settings
looks set to do the same. Issues remain
in unraveling the long-term effect of
exposure to HIV and ARVs on HIVexposed-uninfected children and investigating speech, language, and
memory deficits in older children who
now have earlier access to therapies
that cross the blood-brain barrier. Only
a concerted, multidisciplinary approach
to diagnosing and treating developmental delay, including antiretroviral
therapy, physiotherapy, and early psychological/behavioral therapy will enable these children to reach their full
potential.
4. Newell ML, Dunn DT, Peckham CS, Semprini
AE, Pardi G. Vertical transmission of HIV-1:
maternal immune status and obstetric
factors. The European Collaborative Study.
AIDS. 1996;10(14):1675–1681
5. Brocklehurst P, French R. The association
between maternal HIV infection and perinatal outcome: a systematic review of the
literature and meta-analysis. Br J Obstet
Gynaecol. 1998;105(8):836–848
6. Habib NA, Daltveit AK, Bergsjø P, Shao J, Oneko
O, Lie RT. Maternal HIV status and pregnancy
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7. Rollins NC, Coovadia HM, Bland RM, et al.
Pregnancy outcomes in HIV-infected and
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beneficial effects of maternal antiretroviral therapy on child survival87,88
and it is probable that in addition to
improving child survival, improving
maternal health with HAART would
benefit developmental outcomes in HIVexposed-uninfected children.
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Neurodevelopment in Children Born to HIV-Infected Mothers by Infection and
Treatment Status
Kirsty Le Doaré, Ruth Bland and Marie-Louise Newell
Pediatrics; originally published online October 1, 2012;
DOI: 10.1542/peds.2012-0405
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