Pre-term births and developmental problems in children
born to mothers with HIV are associated with HIV infection, substance use and smoking, Canadian researchers have reported in the journal AIDS. They could not
find a significant relationship with antiretroviral drug exposure.

Some studies have reported higher rates of pre-term
births in mothers living with HIV, and a recently published systematic review
found that in lower- and middle-income countries, exposure to some
antiretroviral regimens in the first trimester of pregnancy was associated with
pre-term birth.

Concerns have also been raised about the risk that
exposure to antiretroviral drugs during pregnancy could lead to
neurodevelopmental problems in children born without HIV.

However, these potential associations are complicated
by the fact that women living with HIV may have higher rates of substance use
and smoking than the general population, in some settings. As these factors are
also associated with pre-term birth and neurodevelopmental problems, any
analysis of the link between HIV, antiretroviral drug exposure and child
development needs to take them into account. Rates of substance use may be higher in some high-income countries compared to lower-income settings, complicating the interpretation of findings from studies conducted in different parts of the world.

Researchers from the University of British Columbia
investigated the relationship between antiretroviral drug exposure, maternal
substance use and socioeconomic factors, and child development in a
retrospective controlled cohort study using provincial databases.

They compared 446 infants born to mothers living with
HIV (exposed but uninfected infants) to 1323 infants born to HIV-negative
mothers, matched for age, infant sex and postal code.

As well as examining the prevalence
of pre-term birth, the researchers also looked at the prevalence of the
following neurodevelopmental disorders in children born between 1990 and 2012:
autism, disturbance of emotions, hyperkinetic syndrome, developmental delay,
intellectual disability and epilepsy.

Maternal drug use was documented
for the period 2000-2012, but not for the first decade of the study.

In the entire sample, 30.0% of
HIV-exposed children and 13.4% of the control group had at least one diagnosed
neurodevelopmental disorder. Univariate analysis of this sample showed that HIV-exposed
children were more than two and a half times more likely to have at least one
neurodevelopmental disorder (odds ratio 2.78, 95% CI 2.14-3.61, p 0.0001).

HIV-exposed children were
approximately three times more likely to have been diagnosed with at least one
of autism, disturbance of emotions, hyperkinetic syndrome or developmental
delay, but there was no significant difference between exposed and unexposed
children in their risk of being diagnosed with intellectual disability or
epilepsy.

An analysis restricted to children
of mothers with complete substance use data (births in the period 2000-2012, 309
exposed and 917 unexposed infants) found a higher prevalence of exposure to
smoking (34.6% vs 8.5%), alcohol use (8.4% vs 1.3%) and drug use (35.9% vs 2.6%) during pregnancy in infants exposed to HIV.

Multivariate
analysis found that the risk of a neurodevelopmental diagnosis was increased in
children exposed to HIV (OR 1.67, 95% CI 1.12-2.48,
p = 0.011), but the risk was greater for children aged six years and over (OR
4.47, 95% CI 3.03-6.59 p 0.0001) and boys (OR 1.98, 95% CI 1.41-2.77,
p 0.0001). Amongst all infants, either substance use or smoking increased the risk of a neurodevelopmental disorder (OR 1.75, 95% CI 1.34-2.27, p 0.0001).

Preterm birth is known to be a predictor of some neurodevelopmental disorders. After adjusting for maternal
substance use and smoking, children exposed to HIV who were born prematurely
were around two and a half times more likely to have a neurodevelopmental
diagnosis (OR 2.66, 95% CI 1.73-4.08; p 0.0001).

Eighty-three per cent of
HIV-exposed children had also been exposed to antiretroviral drugs. Univariate
analysis showed a higher risk of neurodevelopmental disorder in HIV-exposed
children who were not exposed to antiretroviral drugs (OR=2.04; 95% CI:1.23-3.40;
p0.01) compared to those who were. When exposure was stratified
according to drug class and compared to HIV-unexposed children, analysis showed
an elevated risk of neurodevelopmental disorder after exposure to any
antiretroviral regimen, except for regimens based on boosted protease inhibitors.

However, after controlling for
maternal substance use, the association between ARV exposure and
neurodevelopmental disorder disappeared, with the exception that exposure to regimens based on boosted protease inhibitors was found to be protective if substance use
had been recorded during pregnancy (OR= 0.146; 95% CI: 0.04-0.57; p=0.006).

The study authors caution that the
shorter follow-up time for children exposed to boosted protease inhibitors
(introduced in British Columbia for pregnant women in 2007) makes it difficult
to draw definitive conclusions about antiretroviral drugs and
neurodevelopmental outcomes.

“Although the contribution of the
long-term effects of in utero exposures to substances such as
cigarettes, alcohol, and illicit drugs have been unclear in some studies of HEU [HIV-exposed uninfected] neurodevelopment, we have shown that most of these exposures are risk factors
for ND [neurodevelopmental disorders] diagnosis in our study population.”

But the authors say that substance
use, antiretroviral drugs and pre-term birth do not entirely explain the high
rate of neurodevelopmental disorders in children of mothers living with HIV in
British Columbia, and that maternal health, adverse childhood experiences and
other environmental factors may be important influences.

“Our findings furthermore support
the importance of holistic support systems for pregnant women, access to care and treatment
for substance use, to reduce risks of preterm delivery. Our observations
support the need for developmental follow-up and early intervention for HEU
children, notably for males, those born preterm, and those exposed to harmful
substances.”