Health and developmental risks to ARVs in pregnancy

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Paige Williams, senior lecturer on biostatistics at Harvard TH Chan School of Public Health, who studies the health and development of children whose HIV-infected mothers took antiretroviral (ARV) drugs during pregnancy, says of her current research that it focuses on health and developmental problems that might emerge later in life, such as cognitive, hearing, and language impairments, and metabolic problems.

She says: “We found that taking combination antiretroviral drugs during pregnancy does not increase the overall risk of these adverse outcomes in babies born to mothers living with HIV. However, one commonly used drug called zidovudine (or AZT) was linked to about 70% higher risk for metabolic problems in these children. We did not anticipate finding this, since this drug has not previously been linked to metabolic problems. In contrast, many drugs in the class of ARVs known as protease inhibitors were linked to lower risk of metabolic problems in this study, even though this drug class has often been linked to higher risk of issues such as elevated cholesterol.

“We also found over four-fold higher risk of both neuro-developmental and language impairments for children whose mothers took didanosine plus stavudine during pregnancy. These particular drugs are now rarely used during pregnancy due to other safety concerns.

“In addition, while not linked to antiretroviral drug exposures, the percentage of babies with some type of health or developmental problem – about one in four – was surprisingly high. The high rates, particularly for metabolic problems and language impairment, may be partially attributable to other risk factors that are common in our study population, such as low socioeconomic status.”

Williams says: “Regarding the goals of the study, we developed a systematic approach for classifying side effects after birth in children born to mothers with HIV infection. This approach looks for ‘trigger’ events – certain adverse clinical, laboratory, developmental, or cognitive problem – to identify which children require additional follow-up. Confirming these potential adverse reactions to ARVs is costly and may require either a specialised consult or other invasive tests. The SMARTT trigger-based design means not having to conduct these types of tests on every enrolled child.

“Using this trigger-based approach, we were able to combine information across multiple domains in which ARV side effects could occur, such as poor growth, neurologic problems, neuro-developmental problems, hearing or language problems, and metabolic toxicities. This type of study design could serve as a model for other studies aiming to evaluate the safety of ARV exposures during pregnancy.”

Williams said: “Current guidelines by the World Health Organisation and other agencies now recommend that women with HIV start combination antiretroviral treatment during pregnancy, if not already receiving ARVs, and then remain on this treatment for the rest of their lives. As a result, a higher percentage of women will be expected to already be on antiretroviral drugs when they become pregnant. Globally, this will vastly increase the numbers of children with intrauterine exposure to such drugs. Overall, our study results support the safety of these recommendations, but they also suggest that continued monitoring of the safety of such exposures is a critical need for the future.

“Some of our next steps include evaluating whether the side effects observed in children in our study resolve over time, and whether new adverse outcomes emerge over time. We also need to evaluate newer ARV drugs as they are approved and become more widely used during pregnancy. Finally, given the large number of ARV drugs available, we need to conduct assessments to determine the safest combination of ARV drugs and also the safest time during pregnancy to initiate ARVs.”

Objective: To evaluate the safety of in-utero antiretroviral exposure in children born to mothers with HIV, using a trigger-based design.
Design: The Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites to evaluate safety of in-utero antiretroviral drug exposure in HIV-uninfected children born to HIV-infected mothers. Children meeting predefined clinical or laboratory thresholds have more intensive evaluations to determine whether they meet criteria for adverse events.
Methods: Adverse event “cases” were defined for the following domains: growth, hearing, language, neurology, neurodevelopment, metabolic, hematologic/clinical chemistry and blood lactate. We used adjusted log-binomial models to calculate relative risks (RR) of case status overall and within individual domains for various antiretroviral exposures during pregnancy.
Results: Among 2680 youth enrolled between 2007 and 2012 (48% female, 66% black, 33% Hispanic), 48% met a trigger and 25% were defined as a case in at least one domain. Language (13.2%) and metabolic (11.4%) cases were most common. After adjustment for birth cohort and other factors, there was no association of any antiretroviral regimen, drug class, or individual drug with meeting overall case criteria (case in any domain). Within individual domains, zidovudine (74% exposed) was associated with increased risk of metabolic case [RR = 1.69, 95%confidence interval (CI) 1.08–2.64] and didanosine plus stavudine (<1% exposed) with increased risk of both neurodevelopmental (RR = 12.40, 95%CI 5.29–29.08) and language (RR = 4.84, 95%CI 1.14–20.51) cases.
Conclusion: Our findings support current recommendations for combination antiretroviral therapy during pregnancy, although higher risk of metabolic disorder with zidovudine exposure warrants further study.

Harvard TH Chan School of Public Health material
Aids abstract

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