Pediatr Infect Dis J. 2013 Jun;32(6):648-55. doi: 10.1097/INF.0b013e318284129a.

Safety of perinatal exposure to antiretroviral medications: developmental outcomes in infants.

Sirois PA, Huo Y, Williams PL, Malee K, Garvie PA, Kammerer B, Rich K, Van Dyke RB, Nozyce ML; Pediatric HIVAIDS Cohort Study.
Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA. psirois@tulane.edu

 

Abstract

BACKGROUND: This study evaluated effects of perinatal exposure to antiretroviral (ARV) medications on neurodevelopment of HIV-exposed, uninfected infants.

METHODS: HIV-exposed, uninfected infants (age 9-15 months) enrolled in Surveillance Monitoring for Antiretroviral Therapy Toxicities, a multisite prospective surveillance study, completed the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III), assessing cognition, language, motor skills, social-emotional development and adaptive behavior. Linear regression models were used to evaluate associations between Bayley-III outcomes in infants with and without perinatal and neonatal ARV exposure, by regimen (combination ARV [cARV] versus non-cARV), type of regimen (defined by drug class) and individual ARVs (for infants with cARV exposure), adjusting for maternal and infant health and demographic covariates.

RESULTS: As of May 2010, 374 infants had valid Bayley-III evaluations. Median age at testing was 12.7 months; 49% male, 79% black and 16% Hispanic. Seventy-nine percent were exposed to regimens containing protease inhibitors (9% of protease inhibitor-containing regimens also included non-nucleoside reverse transcriptase inhibitors), 5% to regimens containing non-nucleoside reverse transcriptase inhibitors (without protease inhibitor) and 14% to regimens containing only nucleoside reverse transcriptase inhibitors. Overall, 83% were exposed to cARV. No Bayley-III outcome was significantly associated with overall exposure to cARV, ARV regimen or neonatal prophylaxis. For individual ARVs, following sensitivity analyses, the adjusted group mean on the Language domain was within age expectations but significantly lower for infants with perinatal exposure to atazanavir (P = 0.01).

CONCLUSIONS: These results support the safety of perinatal ARV use. Continued monitoring for adverse neurodevelopmental outcomes in older children is warranted, and the safety of atazanavir merits further study.

PMID: 23340561

 

SUPPLEMENT:

The use of antiretroviral (ARV) medications during pregnancy reduces transmission of human immunodeficiency virus (HIV) from mother to child but increases the number of HIV-exposed, uninfected children worldwide. Most pregnant women with HIV in the U.S. receive combination ARV (cARV) therapy. ARVs may have negative effects on infant and child health and development, and the risks for cognitive and behavior problems in ARV- and HIV-exposed children have not been firmly established. The primary objective of this analysis was to evaluate the safety of ARV exposure with respect to the development of HIV-exposed, uninfected infants during the first year of life, while controlling for factors associated with developmental delay in infants and children in the general population.

The Surveillance Monitoring for ART Toxicities (SMARTT) study, conducted by the Pediatric HIV/AIDS Cohort Study (PHACS) network, was designed to evaluate prospectively the safety of in utero and neonatal exposure to ARVs. The study cohorts included infants and children exposed to HIV in utero but not infected and a Reference group without prenatal exposure to HIV or ARVs. The Bayley Scales of Infant and Toddler Development—Third Edition (Bayley-III) (ref.1) were used to assess the development of infants between the ages of 9 and 15 months (the 1-year-old study visit). In utero and neonatal ARV exposures were analyzed by regimen, drug class, and individual ARVs.

Bayley-III domains: Cognitive, Language, Motor, Social-Emotional, and Adaptive Behavior

Definition of regimens

  • Combination ARV (cARV): any maternal regimen containing at least three ARVs from at least two drug classes
  • Neonatal prophylaxis: use of ARVs during the first eight weeks of life, dichotomized as

1. zidovudine monotherapy
2. combination prophylaxis using at least two ARVs

  • Maternal ARV regimens:

1. protease inhibitor (PI)-containing (with or without NNRTIs)
2. non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing (without PI)
3. nucleoside reverse transcriptase inhibitor (NRTI) only

Potential confounders, identified a priori

  • Infant characteristics: age at testing, sex, race, ethnicity, prematurity, birth weight, small for gestational age, and year of birth
  • Maternal health during pregnancy: age at delivery, sexually transmitted infection, use of alcohol, tobacco, or illicit drugs, first CD4% and HIV RNA plasma level (viral load) during pregnancy, and last CD4% and viral load prior to delivery
  • Maternal and caregiver characteristics: household income, education, primary language, cognition, mental health status, and use of alcohol or illicit substances at the time of infant testing

On average, the infants were within age expectations in their performance on the Bayley-III. There were no significant differences in unadjusted mean scores for any Bayley-III domain between the HIV-exposed (n = 347) and Reference (n = 49) groups. There were small but significant differences, however, in the unadjusted mean scores for the HIV-exposed infants compared to population norms for the Bayley-III (Figure 1).

For infants with HIV exposure, lower performance on all five Bayley-III domains was associated with lower maternal/caregiver cognition. Some covariates were associated with either lower or higher performance on specific Bayley-III domains. Prematurity was associated with lower performance on the Cognitive, Language, Motor, and Adaptive Behavior domains. Male sex, small for gestational age, and maternal age ≥ 35 at delivery were associated with lower Adaptive Behavior scores. Infants born in 2007 obtained higher results in all domains except Language compared to those born in 2008-2009. Maternal viral load > 400 copies/mL before delivery was associated with a higher mean score in the Social-Emotional domain, and maternal/caregiver self-reported illicit substance abuse at the time of infant testing was associated with a higher mean score in the Adaptive Behavior domain.

After adjusting for significant covariates, there were no significant differences in mean scores for any Bayley-III domain when ARV exposures were analyzed by regimen and drug class. Neonatal prophylaxis was not associated with any Bayley-III outcome. For infants with in utero cARV exposure (n = 309), individual ARVs were associated with either lower or higher performance on specific Bayley-III domains, as follows:

Lower performance: nelfinavir (Cognitive), atazanavir (Language), tenofovir (Social-Emotional), and lopinavir/ritonavir (Adaptive Behavior);

Higher performance: lopinavir/ritonavir (Language) and lamivudine (Social-Emotional).

In sensitivity analyses adjusting for prematurity and research site, there were no associations of cARV exposure or ARV regimen with any Bayley-III outcome, but the association of atazanavir exposure with lower mean scores on the Language domain remained significant.

Some of the findings were unexpected based upon what we know about infant development. Because this was a safety study, we did not correct for multiple comparisons in the analyses, and it is possible that these findings would not have been significant had we performed the corrections. On the other hand, one or more of the findings could reflect true associations. The relationship between atazanavir and language development, for example, was observed in another study from this same cohort of infants, using different assessment method (ref.2) thus making it possible that this was a true finding.

One of the strengths of this study was the inclusion of maternal/caregiver and family environmental characteristics. Factors affecting infant development in the general population were associated with infant development in this study as well. It is possible that subtle but important differences in learning, behavior, and adaptive skills might emerge as the children grow older, due in part to ongoing processes of brain development and in part to potential changes in the children’s family circumstances and availability of environmental supports and opportunities. The evolving effects of such changes might not become apparent until the children reach school age and confront greater demands for cognitive and behavioral resources.

In summary, these findings support the overall safety of ARVs currently prescribed during pregnancy and the neonatal period. Continued study of infant development is warranted as new ARVs are developed and become widely used. Additional research into the association of atazanavir with language development is also required, and prospective studies are needed to assess the effects of in utero HIV and ARV exposure on child development in older children.

Figure-for-World-Biomedical-Frontiers-7-14-2Figure 1. Unadjusted mean Bayley-III domain scores (with 95% confidence intervals) by HIV exposure status. The mean of the Bayley-III standardization sample is 100 ± 15.

 

References:

  1. Bayley N.  Bayley Scales of Infant and Toddler Development—Third Edition.  San Antonio: Harcourt Assessment Inc.; 2006.
  2. Rice ML, Zeldow B, Siberry GK, Purswani M, Malee K, Hoffman HJ, Frederick T, Buchanan A, Sirois PA, Allison SM, Williams PL; Pediatric HIVAIDS Cohort Study (PHACS).  Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants.  Pediatr Infect Dis J.  2013;32:e406-413.
Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann