Safety of in utero and neonatal antiretroviral exposure: cognitive and academic outcomes in HIV-exposed, uninfected children 5-13 years of age

Molly L Nozyce, Yanling Huo, Paige L Williams, Suad Kapetanovic, Rohan Hazra, Sharon Nichols, Scott Hunter, Renee Smith, George R Seage 3rd, Patricia A Sirois, Pediatric HIVAIDS Cohort Study, William Shearer, Mary Paul, Norma Cooper, Lynette Harris, Murli Purswani, Emma Stuard, Anna Cintron, Ana Puga, Dia Cooley, Doyle Patton, Deyana Leon, Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter, William Borkowsky, Sandra Deygoo, Helen Rozelman, Katherine Knapp, Kim Allison, Megan Wilkins, Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera, Hermann Mendez, Ava Dennie, Susan Bewley, Russell Van Dyke, Karen Craig, Patricia Sirois, Marilyn Crain, Newana Beatty, Dan Marullo, Stephen Spector, Jean Manning, Sharon Nichols, Elizabeth McFarland, Emily Barr, Robin McEvoy, Mobeen Rathore, Kristi Stowers, Ann Usitalo, Kenneth Rich, Lourdes Richardson, Delmyra Turpin, Renee Smith, Arry Dieudonne, Linda Bettica, Susan Adubato, Gwendolyn Scott, Claudia Florez, Elizabeth Willen, Toinette Frederick, Mariam Davtyan, Maribel Mejia, Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio, Molly L Nozyce, Yanling Huo, Paige L Williams, Suad Kapetanovic, Rohan Hazra, Sharon Nichols, Scott Hunter, Renee Smith, George R Seage 3rd, Patricia A Sirois, Pediatric HIVAIDS Cohort Study, William Shearer, Mary Paul, Norma Cooper, Lynette Harris, Murli Purswani, Emma Stuard, Anna Cintron, Ana Puga, Dia Cooley, Doyle Patton, Deyana Leon, Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter, William Borkowsky, Sandra Deygoo, Helen Rozelman, Katherine Knapp, Kim Allison, Megan Wilkins, Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera, Hermann Mendez, Ava Dennie, Susan Bewley, Russell Van Dyke, Karen Craig, Patricia Sirois, Marilyn Crain, Newana Beatty, Dan Marullo, Stephen Spector, Jean Manning, Sharon Nichols, Elizabeth McFarland, Emily Barr, Robin McEvoy, Mobeen Rathore, Kristi Stowers, Ann Usitalo, Kenneth Rich, Lourdes Richardson, Delmyra Turpin, Renee Smith, Arry Dieudonne, Linda Bettica, Susan Adubato, Gwendolyn Scott, Claudia Florez, Elizabeth Willen, Toinette Frederick, Mariam Davtyan, Maribel Mejia, Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio

Abstract

Background: Long-term effects of in utero and neonatal antiretroviral (ARV) exposure on cognitive and academic development in HIV-exposed, uninfected school-age children are unknown.

Methods: HIV-exposed, uninfected children, ages 5-13 years, in Pediatric HIV/AIDS Cohort Study Surveillance Monitoring for Antiretroviral Treatment Toxicities, a US-based multisite cohort study, completed age-appropriate Wechsler intelligence and academic scales (WPPSI-III, WASI, WIAT-II-A). Associations between cognitive and academic outcomes and in utero ARV exposure by regimen, class and individual ARVs were evaluated, adjusting for potential confounders.

Results: Children completing WPPSI-IIIs (n = 350) were 49% male, 74% Black, 25% Hispanic; WASI (n = 337) and WIAT-II-A (n = 415) cohorts were similar. The percentage exposed to combination ARV (cARV) was 84% (WPPSI-III), 64% (WASI) and 67% (WIAT-II-A). Among ARV-exposed children, there were no significant associations between any ARV regimen or class and any cognitive or academic outcome. In addition, in both unadjusted models and after adjustment for caregiver IQ, sociodemographic factors and maternal health and substance use during pregnancy, no individual ARV drug was associated with significantly lower cognitive or academic scores. Factors typically associated with lower cognitive and academic scores in the general population, such as prematurity, small for gestational age, maternal alcohol use and lower maternal cognitive status, were also associated with lower scores in this study.

Conclusions: Overall, the safety of prenatal and neonatal ARV use was supported.

Conflict of interest statement

Conflicts of interest: The authors have no conflicts of interest or funding to disclose.

Figures

Figure 1. Derivation of study samples
Figure 1. Derivation of study samples
Figure 2. Unadjusted mean cognitive and academic…
Figure 2. Unadjusted mean cognitive and academic scores with 95% confidence limits

References

    1. Griner R, Williams PL, Read JS, et al. Pediatric HIV/AIDS Cohort Study In utero and postnatal exposure to antiretrovirals among HIV-exposed but uninfected children in the United States. AIDS Patient Care STDs. 2011;25(7):385–394.
    1. Heidari S, Mofenson L, Cotton MF, Marlink R, Cahn P, Katabira E. Antiretroviral drugs forpreventing mother-to-child transmission of HIV: A review of potential effects on HIV-exposed but uninfected children. J Acquir Immune Defic Syndr. 2011;57:290–296.
    1. Whitmore SK, Zhang X, Taylor A, Blair JM. Estimated number of infants born to HIV-infected women in the United States and five dependent areas, 2006. J Acquir Immune Defic Syndr. 2011;57:218–222.
    1. WHO. Mother-to-child transmission of HIV data and statistics. [Accessed January 28, 2014]; Available at: .
    1. Ivanovic J, Nicastri E, Anceschi MM, et al. Transplacental transfer of antiretroviral drugs and newborn birth weight in HIV-infected pregnant women. Current HIV Research. 2009;7:620–625.
    1. Thorne C, Newell ML. Safety of agents used to prevent mother-to-child transmission of HIV: Is there any cause for concern? Drug Saf. 2007;30:203–213.
    1. Divi RL, Leonard SL, Walker BL, et al. Erythrocebus patas monkey offspring exposed perinatally to NRTIs sustain skeletal muscle mitochondrial compromise at birth and at 1 year of age. Toxicol Sci. 2007;99:203–213.
    1. Divi RL, Einem TL, Leonard-Fletcher SL, et al. Progressive mitochondrial compromise in brains and livers of primates exposed in utero to nucleoside reverse transcriptase inhibitors (NRTIs) Toxicol Sci. 2010;118(1):191–201.
    1. Gerschenson M, Nguyen V, Ewings EL, et al. Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine. AIDS Res Hum Retroviruses. 2004;20:91–100.
    1. Poirier MC, Olivero OA, Walker DM, Walker VE. Perinatal genotoxicity and carcinogenicity of anti-retroviral nucleoside analog drug. Toxicol Appl Pharmacol. 2004;199:151–161.
    1. Calamandrei G, Valanzano A, Puopolo MY, Aloe L. Developmental exposure to the antiretroviral drug zidovudine increases brain levels of brain-derived neurotrophic factor in mice. Neurosci Lett. 2002;333:111–114.
    1. Fundaro C, Genovese O, Rendeli C, Tamburrini E, Salvaggio E. Myelomeningocele in a child with intrauterine exposure to efavirenz. AIDS. 2002;25:299–300.
    1. Rajlakshmi C, Bhattacharyya A, Trigunayat A, Pandey BL. Neurobehavioral profile of F1 and F2 generation mice following one stage zidovudine exposure through pregnancy and lactation. Annals of Neurosciences. 2008;15:69–74.
    1. Venerosi A, Valanzano A, Puopolo M, Calamandrei G. Neurobehavioral effects of prenatal exposure to AZT: a preliminary investigation with the D1 receptor agonist SKF 38393 in mice. Neurotoxicol Teratol. 2005;27:169–173.
    1. Alimenti A, Forbes JC, Oberlander TF, et al. A prospective controlled study of neurodevelopment in HIV-uninfected children exposed to combination antiretroviral drugs in pregnancy. Pediatrics. 2006;118:e1139–e1145.
    1. Culnane M, Fowler M, Lee SS, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. JAMA. 1999;281:151–157.
    1. Kammerer B, Kacanek D, Mayondi G, et al. Pediatric neurodevelopmental functioning following in utero exposure to triple-NRTI-vs PI-based ART in a randomized trial, Botswana. XIX International AIDS Conference; Washington, D.C: Jul 22-27, 2012. abstract WEPE208.
    1. Lindsey JC, Malee KM, Brouwers P, Hughes MD, PACTG 219C Study Team Neurodevelopmental functioning in HIV-infected infants and children before and after the introduction of protease inhibitor-based highly active antiretroviral therapy. Pediatrics. 2007;119:e681–693.
    1. Williams PL, Marino M, Malee K, Brogly S, Hughes MD, Mofenson LM. PACTG 219C Team. Neurodevelopment and in utero antiretroviral exposure of HIV-exposed uninfected infants. Pediatrics. 2010 Feb;125(2):e250–260.
    1. Sirois PA, Huo Y, Williams PL, et al. Pediatric HIV/AIDS Cohort Study. Safety of perinatal exposure to antiretroviral medications: Developmental outcomes in infants. Pediatr Infect Dis J. 2013;32:648–655.
    1. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet. 1999;354:1084–1089.
    1. Brogly SB, Ylitalo N, Mofenson LM, et al. In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children. AIDS. 2007;21:929–938.
    1. LeDoare K, Bland R, Newell ML. Neurodevelopment in children born to HIV-infected mothers by infection and treatment status. Pediatrics. 2012;130:e1326.
    1. Brackis-Cott E, Kang E, Dolezal C, Abrams E, Mellins CA. The impact of perinatal HIV infection on older school-aged children's and adolescents' receptive language and word recognition skills. AIDS Patient Care and STD's. 2009;23 doi: 10.1089/apc.2008.0197.
    1. Smith R, Chernoff M, Williams P, et al. Pediatric HIV/AIDS Cohort Study. Impact of HIV severity on cognitive and adaptive functioning during childhood and adolescence. Pediatr Infect Dis J. 2012;31:592–598.
    1. Ciaranello AL, Seage GR, III, Freedberg KA, Weinstein MC, Lockman S, Walensky RP. Antiretroviral drugs for preventing mother-to-child transmission of HIV in sub-Saharan Africa: Balancing efficacy and infant toxicity. AIDS. 2008;22:2359–2369.
    1. Lanphear BP, Hornung R, Khoury J, et al. Low-level environmental lead exposure and children's intellectual function: an international pooled analysis. Environ Health Perspect. 2005;113(7):894–899.
    1. Bellinger D. Very low lead exposures and children's neurodevelopment. Current Opinion in Pediatrics. 2008;20:172–177.
    1. Bradley RH, Corwyn RF. Socioeconomic status and child development. Annu Rev Psychol. 2002;53:371–399.
    1. Brooks-Gunn J, Duncan GJ. The effects of poverty on children. Future Child. 1997;7(2):55–71.
    1. Wechsler Preschool and Primary Scales of Intelligence — Third Edition. San Antonio: The Psychological Corporation; 2002.
    1. Wechsler Abbreviated Scale of Intelligence. San Antonio: The Psychological Corporation; 1999.
    1. Wechsler Individual Achievement Test—Second Edition—Abbreviated. San Antonio: The Psychological Corporation; 2001.
    1. Aidala A, Havens J, Mellins CA, et al. Development and validation of the Client Diagnostic Questionnaire (CDQ): A mental health screening tool for use in HIV/AIDS service settings. Psychol Health Med. 2004;9:362–379.
    1. Powis KM, Kitch D, Ogwu A, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis. 2011;204:506–514.
    1. Rice ML, Zeldow B, Siberry GK, et al. Pediatric HIV/AIDS Cohort Study Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants. Pediatr Infect Dis J. 2013 Oct;32(10):e406–13.
    1. Lohaugen G, Ostgard H, Martinussen M. Small for gestational age and intrauterine growth restriction decreases cognitive function in young adults. J Pediatr. 2013;163:447–453.
    1. McLoyd VC. Socioeconomic disadvantage and child development. American Psychologist. 1998;53(2):185–204.
    1. Breslau N, Chilcoat HD, Susser ES, et al. Stability and change in childrens intelligence quotient scores: a comparison of two socioeconomically disparate communities. Amer J of Epidem. 2011;154(8):711–717.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir