By Micaela A. Witte and Philip R. Fischer, MD, DTM&H

Ms. Witte is a student at Mayo Clinic Alix School of Medicine, Rochester, MN. Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.

Ms. Witte and Dr. Fischer report no financial relationships relevant to this field of study.

SYNOPSIS: In South Africa, uninfected children exposed to human immunodeficiency virus (HIV) exhibit delays in receptive and expressive language at 24 months compared to non-HIV-exposed children.

SOURCE: Wedderburn CJ, Yeung S, Rehman AM, et al. Neurodevelopment of HIV-exposed uninfected children in South Africa: Outcomes from an observational birth cohort study. Lancet Child Adolesc Health 2019;3:803-813.

Each year, 1.4 million children are born to mothers infected with HIV. Fortunately, because of the use of antiretroviral therapy (ART), many of these children are not infected, creating an entirely new worldwide population of 14.8 million children exposed to but uninfected by HIV. Although previous research has shown that infected children born to HIV-infected mothers show signs of developmental delay, few studies have examined uninfected children exposed to HIV.

Thus, Wedderburn and colleagues studied 248 uninfected children born to HIV-infected mothers and compared them with 895 children born to HIV-uninfected mothers in South Africa to determine whether these children showed signs of developmental delay. Mothers were consented at 20-28 weeks gestation and followed throughout their pregnancies. HIV-infected mothers were treated with ART from the time of their diagnosis. After birth, the children born to HIV-infected mothers were started on ART, and all children were tested for HIV infection at six-month increments. At six months, a subset of 260 children (61 born to infected mothers and 199 born to uninfected mothers) were tested with the culturally appropriate and well-validated Bayley Scales of Infant and Toddler Development, third edition (BSID-III). At 24 months, 732 of the children (168 born to infected mothers and 564 born to uninfected mothers) were tested again with the BSID-III.

At six months, there was no significant difference between the children born to infected mothers and the children born to uninfected mothers in any of the BSID-III subscales. However, at 24 months, the children born to infected mothers showed significantly lower receptive language and expressive language sub-scores compared to the children born to uninfected mothers after adjusting for potential confounding variables (i.e., maternal age, maternal education, maternal depression, maternal tobacco exposure, gestational age, breastfeeding). Specifically, 14% of children born to infected mothers showed signs of receptive language delay compared to only 7% of children born to uninfected mothers. Similarly, 11% of children born to infected mothers displayed signs of expressive language delay compared to only 6% of children born to uninfected mothers. There were no significant differences in the cognition, gross motor, and fine motor sub-scores.

In addition, an exploratory analysis showed that children born to infected mothers with a CD4 cell count of 500 cells per μL or less had lower receptive and expressive language scores than children born to uninfected mothers. There was no significant difference in these sub-scores between children born to infected mothers with a CD4 cell count greater than 500 cells per μL and children born to uninfected mothers.

In summary, the team in South Africa found that HIV/ART exposure was predictive of receptive and expressive language delay at 24 months. This delay also was associated with an infected mother’s CD4 cell count of 500 cells per μL or less.

COMMENTARY

In 1994, Connor and colleagues found that treating HIV-infected pregnant women with ART reduced the risk of HIV transmission to their children.1 Since that time, the use of ART has expanded greatly, with 76% of HIV-infected mothers in middle- and low-income countries receiving ART in 2016. Largely because of this pronounced ART use, maternal to infant transmission of HIV has fallen to less than 5% in these countries.2

The effectiveness of ART in the prevention of HIV transmission has created a growing population of HIV-exposed, uninfected children who have yet to be truly evaluated. The work by Wedderburn and colleagues begins to uncover some of the unique characteristics of this population. Specifically, like children infected with HIV perinatally, HIV-exposed, uninfected children show deficits in language development.3 Thus, HIV infection alone may not fully explain the language delays exhibited by HIV-infected children. More importantly, there may be something about early exposure to HIV that explains this delayed development.

Wedderburn and colleagues hypothesized that this relationship between perinatal HIV exposure and language delay may be associated with maternal immunosuppression, since mothers with a CD4 cell count of 500 cells per μL or less had children with the most pronounced language delays. It is thought that this immunosuppression, or the toxicity of ART itself, may affect neurodevelopment in utero. A recent study conducted by Lauda and colleagues found that HIV-exposed, uninfected children had almost twice as many infection-related hospitalizations in the first two years of life as children not exposed to HIV. This gives added support to the notion that there are consequences to the immunosuppression experienced by these children.4

It also is possible that being raised in a family affected by HIV affects language development. A recent meta-analysis conducted by Madigan and colleagues examined the relationship between the language learning environment and language development outcomes. Results showed a strong positive association between sensitive responsiveness, or caregivers’ ability to attune to and foster child language, and language outcomes. The warmth, or the positive nature of mother-child interactions, also was associated with better language development.5

In a commentary on these findings about the effect of a child’s language learning environment, Heidi Feldman suggested that there may be three other important aspects of the language learning environment that affect language development. Specifically, she stated based on prior research that the quantity of child-directed speech, the quality of the language presented, and the nature of the interactions are extremely important for language development.6 It is through environmental components that children are able to reach their full language potential.

Caregiver illness may negatively affect the language-learning environment. In a recent study conducted by Bell and colleagues, chronic maternal illness was associated with impaired language development in both daughters and sons. Furthermore, for each year that a child was exposed to a mother’s chronic condition, the risk of language delay increased.7 There is something about having a chronically ill mother that impairs the language learning environment.

In the study conducted by Wedderburn and colleagues, the sickest mothers (i.e., the mothers with the lowest CD4 cell counts) had the children with the most pronounced language delays. It is possible that these mothers’ chronic illness impaired their ability to provide the best language-learning environment. However, the degree to which HIV, ART, and the mother-child interaction contribute to language delay is not yet clear. Future research should fully elucidate the cause-and-effect relationships between HIV exposure and language developmental delay with a focus on improving the language environment.

REFERENCES

  1. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994;331:1173-1180.
  2. Bailey H, Zash R, Rasi V, Thorne C. HIV treatment in pregnancy. Lancet HIV 2018;5:e457-e467.
  3. Brackis-Cott E, Kang E, Dolezal C, et al. The impact of perinatal HIV infection on older school-aged children’s and adolescents’ receptive language and word recognition skills. AIDS Patient Care STDs 2009;23:415-421.
  4. Labuda SM, Huo Y, Kacanek D, et al. Rates of hospitalization and infection-related hospitalization among HIV-exposed uninfected children compared to HIV-unexposed uninfected children in the United States, 2007-2016. Clin Infect Dis 2019 Aug. 22. doi: 10.1093/cid/ciz820. [Epub ahead of print].
  5. Madigan S, Prime H, Graham SA, et al. Parenting behavior and child language: A meta-analysis. Pediatrics 2019;144. doi: 10.1542/peds.2018-3556.
  6. Feldman HM. The importance of language-learning environments to child language outcomes. Pediatrics 2019;144. doi: 10.1542/peds.2019-2157.
  7. Bell MF, Bayliss DM, Glauert R, Ohan JL. Developmental vulnerabilities in children of chronically ill parents: A population-based linked data study. J Epidemiol Community Health 2019;73:393-400.