Each year, nearly 1 million HIV-exposed infants are born, but because of life-prolonging drugs and safe infant feeding practices, the rate of mother-to-child transmission (MTCT) is very low, such that most infants will be uninfected.1 As such, public health interest has shifted to quality of life among HIV-exposed uninfected (HEU) children.2
Compared with their uninfected peers, HIV-infected children can present a wide range of neurological impairments including visual, language, motor, and generalized cognitive deficits.3,4 By contrast, much less is known about the neurodevelopment of HEU children. Some have reported no evidence of neurodevelopmental delay,5,6 whereas others have observed lower performance scores at 1 year of age7 and small but significant reductions in neurodevelopmental outcomes.8 Most of these studies were conducted in high-income countries; with few studies about neurodevelopment conducted in low- and middle-income countries.
It has been hypothesized that antenatal HIV exposure itself (without infection) may compromise HEU children's cognitive development, for example, when maternal immune activation negatively affects the developing fetal brain9 (see Supplemental Digital Content Table 1, http://links.lww.com/QAI/B99 for review). However, there is potential for confounding by environmental factors frequently encountered in low-income settings and related to maternal HIV. These include maternal psychological (eg, depression)10, behavioral (eg, compromised caregiving),11 and socioeconomic factors. Indeed, data from low-income countries demonstrate that children born into poverty are more likely to experience impairments in cognitive development,12,13 particularly in Sub-Saharan Africa.14,15 As such, maternal caregiving factors should be studied concomitantly with the effects of HIV exposure, but only few studies have.
An additional consideration for HEU children is that prenatal and postnatal antiretroviral therapy (ART) exposure (through breastfeeding) may impact infant neurodevelopment due to the association between nucleoside reverse transcriptase inhibitors and mitochondrial toxicity.16 Although most ART regimens given to prevent MTCT have demonstrated favorable safety profiles with little evidence for serious adverse events,7,17 studies of the effects of in utero exposure to ART on neurodevelopmental outcomes of HEU children have differed in methodologies and results,5,6 such that data are inconclusive. As such, a better understanding of the impact of HIV and ART on HIV-exposed infants is needed to develop interventions that take into consideration the long-term health needs of this growing segment of the population.
Given the few studies and inconclusive evidence about neurodevelopment in HIV-exposed uninfected HEU infants, we aimed to evaluate neurodevelopment in a sample of HEU and HIV-uninfected (HU) infants <12 months in northern Uganda and assess whether maternal HIV and ART status, demographic and environmental characteristics, and infant growth were predictive of infant neurodevelopment. Specifically, we hypothesized that cognitive development would be worse in HEU infants in comparison with HU infants.
This is a secondary data analysis from the Prenatal Nutrition and Psychosocial Health Outcomes Study (PreNAPS, NCT02922829) and Postnatal Nutrition and Psychosocial Health Outcomes Study (PostNAPS, NCT02915429) conducted at the antenatal care clinic of Gulu Regional Referral Hospital (GRRH) in Gulu, northern Uganda. Together, these studies comprised a longitudinal observational cohort designed to examine the relationships between food security, psychosocial health and nutritional status during pregnancy and postpartum in post-conflict northern Uganda.
Uganda is an appropriate setting in which to evaluate the impact of HIV exposure and antiretrovirals on early infant neurodevelopment. First, the prevalence of HIV among pregnant women in Uganda is high: 7.2% among pregnant women attending antenatal clinics. Second is the widespread and increasing coverage of ART. Approximately 72% of HIV-infected mothers received ART to prevent MTCT in 2012,18 up from 13% in 2005.19
Procedures of the parent studies have been described elsewhere.20,21 Briefly, women (n = 403) were purposively sampled at the GRRH if they met the following eligibility criteria: gestational age between 10 and 26 weeks (assessed with last menstrual period), living within 30 km of GRRH, and a known HIV status. HIV-uninfected women were oversampled to obtain a ratio of 2 HIV-uninfected to 1 HIV-infected participant.22 Mothers were enrolled and followed throughout pregnancy. All PreNAPS participants who delivered after May 9, 2013, were invited to participate in PostNAPS after delivery if the pregnancy resulted in a live singleton birth, and the mother visited the study clinic within 1 week of delivery (n = 228). Dyads with at least one nonmissing assessment were included in this analysis (n = 215).
Data were collected between October 10, 2012, and January 19, 2015. All study instruments were translated by local research staff into Acholi and Langi, the 2 predominant languages. The questionnaires were then back-translated into English by the same team and discrepancies were resolved through discussion involving all the translators, the research assistants, and study staff.
Women's demographics were measured at the prenatal enrollment visit, and included age, marital status (married vs. unmarried), education, and employment. A household asset index modified from the Ugandan National Panel Survey 2009/2010 for households was derived using principal components analysis from self-report of household assets and included ownership of a home, other buildings, land, furniture, appliances, electronics, etc., where higher scores indicated greater wealth.
Maternal HIV status was determined before enrollment in PreNAPS at antenatal care clinics based on the Ugandan government's HIV counseling and testing guidelines.23 ART regimen and adherence were self-reported. All HIV-infected women were initiated on ART and sulfamethoxazole-trimethoprim (Septrin), consistent with the national policy in Uganda. HIV-infected women who were not receiving highly active ART at the first antenatal care visit were given the first-line option B+: tenofovir, lamivudine, and efavirenz (TDF/3 TC/EFV). HIV-infected women receiving highly active ART were given several options for continuing treatment: (1) Duovir-N (zidovodine, lamivudine, nevirapine [AZT/3 TC/NVP]); (2) Duomune (lamivudine, tenofovir, 3 TC/TDF) and nevirapine; and (3) Duomune and efavirenz.
Home Observation for the Measurement of the Environment (HOME) was used to assess maternal quality and quantity of stimulating and supportive interactions as a proxy of the infant developmental milieu at 12 months postpartum.24 This measure has been validated previously in Uganda.25 For this analysis, we used the Infant Toddler version, which includes 45 yes/no items. A total HOME score was generated by summing the number of “yes” responses to each item, with higher scores indicating higher quality of care. The HOME inventory was administered at participant's household when the infant was 12 months of age.
Maternal depression at 6 months postpartum was assessed using the Center for Epidemiologic Studies Depression Scale.26 The Center for Epidemiologic Studies Depression Scale is a 20-item measure assessing depressive symptomatology during the past week in the general population, with higher scores indicating greater number of depressive symptoms, and a range of 0–60. The commonly used cutoff of 16 or greater27 has been validated in this population20 and was used to differentiate probable depression from non-probable depression.
For this analysis, we used women's perceived social support (SS) assessed at 6 months postpartum using a modified 10-item Duke-UNC Functional SS instrument.28 Participants could respond “much less than I would like or never” (scored 1); “less than I would like” (2); and, “as much as I would like” (3) for each question. Scores were summed (range 10–30), such that higher scores reflect lower levels of SS; but for ease of interpretation, we inverted the individual items on the scale before administration such that high scores reflect higher levels of SS.
The Mullen Scales of Early Learning (MSEL) was used to assess infants in the developmental domains of (1) visual reception, (2) gross motor skills, (3) fine motor skills, (4) receptive, and (5) expressive language. Standardized t-scores were generated for each domain. Four scales (visual reception, fine motor, receptive language, and expressive language) are combined to yield the MSEL Composite score. The MSEL Composite score serves as a general measure of fluid intelligence believed to underlie cognitive ability in general.29 The MSEL was selected because it was designed to be more adaptable to resource-constrained settings than the Bayley scales, which need a professional psychologist to administer in a valid manner due to its complexity. The MSEL has been validated and used across multiple studies in sub-Saharan Africa.4,30,31
Infants were assessed for growth parameters; length was measured using a recumbent board and weight was assessed using an infant scale. Developmental outcomes were assessed at the study clinic at approximately 6 and 12 months of age by 2 study staff. Testers held Bachelor's degree in Psychology and Social Work and were trained by a Ugandan psychologist with expertise in infant neurocognitive assessment. All infants were breastfed and HIV-negative (HIV status was determined using DBS for Early Diagnosis).
Distributions of the characteristics of women and children, including the scores for the MSEL, the HOME scale, measures of SS and depression, and demographic factors, were summarized and compared by maternal HIV status using t- or χ2 tests. HIV exposure status was included in models as HU and HEU. Exploratory analyses to assess ART exposure used the same models with a 3-level categorical variable with levels HU, HEU with mothers reporting ART (HEU-ART), and HEU with mothers reporting ART (HEU-nART).
Linear mixed-effects (LME) models were used to analyze 2 repeated measures of child outcomes at 6 and 12 months after delivery: the MSEL Composite score and each of the 5 subscales separately (Gross Motor, Fine Motor, Expressive Language, Receptive Language, and Visual Reception). Each outcome was analyzed separately using LME approach with a common set of covariates based on our previous related research.32,33 These covariates included child sex, maternal age, education level, employment status, marital status, asset index, HIV and ART status, depression symptomatology, and SS. Child age corresponded with assessment time point, which is why age was omitted from models.
Least square (LS) or adjusted mean values with respect to the levels of this categorical variable were obtained from the LME models to reflect average differences over time among subgroups defined by HIV or ART exposure, separately. Because of potential collinearity, the effects of correlated predictors were explored by considering models with correlated variables removed one at a time.
The final models for each MSEL subscale included time of assessment, infant sex, HIV exposure, ART exposure, maternal age, socio-economic status (SES), level of education and marital status, the HOME score, postnatal SS, and depression as covariates. In an additional model, we also evaluated whether the effect of the HOME score on child outcomes differed according to maternal HIV and ART status by including the interaction term between these variables, separately.
We explored potential mediating effects of height-for-age (HAZ) on the relationship between HIV and antiretroviral exposure and child outcomes by adding HAZ as a covariate to the models described above. All statistical tests were 2-sided and P values <0.05 indicated statistical significance. All analyses were performed using SAS 9.4.
Given the available sample size for this analysis of 140 HU infants, 57 HEU-ART infants, and 18 HEU-nART infants (n = 215), and the correlation coefficient of 0.29 between 2 repeated measures of the MSEL Composite scores, we conservatively evaluated the magnitude of differences that were detectable as statistically significant with power of 0.80 or greater in two-sided tests at 0.05 level of significance. The effect sizes, expressed as Cohen's d, (ie, differences between adjusted mean values divided by the adjusted SD) were as follows: 0.35 for the comparison of HU with HEU-ART; 0.62 for the comparison of HEU-ART with HEU-nART, and 0.56 for the comparison of HU with HEU-nART. In other words, differences of the magnitude equal to the SD times d were detectable as statistically significant.
From the 215 dyads available for analyses, 140 women (65%) were HIV−, 57 (27%) were HIV+ and reported currently on ART, and 18 (8%) were HIV+ not taking ART. Overall, HIV+ women were more likely to be unmarried, less educated, and less employed when compared with the HIV− women in this sample (Table 1). There were no significant differences across the 3 groups in maternal age, SS, or HOME scores. A sensitivity analysis revealed no significant differences between dyads with complete (n = 215) and incomplete data (n = 13) comparing characteristics summarized in Table 1 (data not shown).
On average, HU children had higher mean MSEL scores than HEU children at 6 and 12 months of age for both subscales and composite scores (Table 2 and Fig. 1). Scores declined over time for both groups. HEU had lower HAZ scores at 6 and 12 months.
In LME models, HEU infants had lower Mullen Composite [LS mean = 103.10 and standard error (SE) 1.84] and Gross Motor scores (LS mean 53.31 and SE 1.39) than HU children (LS mean 107.04 and SE 1.46 and LS mean 56.72 and SE 1.11, respectively).
Table 3 shows coefficients in the LME models that reflect these differences; for example, β = −3.94 represents the difference between a mean Mullen Composite score of 107.04 and 103.10 (P = 0.03). Controlling for other explanatory variables in the model, HOME total score was associated with higher MSEL Composite (β = 0.81, SE = 0.31, P = 0.01), Receptive Language (β = 0.59, SE = 0.18, P = 0.001), and Expressive Language (β = 0.64, SE = 0.24, P = 0.01) scores. The effects of the HOME score on child outcomes did not differ by maternal HIV status. Women reporting greater postnatal SS had infants with higher Visual Reception (β = 0.25, SE = 0.11, P = 0.03) scores at 6 and 12 months.
In the exploratory analyses assessing impact of ART on neurodevelopment, HEU infants whose mothers were not receiving ART had lower Mullen Composite scores (LS mean 102.34 and SE 2.96) compared with HEU-ART infants (Fig. 1). Statistical significance was not reached (P = 0.07) due to smaller size of no ART exposure relative to other groups. HU infants had the highest Mullen Composite score LS mean, followed by HEU-ART, and HEU-nART infants having the lowest LS mean. A similar pattern was observed with Expressive Language, Receptive Language, and Visual Reception scores.
In the mediation analysis where we evaluated whether further adjustment for child height influenced observed associations, we found that child HAZ was positively associated with all MSEL subscales, including the Mullen Composite score (β = 2.22, SE = 0.72, and P = 0.01, data not in tables). With adjustment for child HAZ, the Mullen Composite score LS mean differences observed among the 2 HIV exposure status groups were attenuated. Although HU infants continued to have the highest Mullen Composite score LS mean (LSMean = 106.49 and SE = 1.45) compared with HEU infants (LSMean = 103.63 and SE = 1.82), these differences were no longer statistically significant (P = 0.11).
We assessed the neurocognitive function of HEU infants at 6 and 12 months of age born to mothers of mixed HIV and ART adherence status using the Mullen Scales of Early Learning. As we had hypothesized, HEU infants in our sample had lower scores in neurodevelopment tests than their HU counterparts across several cognitive domains. Specifically, our results and others34 (Supplemental Digital Content Table 1, http://links.lww.com/QAI/B99 for review) show that HEU children have significantly more motor and language delay than HU infants. In unrelated studies among Ugandan children, we have previously reported lower language development scores among HEU and HIV-infected samples of infants.4,25,32,35 Taken together with results from Thai and Cambodian samples reporting lower verbal intelligence quotient scores among HEU children,8 and a study in DR Congo reporting lower mean MSEL Composite score36, these findings suggest that language production is a sensitive measure of neurocognitive development in HIV-affected children.
In terms of HIV-exposed samples, children in our study presented with a similar range of neurodevelopment scores to other HEU samples of infants in Uganda.4,35 Findings presented here show that cognitive outcomes over time are lower than that seen in the United States or other high-income countries, which is why the standardized scores seem to decline over time for all groups. This is, in itself, an important finding that highlights the at-risk nature of HEU children and the need to continue to focus on identifying programs that not only provide incremental improvements to their cognitive development but also positively shift their developmental trajectories.
Our exploratory results suggest that in utero exposure to ART is not associated with altered development at 6 and 12 months of age. Given that current ART regimens include nucleoside analogues that can potentially cause mitochondrial toxicity, evaluating the impact on neurodevelopment is of relevance. Our findings are in line with previous studies of ART safety and tolerability during pregnancy7 and neurodevelopmental outcomes among HEU children.8,37 Previous studies reporting no association between HIV exposure and neurodevelopment were primarily conducted in children from high-income countries,5,6 suggesting that deficits in early infant neurodevelopment could be the result of a combination of environmental and social risk factors such as poverty, low socioeconomic status, low maternal education, and malnutrition, known or suspected to have adverse influence on developmental growth, especially in low-income settings.12 For example, Alimenti et al37 showed that the lower neurodevelopmental scores observed among HIV- and ART-exposed infants, compared with HU infants, were attenuated after accounting for maternal substance abuse.
We found a positive association between child height-for-age (HAZ) and all MSEL subscales, including the Mullen Composite score. Previous studies from Uganda38 and Tanzania39 have found that wasting and stunting were independently associated with poorer psychomotor and neurodevelopmental outcomes. Given Uganda's high prevalence of child undernutrition (estimated at 35% among children younger than 5 years)40 and the high vulnerability to poor neurodevelopmental outcomes of undernourished infants affected by HIV, wasting and stunting should be considered as markers of children who might benefit from early neurodevelopment interventions coupled with nutritional support.
The HOME measurement24 was designed to assess the quality and quantity of stimulation that a child is exposed to in their home environment as a proxy for quality of caregiving. In our sample, we observed a strong association between the HOME score and the MSEL Composite score (Table 3), such that children living in environments with more stimulation presented with a higher level of general neurocognitive development. Home environment has been associated with greater gains in cognitive and language in Italy.41 The relevance of the home environment to the developmental milieu supports previous findings from an intervention in Uganda where participation in a year-long parenting skills training program increased the quality of the home environment (HOME score) and the child MSEL Receptive Language score.32 Taken together, these results suggest that programs for HIV-affected children that are family-oriented with a strong emphasis on parent–child relationships may support optimal child development.
Women in our study reporting higher levels of SS had infants with higher MSEL scores, also as in previous studies.42,43 SS may improve self-esteem and sense of well-being by increasing available social and tangible resources.44 A qualitative study in South Africa showed that informal social networks are an important resource for coping with financial and health adversities among HIV-infected individuals.45 Collectively, these results highlight the importance of the social environment for child development and suggest that SS can be a valuable and potentially modifiable component of child-development interventions aimed toward at-risk children in low- and middle-income countries. Understanding the type of postpartum support that is most helpful to mothers may be an effective strategy to bolster early cognitive development in this context.
Results should be interpreted in light of study limitations. We recognize that in this secondary analysis, the sample size might not have been adequate to capture all potentially practically meaningful differences of approximately 1/3–1/2 of the standard deviation; however, many of the differences corresponded to larger effect sizes and were detected as statistically significant. The clinical significance of these findings remains to be determined. In addition, we relied on self-report of ART and adherence, which might have been prone to recall errors.
Despite study limitations, results presented here contribute to the limited literature on HIV- and ART-exposed children and its relation with cognitive development in the first year of life. Although findings are reassuring, examination of the effects of HIV and ART exposure on child cognitive development beyond 1 year are warranted.
The authors thank Angela Arbach, the NAPS study team (Winnifred Achoko, Harriet Achola, Geoffrey Abwola, Joe Cord, Annet Biribiwa), and most of all, the NAPS study participants.
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low-income country; child development; HIV; ART
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