Antiretroviral therapies taken by pregnant HIV-positive mothers are very effective for the prevention of mother-to-child transmission (PMTCT) of HIV [1–3]. Many nations have recently scaled up provision of antiretroviral therapy to HIV-infected pregnant women in accordance with the Millennium Development Goals  and the 2011 United Nations Political Declaration on HIV and AIDS . The 2013 World Health Organization (WHO) guidelines on PMTCT of HIV recommend combination antiretroviral therapy (cART) during pregnancy to reduce maternal viral load and prevent viral drug resistance . In countries where no acceptable, feasible, affordable, sustainable, or well tolerated alternative to breast-feeding exists, it is recommended that women continue cART during exclusive breast-feeding, regardless of CD4 cell count, until the infant is 6 months’ old. This was subsequently extended to include continued breast-feeding with the addition of complementary foods until weaning at 12 months of age . For cART in pregnancy, the US Department of Health and Human Services guidelines  recommend the use of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or one of two boosted protease inhibitor(s) At the time of this study, the preferred regimen in pregnancy was zidovudine (ZDV)/lamivudine (3TC) and lopinavir/ritonavir .
Despite the substantial benefit related to the PMTCT of HIV, exposure to cART has been associated with several undesirable pregnancy outcomes including an increased risk of premature delivery [8–11]. Published results are mixed with respect to low birth weight and still births in cART-treated pregnancies [8,11]. Perinatal exposure to ZDV has been associated with transient anemia in the neonate . A link with mitochondrial dysfunction is suggested by some but not all cohorts [13–15].
Several studies have reported developmental delay in HIV-infected infants treated with cART when compared with HIV-exposed uninfected (HEU) infants [16–18]; however, it has been difficult to clarify how much of this effect may be related to HIV infection of the brain versus a potential adverse drug effect of cart . In fact, early cART may be protective for the neurological development of HIV-infected infants .
Although a small Canadian study suggested that HEU infants exposed to perinatal cART (n = 39) had lower development scores than nonexposed infants born to mothers infected with hepatitis C virus (n = 24), this difference became nonsignificant after controlling for maternal substance use . Other studies suggest that the neurocognitive development of HEU infants is not negatively impacted by antepartum antiretroviral exposure [18,21–23], although two studies questioned the delayed development of language with in-utero Atazanavir exposure [24,25]. The impact of a combination of antepartum cART exposure followed by prolonged postpartum exposure during breast-feeding is unknown, yet the number of exposed infants is large and rising. Rapid and essential brain development occurs during the first year of life . As ZDV and 3TC (but not lopinavir/ritonavir) are well secreted into breast milk [27–29] and cross the blood-brain barrier, the impact of long-term exposure to NRTIs on the developing infant's brain is of significant concern.
To better understand the potential neurodevelopmental effects of such exposure, we conducted neurocognitive assessments on HEU infants born to HIV-infected women previously enrolled in the Aluvia Study in Lusaka, Zambia  who were treated with cART throughout pregnancy and breast-feeding, as well as on infants born to HIV-uninfected women from the same community.
Between June 2011 and August 2013, 200 children aged 15–36 months were recruited to participate in this double-cohort study of cognitive and language outcomes. All participants lived within a single district of Lusaka, which includes the neighborhoods of Chelstone, Kamanga, and Avondale. Each mother answered a baseline demographic questionnaire and their infant underwent an assessment of cognitive and language development, anthropometric measurements, and biological sampling of finger capillary blood. Cognitive and language development was assessed using the standardized Capute Scales Clinical Adaptive Test/Clinical Linguistic and Auditory Milestone Scale (CAT/CLAMS). Gestational age at birth was determined by recollection of the date of the last menstrual period, as screening ultrasounds were not generally available.
The total time required by the mother and child to perform all of the above assessments was approximately 30–60 min. A stipend to cover the cost of a meal while delayed for testing was offered to all mothers (equivalent to US$6).
HIV-exposed uninfected participants
The Aluvia Study was an open-label, single-arm trial that enrolled cART-naive, HIV seropositive pregnant women with the intent to breast-feed. Detailed inclusion and exclusion criteria for women enrolled in the Aluvia Study can be found in the supplemental materials. HEU children of women enrolled in the Aluvia Study based at Chelstone Clinic were recruited for this study. Mothers received ZDV 300 mg/3TC 150 mg twice daily and lopinavir 200 mg/ritonavir 50 mg (two tablets) twice daily, to start between 14 and 30 weeks of gestation until weaning was complete. A single dose of nevirapine (sdNVP) was given to all mothers in labor and to infants within 48 h postpartum. Infants also received ZDV liquid for 7 days postpartum. Maternal cART was continued during 6 months of exclusive breast-feeding and then 6 months of complementary feeding, with weaning between 12 and 13 months of age. Mothers remained on cART indefinitely thereafter as per WHO Option B+.
Control infants were children of HIV-seronegative mothers living in the same community as the HEU participants. Zambian child health guidelines recommend that children attend under-5 clinics monthly from birth to 5 years for vaccinations and health promotion campaigns. Asymptomatic children were recruited from the local ‘under-5’ clinics.
Inclusion and exclusion criteria
The inclusion criteria were being between 15 and 36 months for the infant, a minimum maternal age of 15 years, the ability to give informed consent, and to attend follow-up visits with the child if any abnormality was found during testing. Children were included in the HEU group if the infant was documented to be HIV-seronegative, with negative RNA PCR heel prick dried blood spot (DBS) testing. Children were included in the control group if the mother had a screening HIV test during pregnancy with a known negative result. Children were excluded from the study if they had a preexisting known major chronic illness likely to influence neurodevelopment such as congenital anomalies (chromosomal disorders, hydrocephalus, spina bifida, among others), chronic severe hematological or metabolic disorders (sickle cell disease, heart/lung/liver disease, juvenile diabetes, among others), or active tuberculosis. As well, children were excluded if they had an active acute illness (fever, pneumonia, malaria, among others), or were HIV DBS RNA PCR-positive (HEU children), or HIV-seropositive (controls).
Procedure for cognitive assessment
Given the study population's age, a measure of early childhood development was indicated, to assess early developmental skills that tend to be species specific and less impacted by environment . Cognition and language were assessed with the Capute CAT/CLAMS . The CAT measures early nonlanguage-based problem-solving abilities and the CLAMS measures early language-based problem-solving abilities and language comprehension/expression. Items require demonstration and/or parental report . The scale has been well correlated with the cognitive and language aspects of the Bayley Scales of Infant Development-2nd Edition (BSID-II) [34,35] [CAT Development Quotient (r = 0.582, P = 0.0001), CLAMS Development Quotient (r = 0.718, P = 0.0001), Full-Scale Developmental Quotient (FSDQ) (r = 0.742, P = 0.0001)]  as well as a neurodevelopmental assessment for risk of neurological complications of AIDS . The Capute Scales was also selected as the primary outcome because of the need for a transportable, time-efficient assessment that could be administered by medical students and/or allied health workers , for its established generalizability [34–36], and use in the developing world setting [37–39].
Assessors were allied health professionals or medical students with standardized training in the CAT/CLAMS in a university developmental program. All assessments were administered by a pair of assessors, to enhance standardization of administration. The child's parent(s)/caregiver(s) were permitted to be present for the assessment, which was administered and scored in a standardized fashion . A single local bilingual pediatric nurse provided verbatim translation of the assessor's instructions. Results of all assessments were then reviewed by a Developmental Behavioral Pediatrician based in a university progra. The CAT and CLAMS are scored independently resulting in a CAT Developmental Quotient and a CLAMS Development Quotient, averaged to yield the FSDQ. The Capute Scales are primarily used as an indicator of developmental delay, and a Development Quotient less than 85 is consistent with an abnormal finding indicative of mild to moderate delays in development . All infants who scored less than 85 on the FSDQ were referred for a pediatric consultation and thereafter referral to appropriate specialty services.
Procedure for biological sampling and testing
Following cognitive assessment, all children had finger prick DBS collected and stored for HIV testing. Briefly for HEU children, HIV RNA PCR testing was done using the Gen-Probe Aptima HIV RNA Qualitative Assay (Hologic Inc, Bedford, Massachusetts, USA), whereas in controls, HIV serology was done on the DBS using the Avioq HIV-1 Microelisa system (Avioq Inc, Durham, North Carolina, USA) according to the manufacturer-'s protocol.
An FSDQ less than 85 [−1 standard deviation (SD)] was the prespecified primary outcome. Detection of a difference using this approach would reflect subtle, potentially nondisabling differences in development. Covariates analyzed were maternal age (years), maternal education (>primary vs. ≤primary), family income per month (units of 100 000 kwacha), marital status (married vs. single/separated/divorced/widowed), duration of breast-feeding (weeks), infant age (months), infant birth weight (kg), and gestational age at birth (weeks).
Univariate logistic regressions of FSDQ less than 85 on all of the covariates listed above were performed, followed by a multivariable logistic regression including group (HEU vs. controls) and all variables significantly associated with FSDQ less than 85 in the univariate analyses: monthly income, maternal education, infant age, and birth weight. Significance of variables in logistic regressions was determined by a likelihood-ratio test comparing a model containing the variable vs. one with it removed. A P value less than 0.05 suggests that inclusion of the variable significantly increased the fit of the model. All analyses were carried out in R.
The logistic regression analyses were repeated for CAT Development Quotient and CLAMS Development Quotient less than 85 individually, using the same covariates in the multivariable models as for FSDQ. Given that lower birth weight may be causally linked to both the group variables (HEU children are more likely to be born preterm) and to the neurodevelopmental outcome, we also conducted sensitivity analyses that excluded birth weight in the multivariable models.
Ethical approval for the study was obtained from the research ethics board of the University of Zambia. All mothers provided informed written consent.
A total of 116 women who were enrolled in the Aluvia study were approached to participate in the cognitive assessment substudy and all consented. Among their children, 97 met the inclusion criteria. Nineteen (19) children were excluded because of incomplete testing (n = 6), not being within age requirements (n = 10), or unknowingly repeating the assessment (n = 2). A total of 172 HIV-uninfected women were approached to participate in the study. Twenty refused because of inadequate time available for their participation. Among the 152 HIV-uninfected women consented to participate in the study, four had infants who were not within age requirement and were excluded. A further 45 children were excluded postassessment when it was realized that they had received improper testing by a single assessor. None of the HEU infants were HIV RNA PCR-positive and none of the controls were HIV-seropositive. Therefore, 200 children were included in the analyses (HEU, n = 97; controls, n = 103). The maternal and child demographic information is provided in Table 1.
The CAT, CLAMS, and FSDQ scores are presented in Table 2.
Full-Scale Developmental Quotient
Eight (8.3%) HEU participants and 15 (14.6%) control infants had FSDQ scores of less than 85. In the univariate logistic regressions, lower family income [odds ratio (OR) = 0.93, 95% confidence interval (CI) = 0.82–0.99, P = 0.02], less maternal education (OR = 0.41, 95% CI = 0.16–0.99, P = 0.047), older infant age (OR = 1.08, 95% CI = 1.01–1.17, P = 0.03), and lower birth weight (OR = 0.16, 95% CI = 0.05–0.44, P < 0.001) were associated with greater odds of FSDQ less than 85, whereas Group (control/HEU) was not (OR = 1.88, 95% CI = 0.77–4.87, P = 0.16). Gestational age at birth (P = 0.10), duration of breast-feeding (P = 0.12), infant sex (P = 0.49), maternal age (P = 0.5), and marital status (P = 0.11) were not significantly associated with the odds of FSDQ less than 85. The ORs of the significant variables suggest that for every increase of 100 000 kwacha in monthly income, the odds of having FSDQ less than 85 are reduced by approximately 7%, that mothers having a secondary education or above reduce the odds of her infants having FSDQ less than 85 by about 59%, that for every month increase in infant age, the odds of having FSDQ less than 85 are increased by about 8%, and that for every increase of 1 kg in birth weight, the odds of having FSDQ less than 85 are decreased by approximately 84%. Only one HEU child and two controls scored less than 70 on the FSDQ.
In the multivariable analysis including group, income, maternal education, infant age, and birth weight, only lower birth weight (OR = 0.15, 95% CI = 0.04–0.45, P < 0.001) remained independently associated with FSDQ less than 85. Group was not significantly associated with the odds of FSDQ less than 85 (OR control/HEU = 1.07, 95% CI = 0.35–3.25, P = 0.90; Table 3). Missing data on some variables reduced the number of infants in the analysis to 185, with 19 infants having FSDQ less than 85. A sensitivity analysis with birth weight removed from the multivariable model gave qualitatively similar results with no significant difference between the groups in the odds of FSDQ less than 85 once infant age, monthly income, and maternal education were taken into account (Table S1 in supplementary material).
Clinical Adaptive Test Development Quotient
For CAT Development Quotient, lower income (OR = 0.91, 95% CI = 0.79–0.99, P = 0.014), older infant age (OR = 1.13, 95% CI = 1.05–1.23, P = 0.001), and lower infant birth weight (OR = 0.20, 95% CI = 0.07–0.54, P = 0.001) were significantly univariately associated with greater odds of scoring less than 85. Group was not significantly associated with the odds of scoring less than 85 (OR controls/HEU = 1.04, 95% CI = 0.42–2.62, P = 0.93). After including income, maternal education, infant age, infant birth weight, and group (as for the FSDQ) in a multivariable logistic regression, older infant age (OR = 1.17, 95% CI = 1.05–1.31, P = 0.003) and lower birth weight (OR = 0.16, 95% CI = 0.04–0.56, P = 0.004) remained significantly associated with the odds of scoring less than 85. Group (OR control/HEU = 0.31, 95% CI = 0.08–1.06, P = 0.06) was not significantly associated with the odds of scoring less than 85 in the multivariable model, although a trend may be present. A sensitivity analysis with birth weight removed gave qualitatively similar results with no significant difference in CAT Development Quotient less than 85 between the groups (P = 0.07, Table S1).
Clinical Linguistic and Auditory Milestone Scale Development Quotient
For CLAMS Development Quotient, lower income (OR = 0.88, 95% CI = 0.77–0.96, P < 0.001), less maternal education (OR = 0.39, 95% CI = 0.16–0.87, P = 0.02), lower infant birth weight (OR = 0.27, 95% CI = 0.10–0.64, P = 0.002), and Group (OR Control/HEU = 2.33, 95% CI = 1.03–5.65, P = 0.04) were significantly univariately associated with the odds of scoring less than 85.
After including the income, maternal education, infant age, and birth weight in a multivariable logistic regression, lower income (OR = 0.91, 95% CI = 0.80–0.99, P = 0.046) and lower birth weight (OR = 0.29, 95% CI = 0.11–0.73, P = 0.008) remained significantly associated with CLAMS Development Quotient less than 85. Group (OR control/HEU = 1.90, 95% CI = 0.75–5.03) had a nonsignificant P value of 0.18. Again, a sensitivity analysis with birth weight removed gave qualitatively similar results with no significant difference in CLAMS Development Quotient less than 85 between the groups (P = 0.20) and monthly income retaining significance (Table S1).
This study is the first to assess the cognitive and language outcomes in HEU infants exposed to both antenatal and 1 year of postnatal cART exposures as per the new WHO guidelines. Our study did not support the presence of increased cognitive or language delay for HEU children compared with uninfected unexposed controls from the same community. This is reassuring, especially in light of the long exposure and the fact that ZDV and 3TC are well secreted in breast milk . This finding is important in terms of the uptake of cART regimens around the world, as countries are increasing cART provision. For example, Zambia has reached its target goal of providing 90% of HIV-infected pregnant women with antiretroviral medications . With this increased cART coverage to pregnant women throughout pregnancy and longer infant exposure to antiretrovirals through breast-feeding, an unprecedented number of children are being exposed to long-term cART. Thus, it is important to follow-up on the development of these children.
Analyses of our data showed that lower birth weight was significantly associated with an FSDQ score less than 85, after controlling for other important variables, a score that is indicative of developmental delay. Additionally, lower income, less maternal education, and lower birth weight were significantly associated with a CLAMS Development Quotient less than 85, which is indicative of a language delay, and lower birth weight and older infant age were associated with a CAT Development Quotient less than 85, which is indicative of a cognitive delay. The association between older infant age and CAT Development Quotient scores less than 85 could reflect a limitation of the assessment tool, which may have reduced sensitivity for developmental delay at lower ages. It is also possible that as children get older, deficits are apparent in more complex skills that are not seen in earlier stages of development . These possibilities imply that longer-term follow-up studies of older children may be required to assess whether deficits emerge with further development in HEU children.
Lower income was also significantly associated with lower language score, something expected based on current child development literature [42–44], and presumably related to the possibility that lower-income families have lower literacy levels and provide less language stimulation. Another possible explanation is that families of lower income in Lusaka were less likely to speak English, and therefore children may have had less reliable scores because of difficulties in translation or other examiner miscommunication.
Finally, lower birth weight was also associated with an increased risk of scoring less than 85 on CAT Development Quotient, CLAMS Development Quotient, and FSDQ, as could be expected based on literature of low-birth-weight children [45–47]. Despite the fact that our HEU group had lower birth weight, this did not translate into significantly lower development scores in that group.
A limitation to the study was that there was more than one assessor in the study, potentially introducing inter-rater variability. The use of a standardized assessment administered in pairs with oversight by a Developmental Pediatrician mitigates this risk. The forty-five control infants were excluded because of an error in testing by a single assessor, following an attempt to include local staff. There was no evidence of significant variation in scores by assessor once this single assessor was removed.
A further limitation was the choice of the Capute Scales itself. As a screening tool, it does not have the ability or the depth to diagnose specific cognitive or language delays in children. However, given the limited resource setting in which the study was conducted, the lack of a validated local measure, and the correlation to the BSID II [34–36], this assessment proved the most feasible. Furthermore, measurement of skills at this age tends to reflect species-specific skills that are basic and less influenced by cultural exposures. Indeed, the CAPUTE has been useful in other developing world studies [37–39]. The control infant scores were generally similar to those of US infants wherein the tools were developed , which suggests that this is a useful test in this context. This approach to tool assessment has also recently been used in other African contexts . The choice of a score cutoff of less than 85 (1 SD) as outcome was a conservative choice, as this would reflect only mild to moderate delays. Detection of a difference using this approach would reflect subtle, potentially nondisabling differences in development.
Owing to the limited sample size and therefore wide CIs, this study cannot rule out the possibility of an increased relative risk of delay in the HEU group particularly related to nonverbal skills. Future assessment of the population at an older age with functional and culturally sensitive measures is indicated.
Our study did not support the presence of an adverse effect on cognitive or language development with prolonged antepartum and postpartum cART exposure. Larger studies and studies of older HEU children will be required to confirm these findings.
We would like to thank Malembe Mumba, for contributing to this project by performing several neurocognitive assessments, and Barry Picov for coordinating Aluvia study support. We would also like to thank the mothers and infants of the Chelstone clinic who participated in this project.
Funding: This study was partially supported by Abbvie, Rotary International, The Stephen Lewis Foundation, The Mount Sinai Foundation, ViiV, and The University of Toronto CREMS program for the Aluvia study; and by the Canadian Institutes for Health Research (Team grant in Cellular Aging and HIV comorbidities in Women and Children TCO-125269 to HCFC and MSS).
Conflicts of interest
There are no conflicts of interest.
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