Globally, over half of all adults living with HIV (LWH) are women, giving birth annually to over 1.4 million children ; a majority of whom are HIV-exposed but uninfected (HEU).
Antiretroviral treatment for prevention of vertical transmission of HIV began in 1994, with zidovudine monotherapy during pregnancy  and has evolved from single drug class regimens, to combination antiretroviral therapy (cART). Over 97% of mothers LWH in Canada had received cART during pregnancy in 2014 , whereas guidelines for HIV-exposed infants recommended 6 weeks of prophylaxis after birth . Recent guidelines for pregnant women LWH indicate all women receive lifelong cART [4,5]. With access to at least 4 weeks of cART prior to delivery, and without breastfeeding, less than 1% of infants born to women LWH acquire HIV in Canada .
Many antiretroviral drugs affect human DNA and have been associated with various adverse effects [6–8], whereas concerns remain that prenatal antiretroviral exposure could impair infant development. HEU studies, however, require careful consideration of sociodemographic and maternal risk factors which likely influence infant developmental health and are often prevalent among families affected by HIV.
In addition, preterm birth, low socioeconomic status, and prenatal exposure to opiates are known predictors of poorer cognitive outcomes in children [9–12]. A 2006 study of cART-exposed HEUs aged 18–36 months reported similar development and adaptive behavior scores to controls but only after adjusting for maternal substance use, confirming the influence of this exposure . Few studies investigating neurodevelopmental outcomes among HEUs in high-income settings have accounted for such factors. The Pediatric HIV/AIDS Cohort Study reported lower cognitive and academic achievement scores among HEU youth in the United States compared with population norm means after adjusting for demographic covariates; however, the study lacked in-utero exposures data and demographically matched HIV-unexposed controls . A Canadian study raised the possibility of negative effects on HEU neurodevelopment but did not observe an association with maternal substance use . Our retrospective pilot study of HEU children in British Columbia showed concerning prevalences of autism, behavioral problems, and developmental delay . However, studies in resource-limited settings, in which maternal substance use may be less prevalent, saw no difference in developmental outcomes between HEUs and HIV-unexposed uninfected (HUUs) [17,18]. Taken together, these findings reflect environmental and maternal risk factors may influence and confound studies on HEU development.
Fetal genotoxicity, mitochondrial toxicity, lower infant birthweight and length, developmental delay, in addition to heart and neurological defects have been reported in children with prenatal antiretroviral exposure [19–22]. Several studies in both high-income and resource-limited settings have suggested a relationship between antiretroviral regimens and preterm birth [21,23–26], an outcome that is associated with a spectrum of neurological disorders [27–29]. Maternal substance use involving alcohol, tobacco, and cocaine is also documented as a risk factor toward preterm birth [30,31].
Long-term effects of perinatal exposure to antiretroviral drugs and a maternal HIV ‘milieu’ are largely unknown. Longitudinal studies in children exposed to HIV/antiretrovirals are confounded by factors disproportionately affecting families LWH, and often lack scope, statistical power, and/or length of follow-up past infancy.
The current study utilizes retrospective analysis from a controlled cohort of HEU children born in British Columbia, Canada, to capture long-term neurodevelopmental outcomes as diagnoses of neurodevelopmental disorders relative to HUU children. We hypothesize HEUs will have increased odds of neurodevelopmental disorders compared with HUU children. Possible associations between maternal substance use and antiretroviral exposures (type and duration) and these disorders were also investigated.
Retrospective controlled cohort study from provincial database sources
Retrospective analysis was conducted on HEU children born in British Columbia between 1 January 1990 and 31 December 2012, who had personal health numbers on record. Data were additionally collected for HUU children matched 3 : 1 (∼99%) for each HEU child on age, sex, and geocode (first three-digit postal code of the mother's address at time of child's birth).
From Population Data BC, datasets were obtained from the British Columbia Ministry of Health (Medical Services Plan) , Perinatal Services BC , British Columbia Vital Statistics Agency [34,35], and medical chart information from The Oak Tree Clinic, BC Women's Hospital, Vancouver, British Columbia . From these sources, datasets were merged to create three statistical models. Neurodevelopmental disorders in our study are broadly defined as a group of chronic, interrelated, co-occurring disorders manifesting in early childhood in which development of the central nervous system is disturbed . Six neurodevelopmental disorders commonly diagnosed in childhood and adolescence were investigated: autism, disturbance of emotions, hyperkinetic syndrome, developmental delay, intellectual disability, and epilepsy. Diagnoses were classified according to the International Statistical Classification of Diseases 9th Revision codes . ‘Any neurodevelopmental disorder’ diagnosis was classified as a binary outcome (≥1 diagnosis or none).
From 1 April 2000 until 31 March 2008, maternal drug use during pregnancy is defined as documentation by a healthcare provider of prescription, nonprescription, or illicit drug use by the mother as a risk factor in their pregnancy. From 1 April 2008 until 31 December 2012, maternal drug use is defined as maternal use of any of the following: heroin/opioids, cocaine, methadone, solvents, or marijuana at any point during pregnancy in addition to prescription, ‘other’, or unknown drugs as a risk to the pregnancy.
For multivariable models, age at follow-up was defined as above or below the median age of children on 31 December 2012, when data were obtained.
HEUs in this dataset were analyzed based on predominant maternal antiretroviral regimen exposure: (0) none; (1) nucleoside reverse transcriptase inhibitors (NRTIs) only; (2) NRTIs + non-NRTI (NNRTI); (3) NRTIs + protease inhibitor (unboosted); (4) NRTIs + protease inhibitor (boosted with ritonavir). Among HEUs for whom treatment duration was known, those with no in-utero antiretroviral exposure were compared with HEUs with any maternal antiretroviral exposure (irrespective of class type), stratified by exposure duration: none, more than 0–13, more than 13–26, or more than 26 weeks. Antiretroviral regimens interrupted or changed during pregnancy were combined to give total exposure.
Associations were measured using odds ratios (ORs) of neurodevelopmental disorder (ND) diagnosis between HEUs and HUUs. Crude and adjusted ORs were calculated using the Mantel–Haenszel method. Adjusted ORs presented were obtained from multivariable logistic regression. Significance from Pearson chi-squared tests was achieved when P < 0.05. Likelihood ratio tests (LRTs) determined which variables were included in the multivariable model (P < 0.1). Interactions were measured using Pearson chi-squared tests for homogeneity and LRTs (P < 0.1). Univariate comparisons between antiretroviral (regimen types) and neurodevelopmental disorder were presented as crude ORs of any neurodevelopmental disorder diagnosis. Univariate analysis of neurodevelopmental disorder diagnoses by treatment durations among HEUs are presented as proportions (%) of any neurodevelopmental disorder diagnosis. Statistical analysis was performed using STATA IC 13 (StataCorp. 2013, College Station, Texas, USA).
HIV-exposed uninfected: higher odds of neurodevelopmental disorders in crude and multivariable analysis
Medical services plan history, vital statistics, and perinatal information were available for 446 of 451 recorded HEU births in British Columbia during the study period. Three statistical models were created to investigate neurodevelopmental disorder diagnoses in HEUs from three perspectives: Model 1: All HEUs on record born in British Columbia between 1990 and 2012 (univariate); Model 2: HEUs with complete vital statistics data, that is, maternal and gestational age, lacking maternal substance use data (multivariable); and Model 3: HEUs born from 1 April 2000 to 31 December 2012 to account for maternal substance use records (multivariable). A total of 446 HEU children and 1323 HUU children were included in Model 1 (Table 1). In this univariate model including all children, 134 (30.0%) of HEUs had at least one neurodevelopmental disorder diagnosis during the study period compared with 177 (13.4%) in the HUU controls, corresponding to a nearly three fold increase in odds [OR = 2.78; 95% confidence interval (CI): 2.14–3.61; P < 0.0001]. Compared with HUUs, HEUs had increased odds of having at least one of the following diagnoses: autism (OR = 3.01; 95% CI: 1.18–7.63; P = 0.02), disturbance of emotions (OR = 2.93; 95% CI: 1.87–4.59; P < 0.001), hyperkinetic syndrome (OR = 3.30; 95% CI: 2.27–4.77; P < 0.0001), and developmental delay (OR = 3.53; 95% CI: 2.51–4.97; P < 0.0001) but not of having diagnoses of intellectual disability (OR = 0.99; 95% CI: 0.2–4.92; P = 0.99) or epilepsy (OR = 5.94; 95% CI: 3.46–10.22; P = 0.076). Despite concerns that HEUs may have more chronic morbidities, HEUs were not at increased odds of having diagnoses of asthma (OR = 1.02; 95% CI: 0.78–1.32; P = 0.90) or any neoplasms (OR = 0.66; 95% CI: 0.43–1.01; P = 0.06); these diagnoses were selected a priori. Fewer than six deaths were reported within each cohort.
In the second model, a total of 411 HEUs and 1224 HUUs were analyzed (Table 2). After adjusting for age at follow-up and sex, the odds of any neurodevelopmental disorder remained higher in HEUs compared with HUUs (OR = 2.78; 95% CI: 2.11–3.65; P < 0.0001). Odds of any neurodevelopmental disorder were greater in children with more than 11 years of age at follow-up compared with those 11 or less of age (OR = 2.18; 95% CI: 1.66–2.87; P < 0.0001) after adjusting for HIV exposure status and sex. Odds of neurodevelopmental disorder diagnosis were also independently higher in males compared with females (OR = 1.76; 95% CI: 1.35–2.30; P < 0.0001).
To account for prenatal exposures to maternal substance use, a separate analysis was conducted on 309 HEUs and 917 HUUs born between 1 April 2000 and 31 December 2012 (Table 3). Compared with HUUs, a significantly higher proportion of HEUs were exposed in utero to maternal smoking (HEUs: N = 107, 34.6%; HUUs: N = 78, 8.5%; P < 0.0001), alcohol use identified as a risk to the pregnancy (HEUs: N = 26, 8.4%; HUUs: N = 12, 1.3%; P < 0.0001), and drug/substance use (HEUs: N = 111, 35.9%; HUUs: N = 24, 2.6%; P < 0.0001). Smoking and drug/substance use were collinear and combined into one trichotomized variable. The OR for this variable is presented as a summary estimate of levels 1 and 2 [i.e. (1) Either smoking or drug/substance use; or (2) both smoking and drug/substance use at any point during the pregnancy] compared with (0) Neither smoking or drug/substance use. A homogeneity test of ORs for this estimate indicated no difference between the strata (P > 0.2).
Table 3 presents ORs of any neurodevelopmental disorder diagnosis after adjusting for age at follow-up, sex, and exposure to maternal drug/substance use and/or smoking. HEUs showed higher odds of having at least one neurodevelopmental disorder diagnosis relative to HUUs, although the odds were reduced relative to the previous model (OR = 1.67; 95% CI: 1.12–2.48; P = 0.011). The adjusted odds of any neurodevelopmental disorders were higher for those at least 6 years of age (OR = 4.47; 95% CI: 3.03–6.59; P < 0.0001), males (OR = 1.98; 95% CI: 1.41–2.77; P < 0.0001), and for children exposed to drugs/substances and/or smoking during pregnancy (OR = 1.75; 95% CI: 1.34–2.27; P < 0.0001). There was no evidence for interactions (LRT P > 0.1) in any covariates investigated.
Demographic and perinatal characteristics of HEU and HUU children are given in Supplemental Digital Content 1, https://links.lww.com/QAD/B348. Crude and adjusted ORs for each covariate are presented in Supplemental Digital Content 2, https://links.lww.com/QAD/B348.
Role of preterm birth in neurodevelopment
Preterm birth lies on the ‘causal pathway’ for some neurodevelopmental disorders directly influencing multivariable analysis if adjusted for, as it is an important predictor and may act as a mediator for other influences on neurodevelopment. This covariate was therefore considered in a separate analysis to explore its influence on neurodevelopmental disorder diagnosis. HEUs in Models 2 and 3 had a nearly three-fold increased odds of preterm birth (<37 weeks gestational age) compared with HUUs (P < 0.0001 in both analyses), and the association was attenuated after adjusting for maternal substance use and/or smoking (Model 3: OR = 2.66; 95% CI: 1.73–4.08; P < 0.0001). Unsurprisingly, preterm birth was independently associated with higher odds of neurodevelopmental disorder diagnosis in both multivariable models (Model 2: OR = 2.49; 95% CI: 1.72–3.61; P < 0.0001; Model 3: OR = 2.95; 95% CI: 1.87–4.63; P < 0.0001).
Increased odds for neurodevelopmental disorder diagnosis in HEUs were attenuated after adjusting for age at follow-up, sex, and preterm birth (OR = 1.87; 95% CI: 1.31–2.67; P = 0.001). Similar results were observed in additional analysis; after including preterm birth in addition to age at follow-up, sex, and maternal drug/substance use and/or smoking, this association was further reduced and no longer statistically significant (OR = 1.49; 95% CI: 0.99–2.24; P = 0.055). This alteration of effects reflects preterm birth as an important mediator of adverse neurodevelopment for both cohorts – particularly in HEUs.
Antiretrovirals and neurodevelopmental disorder odds
Antiretroviral regimens for pregnant women LWH have evolved over the study period: from no treatment, to mono/dual therapy treatment with NRTIs only, and eventually to cART (beginning in 1997) with regimens involving a minimum of two different drug classes. HEUs in our cohort have therefore been exposed to different regimens, for different durations, depending on year of birth, affecting length of follow-up time, and likelihood of neurodevelopmental disorder diagnosis as illustrated in Supplemental Digital Content 3, https://links.lww.com/QAD/B348. Age at follow-up and regimen type were therefore collinear, limiting multivariable analysis.
The vast majority of HEUs (370/446) had any in-utero antiretroviral exposure compared with only 76 HEUs who had none. Of the 370 antiretroviral-exposed, 101 (27.3%) had at least one neurodevelopmental disorder diagnosis, compared with 33 (43.4%) in those unexposed. HEUs with no prenatal antiretroviral exposure thus had a two-fold increase in odds of neurodevelopmental disorder diagnosis compared with those who did have any exposure (OR = 2.04; 95% CI: 1.23–3.40; P < 0.01) in univariate analysis (Table 4).
HEUs (N = 441) were analyzed for frequency of neurodevelopmental disorder diagnosis stratified by predominant in-utero antiretroviral regimen exposure. Neurodevelopmental disorder frequencies were then compared with those in their respective matched HUUs (total HUU; N = 1306), for each antiretroviral exposure type as illustrated in Table 4. HEUs exposed to other types of regimens were excluded (N < 6). HUU controls served as references in each OR, to ensure equal follow-up and neurodevelopmental disorder diagnosis likelihood. Odds of any neurodevelopmental disorder diagnosis were higher for HEUs with no antiretroviral exposure compared with their matched HUUs (OR = 3.38; 95% CI: 1.92–5.96; P < 0.0001), NRTIs only (OR = 4.88; 95% CI: 2.45–9.76; P < 0.0001), NRTIs + NNRTI (OR = 2.46; 95% CI: 1.33–4.55; P < 0.004), NRTIs + protease inhibitor (unboosted) (OR = 2.73; 95% CI: 1.74–4.29; P < 0.0001), but not for those exposed predominately to the NRTIs + protease inhibitor (boosted) regimen (OR = 1.83; 95% CI: 0.79–4.22; P = 0.16). The children in this last comparison had shorter follow-up time than the other classes (as this regimen was not extensively utilized until 2007, Supplemental Digital Content 3a, https://links.lww.com/QAD/B348) likely underestimating diagnoses frequencies.
A multivariable analysis was conducted for HEUs only born after 1 April 2000 (N = 306) with less neurodevelopmental disorder diagnoses follow-up time. After adjusting for age at follow-up, sex, maternal substance use and/or smoking, the only antiretroviral class with a significant (lower) difference in odds of any neurodevelopmental disorder diagnosis (compared with HEUs with no maternal antiretroviral exposure) was in the NRTI + protease inhibitor (boosted) class (OR = 0.146; 95% CI: 0.04–0.57; P = 0.006).
Crude frequencies of neurodevelopmental disorder diagnosis were analyzed among 441 HEUs for whom duration of prenatal antiretroviral exposure was known, as illustrated in Fig. 1. As this analysis involved HEUs only, associations were presented as proportions (%) and compared univariately. Forty-two percent (95% CI: 30.9–54.0) of HEUs who had no antiretroviral exposure to antiretroviral drugs in utero had at least one neurodevelopmental disorder diagnosis. Fifty-three percent (95% CI: 42.1–63.0) of HEUs exposed to antiretroviral drugs for more than 0–13 weeks had at least one neurodevelopmental disorder diagnosis. HEUs exposed to antiretroviral drugs for more than 13–26 and more than 26 weeks had fewer neurodevelopmental disorder diagnoses (22.2%, 95% CI: 16.1–29.4; and 11.2%, 95% CI: 5.9–18.8, respectively) than HEUs with no antiretroviral exposure and those exposed to antiretrovirals for more than 0–13 weeks (P < 0.05).
Among HEUs (solely) born after 1 April 2000 (N = 309), again with shorter clinical follow-up time, a limited multivariable logistic regression was conducted. After adjusting for age at follow-up, sex, maternal substance use and/or smoking, the only antiretroviral duration with a significant (lower) difference in odds of neurodevelopmental disorder diagnosis (compared with HEUs with no maternal antiretroviral exposure) was in HEUs with more than 26 weeks of exposure (OR = 0.270; 95% CI: 0.08–0.96; P = 0.043). Specific antiretroviral drugs used are detailed in Supplemental Digital Content 4, https://links.lww.com/QAD/B348.
Our study is the first retrospective analysis conducted to date presenting long-term neurodevelopmental outcomes in HEU children and adolescents from comprehensive healthcare records. We found a significantly higher prevalence of neurodevelopmental disorder diagnoses in the HEU cohort (30%), twice as high as seen in HUUs (13%), and in 2001 national estimates for mental disorders in children aged 4–17 years (14%) . The exact causes behind this are multifactorial, whereas complex relationships with HIV and antiretroviral drugs make it further difficult to pinpoint.
Maternal drug/substance use, smoking, and preterm birth contributed significantly to the increased odds of neurodevelopmental disorder diagnosis observed in HEUs born after 1 April 2000; however, after adjusting for these factors, in addition to other demographic covariates, the association remained, though attenuated. It is important to note that preterm birth may also be a significant mediator of antiretrovirals’ effects on neurodevelopment, albeit HEUs with no maternal antiretroviral exposure were found to have a significantly higher frequency of neurodevelopmental disorders compared with HEUs with any exposure. Although the contribution of the long-term effects of in-utero exposures to substances such as cigarettes, alcohol, and illicit drugs have been unclear in some studies of HEU neurodevelopment, we have shown that most of these exposures are risk factors for neurodevelopmental disorder diagnosis in our study population. However, we also recognize that there was very likely underreporting of these behaviors among HIV-uninfected mothers who tend to not be as closely monitored as HIV-infected mothers in British Columbia, possibly resulting in differential misclassification of this exposure. Low-barrier, trauma-informed tertiary and multidisciplinary care for women LWH in British Columbia provided by the Oak Tree Clinic reflects detailed and comprehensive medical records on more than 95% of all British Columbia HEU births. Records of maternal substance use among pregnant women LWH is particularly well captured by the Oak Tree Clinic Team in HEUs. Social desirability bias, however, is still a limitation toward the underreporting of this variable in both cohorts.
In line with previous studies that showed higher frequencies of preterm birth among women LWH [40,41], odds of preterm birth were significantly higher in the HEU cohort after adjusting for maternal substance use and smoking, therefore making these key influences for the high neurodevelopmental disorder prevalence in HEUs. It is possible that antiretroviral exposures may play a role, although this was not supported by our study. Studies which found increases in preterm birth among children prenatally exposed to certain antiretroviral regimens [21,23–26] warrant future investigations on preterm birth among HEUs in this population.
We found no evidence that any specific maternal regimen or treatment duration increased the odds of neurodevelopmental disorder diagnosis. Reassuringly, we support previous research that found no associations between in-utero antiretroviral exposure and long-term developmental effects , or neurological conditions  in children. Our findings suggest cART may have a protective effect on HEU neurodevelopment, although further large-scale studies are needed to confirm this result in other settings. Similarly, although our HEU model shows lower odds of neurodevelopmental disorders among children exposed to boosted protease inhibitor regimens compared with those with no antiretroviral exposure, these results must be interpreted with caution. Boosted protease inhibitors became commonly prescribed in British Columbia starting in 2007, affording much shorter follow-up time in that group, hence a lower likelihood of having received a neurodevelopmental disorder diagnosis. A majority of the HEU mothers in the study who did not receive any antiretroviral treatments during pregnancy largely come from an earlier era (pre-1997) and may therefore have had more advanced HIV, or did not access prenatal or HIV care during pregnancy. Therefore, it is not possible to make any definitive inferences between specific antiretroviral drugs and the outcomes investigated. Additional research may distinguish between the effects of exposure to maternal HIV infection and antiretroviral drugs, and account for their respective effects on infant neurodevelopment.
Our results are reported despite having limited data on other variables known or suggested to negatively affect early child development, such as prenatal exposure to other maternal infections , other maternal medications, poverty, and/or adverse childhood experiences. Furthermore, records on parental mental health and education were additionally unavailable. Lack of breastfeeding (among our HEU cohort relative to HUUs) may adversely influence neurodevelopment in HEUs, as studies have demonstrated advantages of breast milk on neurodevelopment relative to formula feeding or partial breastfeeding [45,46]. It is therefore possible that differences in neurodevelopmental disorder diagnoses between HEUs and HUUs in our study may be attributable to higher occurrences of adverse exposures and less breastfeeding in HEUs that were unaccounted for. Future studies conducted on HEUs should therefore strive to capture comprehensive data on these possible confounders.
We present novel evidence for a concerningly high rate of neurodevelopmental disorders in British Columbia HEUs, not entirely explained by maternal substance use, antiretrovirals, or preterm birth, suggesting maternal health, adverse childhood experiences, and other environmental factors are important influences. Although causal mechanisms for this prevalence are likely interrelated, our results highlight the need for close developmental monitoring and access to early intervention for HEU children past infancy. This is of particular importance in Canada as HEU follow-up monitoring currently varies considerably between provinces, from as little as 18 months to as long as 18 years, in addition to other settings with limited monitoring for HEUs.
Our findings furthermore support the importance of holistic support systems for pregnant women; particularly access to care and treatment for substance use to reduce risks of preterm delivery. Our observations support the need for developmental follow-up and early intervention for HEU children, notably males, those born preterm, and those exposed to harmful substances. It is important to highlight the disproportionate hardships and socioeconomic confounders that impact families LWH, reflecting that HEU children may represent a different risk category all together. The increased odds of neurodevelopmental disorders among HEUs in our study have not been proven to be a direct effect of exposure to HIV or antiretrovirals themselves and are likely associated with the social and environmental conditions that children born to women LWH are affected by. Despite reassuring results, our analysis is limited, and sustained comprehensive evaluations for antiretroviral safety are still needed, especially as many neurodevelopmental disorders are undiagnosed until later in childhood. As the population of HEU children grows, so does antiretroviral usage and availability, including newer antiretroviral drugs with limited HEU data, thereby proportionally increasing exposure to antiretrovirals during early neurodevelopment.
M.P. designed and conducted the analysis and wrote the article. M.A.B. aided in acquisition and analysis of the datasets and reviewed/edited the article. A.Q.Q., E.J.M., L.J.S., J.C.F. aided in the acquisition of the study's ethical approval and datasets, contributed to the discussion, and reviewed/edited the article. A.A., P.J., and H.C.F.C. conceived the study, aided in the acquisition of the study's ethical approval and datasets, aided in the analysis, contributed to the discussion, and reviewed/edited the article. This work was funded through the Canadian Institutes of Health Research (CIHR, TCO-125269) Team Grant on Cellular Aging and Comorbidities in Women and Children (CARMA). Special thanks to Rebecca Thomson (London School of Hygiene and Tropical Medicine) for her expertise and guidance throughout the study.
Disclosure from Population Data BC: ‘All inferences, opinions, and conclusions drawn in this retrospective study are those of the authors and do not reflect the opinions or policies of the Data Steward(s)’.
Other coinvestigators from the CIHR Team Grant on Cellular Aging and HIV Comorbidities in Women and Children (CARMA) include Jason Brophy (University of Ottawa); Deborah Money, Joel Singer, Melanie Murray, Jerilynn Prior, and Neora Pick (University of British Columbia); Hugo Soudeyns, Fatima Kakkar, and Normand Lapointe (University of Montreal); Ari Bitnun, Mary Lou Smith, and Michael Silverman (University of Toronto).
Conflicts of interest
There are no conflicts of interest.
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