Abstract
Background:
Lifelong HIV and antiretroviral therapy (ART) may confer neurodevelopmental (ND) risk on the children of women with perinatally-acquired HIV infection (PHIV).
Setting:
We analyzed data from HIV-exposed uninfected (HEU) infants born to women with PHIV vs. non-perinatally acquired HIV (NPHIV) enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study.
Methods:
Using the Bayley Scales of Infant and Toddler Development, 3rd Ed. (Bayley-III), we compared ND outcomes at 1 year of age in HEU infants born to women with PHIV vs. NPHIV. Those with valid Bayley-III data at 1 year of age and a mother born after 1982 were included. Cognitive, language, and motor domains were assessed as continuous composite scores. Linear mixed effects models were fit to estimate the mean difference in Bayley-III scores between groups, adjusting for confounders.
Results:
550 women with HIV gave birth to 678 HEU children (125 and 553 born to women with PHIV and NPHIV respectively). Mean scores for each of the Bayley-III domains were not significantly different between infants born to women with PHIV vs NPHIV in unadjusted models. After adjustment, infants of women with PHIV had lower language (91.9 vs 94.8, p=0.05) and motor (93.7 vs 96.8, p=0.03) composite scores but no differences in cognitive composite scores.
Conclusion:
Cognitive domain outcomes of infants born to women with PHIV vs NPHIV are reassuring. Differences in early language and motor functioning, while of modest clinical significance, highlight the importance of long-term monitoring of neurodevelopment in children of women with PHIV.
Keywords: Neurodevelopment, HIV-exposed uninfected infant, Women with Perinatal HIV
Introduction
Despite some conflicting reports, several studies have reported worse neurodevelopment in HIV-exposed uninfected (HEU) compared to HIV-unexposed uninfected (HUU) infants and children.1–5 In utero atazanavir exposure has been reported in previous U.S. studies to be associated with language delay,6,7 and a South African study reported an association between cumulative maternal viremia and poor infant neurodevelopmental outcomes.8 Women with perinatally-acquired HIV (PHIV) often have increased viremia during pregnancy compared to those with non-perinatally acquired HIV (NPHIV).9–11 In addition, the neurocognitive and psychosocial impact of lifelong HIV and antiretroviral therapy (ART) in women with PHIV may present neurodevelopmental risk to their offspring.
Mechanisms that contribute to normal and abnormal brain development begin during gestation and often involve critical time periods in utero as well as varying exposures in the in utero environment. Increasing evidence also suggests that neurodevelopmental disorders may result from a combination of genetic susceptibility and fetal cell programming which is modified by in utero triggers or events.12 In certain neurodevelopmental disorders, there may be no gross architectural abnormalities in the brain but instead, changes at the cellular level which may have resulted from alterations in the in utero milieu. In addition, depending on the timing of in utero exposure, differing deficits in fetal neurodevelopment may occur. Synapse formation largely begins during the third trimester,13 and neurological functions linked to this basic biological process may be greatly affected if in utero alterations occurred during this critical window. In utero HIV and ARV exposure represent particular exposures which may affect postnatal neurodevelopment.2,4,5
Women with PHIV, who may confer a unique in utero environment of lifelong HIV infection and salvage regimen ART to their fetuses, are now living longer and giving birth to their own offspring – HEU infants whose neurodevelopmental outcomes have not yet been studied. Although much research has been published on specific in utero HIV/ARV exposure in HEU infants compared to HUU infants, little has been published evaluating the relationship of maternal PHIV to early infant neurodevelopmental outcomes. The objective of our study was to assess the association of maternal PHIV with infant neurodevelopment at one year of age.
Materials and Methods:
Study Population
The Surveillance Monitoring for ART Toxicities (SMARTT) study is a large prospective cohort study of women living with HIV (WLHIV) and their children in the United States (U.S.), including Puerto Rico, conducted by the Pediatric HIV/AIDS Cohort Study (PHACS) network, and designed to assess maternal and infant safety of ART prescribed for maternal health and the prevention of mother-to-child transmission (PMTCT) of HIV. The PHACS SMARTT study has been enrolling participants since 2007 across 18 sites.14,15 For this analysis, we included singleton HEU infants who had valid Bayley Scales of Infant and Toddler Development (Bayley-III)16 cognitive, language, or motor scores at age 1 +/− 4 months and maternal mode of HIV acquisition information available. Mothers of HEU infants eligible for inclusion in this analysis were born after 1982 and were ages 13–35 at the time of delivery in order to maintain a similar age range between mothers with PHIV vs. NPHIV. Children with HIV infection and those whose mother/primary caregiver were unable to participate in the neurodevelopmental assessment in English were excluded. Institutional review boards at Harvard T.H. Chan School of Public Health and at each site approved the protocol, and all participating women provided written informed consent.
Outcomes
The primary outcome was neurodevelopmental functioning at age 1, measured using the Bayley-III.16 The Bayley-III is normed for infants and young children, ages 1–42 months, and provides standardized measures of infant development. Since the Bayley-III is only available in English, mother/infant dyads whose primary language was Spanish were not administered the Bayley III. Additionally, if the mother’s English fluency was considered sufficient and the Bayley-III was administered, the administering psychologist reviewed the results and categorized them as invalid if it was deemed that behaviors, illness, or other issues may have adversely impacted the mother or child’s ability to participate and respond to Bayley-III activities. Composite scores for cognitive, language and motor domains were used. Scales for each of these domains were administered by psychologists via direct observation and interaction with the infant. Each composite scale has a mean of 100 and standard deviation of 15 for the population norm. Scores were not adjusted for prematurity to obtain precise assessments of infants’ current developmental functioning. All Bayley-III results categorized as invalid or of questionable validity by the administering psychologist were reviewed by PHACS psychologists (RS, KM), and all assessments with test scores judged by this latter group as invalid were excluded from the analysis. Each domain was also evaluated as a dichotomous variable, where an abnormal score was defined as a standard score < 78 [1·5 standard deviations (SD) below the mean].
Primary Exposure of Interest
The primary exposure of interest was the maternal mode of HIV acquisition: PHIV vs NPHIV. This information was obtained through self-report and medical record review as previously reported.10 If this information was not available from the PHACS SMARTT study, data from the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network P1025 study was used among women who co-enrolled in IMPAACT P1025 and gave permission for their IMPAACT P1025 data to be used.
Covariates
Information on potential confounders including maternal age at delivery, race/ethnicity, maternal/caregiver highest education level, household income, maternal/caregiver Wechsler Abbreviated Scale of Intelligence (WASI) Full Scale Intelligence Quotient (FSIQ)17 score, presence of maternal mental health condition(s), earliest CD4 cell count in pregnancy, in utero ART exposure, and English monolingual vs. bilingual environment were collected at study visits as per the SMARTT study protocol. The WASI is a widely used, nationally standardized, and reliable measure of intelligence for English-speaking children and adults, ages 6–89 years. Maternal mental health status was assessed with the Client Diagnostic Questionnaire (CDQ),18 a screening instrument developed and validated for populations affected by HIV. The CDQ was administered by the PHACS site psychologist as a face-to-face interview to assess presence of symptoms of psychiatric illness, including depression, anxiety, alcohol and illicit substance abuse, posttraumatic stress disorder and psychosis. For the diagnosis of any disorder, the sensitivity, specificity and overall accuracy of the CDQ have been reported as 91%, 78%, and 85%, respectively.18 Both the WASI and CDQ were routinely administered at the same study visit when the Bayley-III was performed.
For women receiving multiple ART regimens in pregnancy, the ART regimen with the longest duration of use during pregnancy was chosen. If two or more ART regimens had similar durations of use during the pregnancy, the most potent regimen was included in the analysis. ART regimens were categorized in the following order of potency, from most potent to least potent: regimen with ≥3 classes of ARVs, integrase strand inhibitor (INSTI)-based ART, protease inhibitor (PI)-based ART, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART, nucleoside reverse transcriptase inhibitor (NRTI)-based ART (i.e., ≥3 NRTIs), non-combination ART regimen, and no antiretrovirals (ARVs)/unknown.
Statistical Analysis
Baseline characteristics were compared between HEU infants of women with PHIV vs. those of women with NPHIV using Wilcoxon, Chi-square, or Fisher’s exact tests as appropriate. We also compared baseline characteristics of participants with vs. without valid Bayley-III tests within 4 months of age 1 year. Linear mixed effects models were fit to estimate unadjusted and adjusted means of each infant Bayley-III domain outcome by maternal PHIV status, with a random effect for mother/caregiver to account for the clustering effect of siblings. Maternal age, child race/ethnicity, maternal/caregiver education level, maternal/caregiver WASI score, and the household primary language were considered a priori confounders. Other covariates, such as tobacco use during pregnancy, illicit drug use during pregnancy, in utero ARV exposure to ≥3 ARV classes, number of functional limitations, maternal mental health and in utero CD4 count, were included post hoc in the full adjusted multivariable model if they changed the unadjusted effect estimate for maternal PHIV status by at least 10%. A complete case approach was used for all models. Comparisons between Bayley-III domain means are presented as adjusted means, setting covariates to their mean values. Statistical analyses were performed using SAS® 9·4 (SAS Institute, Cary, NC.). Sensitivity analyses were conducted to assess the robustness of findings when adjusting for maternal WASI FSIQ as a continuous vs categorical variable.
Results
A total of 2876 SMARTT WLHIV/infant dyads enrolled between April 1, 2007 and July 1, 2018. After excluding HIV-infected infants, multifetal gestations, those with missing or unknown maternal mode of HIV acquisition, mothers outside of the eligible age range or born prior to 1983, and HEU infants who had invalid or missing Bayley-III scores, 678 HEU infants were available for analysis [125 HEU infants born to 104 women with PHIV (HEU-PHIV) and 553 infants to 446 women with NPHIV (HEU-NPHIV)]. (Figure 1) HEU-PHIV infants were more likely to be born after 2013 than HEU-NPHIV infants (50% vs. 38%, p=0·01). Women with PHIV were younger on average at delivery (median age 22·8 vs. 25·4 years, p<0·01), more frequently had a CD4 cell count <200 cells/mm3 (21% vs. 10%, p<0·01) during pregnancy, and more frequently received an ART regimen in pregnancy consisting of ≥3 ARV drug classes (18% vs. 3%, p<0·01). (Table 1) In addition, median maternal/caregiver WASI scores were higher among HEU-PHIV compared to HEU-NPHIV infants (91 vs. 86, p<0·01). Compared to infants without available valid Bayley-III data, infants with valid Bayley-III data were less frequently Hispanic (16% vs. 42%, p<0·01) and more likely to be in an English monolingual environment (86% vs. 59%, p<0·01), but maternal PHIV status and other baseline characteristics did not differ between these groups (data not shown).
Figure 1. Study Population Derivation.
SMARTT=Surveillance Monitoring of ART Toxicities; HEU-PHIV=HIV-exposed uninfected infant born to woman with perinatally acquired HIV; HEU-NPHIV=HIV-exposed uninfected infant born to woman with non-perinatally acquired HIV
Table 1.
Characteristics of HIV-exposed uninfected infants by maternal HIV status
| HEU-PHIV Infants (n=125) | HEU-NPHIV Infants (n=553) | Total (n=678) |
p value | |
|---|---|---|---|---|
| Age, years | 1.1 (1.0, 1.2) | 1.1 (1.0, 1.2) | 1.1 (1.0, 1.2) | 0.32 |
| Female | 61 (49) | 262 (47) | 323 (48) | 0.77 |
| Birth year | 0.01 | |||
| 2007–2009 | 10 (8) | 94 (17) | 104 (15) | |
| 2010–2013 | 52 (42) | 247 (45) | 299 (44) | |
| 2014 or after | 63 (50) | 212 (38) | 275 (41) | |
| Race/ethnicity | 0.10 | |||
| Non-Hispanic White | 8 (6) | 26 (5) | 34 (5) | |
| Non-Hispanic Black | 83 (66) | 424 (77) | 507 (75) | |
| Hispanic | 28 (22) | 81 (15) | 109 (16) | |
| Other | 6 (5) | 22 (4) | 28 (4) | |
| Biological Mother as Caregiver | 123 (98%) | 544 (98%) | 667 (98%) | 0.98 |
| Maternal/Caregiver language | 0.59 | |||
| English | 118 (94) | 505 (91) | 623 (92) | |
| Bilingual/Multilingual English and other | 6 (5) | 37 (7) | 43 (6) | |
| Other | 1 (1) | 11 (2) | 12 (2) | |
| Annual household income, USD | 0.56 | |||
| ≤ $20,000 | 92 (75) | 400 (74) | 492 (74) | |
| $20,001 – $50,000 | 26 (21) | 125 (23) | 151 (23) | |
| > $50,000 | 5 (4) | 14 (3) | 19 (3) | |
| Missing | 2 | 14 | 16 | |
| Preterm birth (< 37 weeks) | 16 (13) | 76 (14) | 92 (14) | 0.79 |
| Small-for-gestational age | 13 (10) | 51 (9) | 64 (9) | 0.68 |
| Maternal age at infant birth, years | 22.8 (20.7, 25.3) | 25·4 (22.8, 27.7) | 24·9 (22.3, 27.4) | <0.01 |
| Maternal education level | 0.80 | |||
| Less than high school | 35 (28) | 161 (29) | 196 (29) | |
| At least high school | 90 (72) | 392 (71) | 482 (71) | |
| Maternal WASI score | 91 (83, 100) | 86 (76, 97) | 87 (77, 97) | <0.01 |
| Maternal mental health problem | 39 (32) | 176 (33) | 215 (32) | 0.85 |
| Number of functional limitations experienced by mother | 0.86 | |||
| None | 91 (73) | 399 (73) | 490 (73) | |
| 1–2 | 25 (20) | 116 (21) | 141 (21) | |
| > 2 | 8 (6) | 30 (6) | 38 (6) | |
| Missing | 1 | 8 | 9 | |
| Maternal tobacco use in pregnancy | 15 (12) | 104 (19) | 119 (18) | 0.09 |
| Maternal alcohol use in pregnancy | 11 (9) | 44 (8) | 55 (8) | 0.72 |
| Maternal marijuana use in pregnancy | 10 (8) | 56 (10) | 66 (10) | 0.62 |
| Earliest maternal CD4 in pregnancy, cells/mm³ | <0.01 | |||
| < 200 | 26 (21) | 54 (10) | 80 (12) | |
| 200 – 350 | 27 (22) | 103 (19) | 130 (20) | |
| 351 – 500 | 25 (20) | 100 (18) | 125 (19) | |
| > 500 | 44 (36) | 286 (53) | 330 (50) | |
| Missing | 3 | 10 | 13 | |
| Earliest maternal log HIV RNA level in pregnancy | 2.8 (1.7, 4.0) | 2·8 (1.6, 4.0) | 2·8 (1.7, 4.0) | 0.51 |
| In utero ART exposure | <0.01 | |||
| ≥ 3 ARV class regimen | 22 (18) | 17 (3) | 39 (6) | |
| INSTI-based | 15 (12) | 55 (10) | 70 (11) | |
| PI-based | 68 (55) | 331 (62) | 399 (61) | |
| NNRTI-based | 14 (11) | 71 (13) | 85 (13) | |
| NRTI-based | 1 (1) | 45 (8) | 46 (7) | |
| Other | 2 (2) | 8 (2) | 10 (1) | |
| None/unknown | 1 (1) | 4 (1) | 5 (1) |
All continuous variables expressed as median (interquartile range) and categorical variables as n (%); p values from Wilcoxon, Chi-square or Fisher’s Exact test as appropriate except where noted.
ART=Antiretroviral Therapy, ARV=Antiretroviral, HEU-NPHIV=HIV-exposed uninfected infants born to women with non-perinatally acquired HIV, HEU-PHIV=HIV-exposed uninfected infants born to women with perinatally acquired HIV, INSTI=Integrase Strand Transfer Inhibitor, NNRTI=Non-Nucleoside Reverse Transcriptase Inhibitor, NRTI=Nucleoside Reverse Transcriptase Inhibitor, PI=Protease Inhibitor, USD=US dollars, WASI=Wechsler Abbreviated Scale of Intelligence
Mean Bayley-III cognitive and motor composite scores were similar between HEU-PHIV and HEU-NPHIV infants in unadjusted models (Table 2). However, mean language composite scores were on average 2·5 points lower for HEU-PHIV compared to HEU-NPHIV infants. The proportion of infants with abnormal cognitive and motor scores was 3·1% and 4·1% respectively and similar between groups. However, a greater proportion of HEU-PHIV infants had an abnormal language score compared to HEU-NPHIV infants (11·2% vs. 5·9%, p=0·05). After adjustment for confounders, HEU-PHIV infants had lower language (mean of 91.9 vs 94.8, p=0·05) and motor (mean of 93·7 vs 96·8, p=0·03) composite scores, but no differences in cognitive composite scores (Table 2).
Table 2.
Unadjusted and adjusted mean Bayley Scales composite scores comparing infants of women with perinatally vs. non-perinatally acquired HIV
| Bayley Scales III Domain | Unadjusted Mean Estimates (95% CI) | Adjusted Mean Estimates (95% CI) | ||||
|---|---|---|---|---|---|---|
| HEU-PHIV | HEU-NPHIV | p value | HEU-PHIV | HEU-NPHIV | p value | |
| Cognitive1 | 102.8 (100.3, 105.3) | 103.8 (102.6, 105.0) | 0.47 | 100.0 (95.8, 104.3) | 102.4 (98.3, 106.4) | 0.14 |
| Language2 | 93.8 (91.4, 96.2) | 96.3 (95.2, 97.5) | 0.06 | 91.9 (88.5, 95.3) | 94.8 (92.2, 97.3) | 0.05 |
| Motor3 | 96.2 (93.9, 98.5) | 97.8 (96.7, 98.9) | 0.21 | 93.7 (90.1, 97.2) | 96.8 (93.4, 100.2) | 0.03 |
All models adjusted for maternal age, race/ethnicity, WASI score, and English monolingual or bilingual language environment.
Additional adjustment for maternal tobacco use in pregnancy, illicit drug use in pregnancy, maternal functional limitations, maternal CD4 in pregnancy, and in utero exposure to ≥3 ARV drug classes.
Additional adjustment for maternal CD4 in pregnancy
Additional adjustment for maternal CD4 in pregnancy, in utero exposure to ≥3 ARV drug classes, and maternal mental health condition.
CI=Confidence Interval, HEU-NPHIV=HIV-exposed uninfected infants born to women with non-perinatally acquired HIV, HEU-PHIV=HIV-exposed uninfected infants born to women with perinatally-acquired HIV.
Discussion
In this large U.S. cohort of WLHIV and their infants, we found similar cognitive outcomes between HEU-PHIV and HEU-NPHIV infants and clinically minor differences in language and motor development between groups. These early results are reassuring. To our knowledge, this is the first paper to report neurodevelopmental outcomes among infants of women with PHIV.
Bayley-III scores in each domain among HEU infants in our study were largely in the normal range compared to Bayley-III reference standards and also similar to scores found in other studies utilizing the Bayley-III in 1–2 year old HEU infants and children.4,19 Bayley-III cognitive and motor scores from our HEU population were similar to or higher than pooled mean estimates of Bayley-I and Bayley-II version mental developmental index and psychomotor developmental index scores from a recent meta-analysis of HEU infants (105 vs. 83 for cognitive and 97 vs. 95 for motor scores, respectively)2; however, higher Bayley-III scores compared to Bayley-II may be related in part to structural differences between the Bayley-II and Bayley-III and to inclusion of infants and toddlers at risk for developmental delay in the Bayley-III normative sample. In adjusted models we observed an overall 3 point lower mean Bayley-III language score and 3·1 point lower mean motor score in HEU-PHIV infants compared to HEU-NPHIV infants. However, these differences may be of limited clinical significance at this early age, and both groups on average had scores within the average range in all Bayley-III domains. The higher rate of abnormal Bayley-III language scores in HEU-PHIV is notable and warrants ongoing monitoring, but the small numbers who had this outcome precluded further multivariable analysis.
While neurodevelopmental functioning of HEU-PHIV infants at age one is reassuringly similar to that of HEU-NPHIV infants in the U.S., long-term neurodevelopmental follow-up of HEU-PHIV infants remains important, given the plasticity of neurodevelopment over time in growing children as well as other factors from the in utero period through childhood/adolescence which could influence long-term neurodevelopment in this population. Women with PHIV have lifelong infection, immunosuppression, and immune activation which could affect the in utero inflammatory marker environment of their infants.20 Consequently, maternal inflammation during pregnancy may be associated with poor long-term neurodevelopment and even mental health in offspring of these women.21,22 In addition, maternal cognitive function is associated with child neurodevelopment, and though women with PHIV in our cohort achieved significantly higher cognitive scores compared to women with NPHIV, other populations of women with PHIV may be at risk for more neuropsychological risk later in life. In South Africa, youth living with PHIV have demonstrated abnormal grey and white matter volume and structure which was directly correlated with general intellectual functioning as measured by the WASI.23 A U.S. study reported increased risk of cognitive and psychiatric problems among PHIV adolescents with previous CDC Class C HIV disease.24 Specific neuropsychological domains such as processing speed,25,26 set shifting,27 verbal fluency,27 and aspects of executive functioning28,29 appear to be affected in PHIV children/adolescents; such selective deficits may influence future parenting behaviors. In populations where women with PHIV of childbearing age show significant neurocognitive impairment, it may be valuable to monitor the long-term neurodevelopment of their offspring and provide appropriate early intervention and parental education/support if deficits are observed.
Studies have shown that adverse childhood experiences may exert long-lasting biological aging and affect long-term health into adulthood.30 While there were no differences between women with PHIV vs. NPHIV for mental health disorders, it is notable that one third of women in both groups had a mental health disorder. In another analysis of women with HIV in PHACS SMARTT, 32% of women with HIV had at least one psychiatric disorder, with post-traumatic stress disorder the most highly reported and substance use disorder identified in 9%.31 The prevalence of any psychiatric disorder among women with HIV in PHACS SMARTT was similar to HIV-uninfected women recruited from the same medical centers but higher than observed among adults in general and non-pregnant women pregnant women in a large scale U.S. population surveys.32,33 Because of this, monitoring of HEU children born to women with PHIV who have experienced neuropsychological stress and/or behavioral health challenges is also important, and early intervention may prove beneficial for both mother and child since such services provide education, counseling, and support.
This study is limited by lack of detailed information regarding maternal HIV and health status at the time when the Bayley-III was obtained and the fact that the Bayley-III was only available in English for participants, potentially introducing bias to our findings. However, potential health challenges would have occurred later in time than the exposure variable and could potentially be on the causal pathway. The Bayley III may underestimate developmental delay in infants,34,35 although we adjusted our cutoff score for impairment in light of this concern. As with many research studies, the convenience sample design within a research cohort infrastructure where participants were primarily recruited from HIV tertiary care centers likely conferred more regular, high quality health care and monitoring of participants as well as increased attention to health needs, thus decreasing the generalizability of the study.
In conclusion, HEU-PHIV infants do not appear to be at overall increased risk for poor neurodevelopment in the first year of life compared to HEU-NPHIV infants. These results are generally encouraging for young women with PHIV who may have concerns regarding their ability to successfully parent and have healthy children with normal neurodevelopment. However, given the multifactorial etiology of long-term neurodevelopment, the potential influence of maternal factors, and the rapid pace at which new ART is becoming available for WLHIV during pregnancy, long-term monitoring of HEU-PHIV infants and their mothers remains important.
Acknowledgments
We thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS. The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) (Principal Investigator: George Seage; Program Director: Julie Alperen) and the Tulane University School of Medicine (HD052104) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Ellen Chadwick; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson).
Funding sources
The Pediatric HIV/AIDS Cohort Study (PHACS) was supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development (NICHD) with co-funding from the National Institute Of Dental & Craniofacial Research (NIDCR), the National Institute Of Allergy And Infectious Diseases (NIAID), the National Institute Of Neurological Disorders And Stroke (NINDS), the National Institute On Deafness And Other Communication Disorders (NIDCD), Office of AIDS Research (OAR), the National Institute Of Mental Health (NIMH), the National Institute On Drug Abuse (NIDA), and the National Institute On Alcohol Abuse And Alcoholism (NIAAA), through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) and the Tulane University School of Medicine (HD052104).
Footnotes
Declaration of Interests
The authors have no financial disclosures to report.
Note: The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or U.S. Department of Health and Human Services.
Meeting at which part of this data has been presented:
Conference on Retroviruses and Opportunistic Infections (CROI), March 2019, Seattle, Washington, USA
REFERENCES
- 1.Van Rie A, Mupuala A, Dow A. Impact of the HIV/AIDS epidemic on the neurodevelopment of preschool-aged children in Kinshasa, Democratic Republic of the Congo. Pediatrics. 2008;122(1):e123–128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.McHenry MS, McAteer CI, Oyungu E, et al. Neurodevelopment in Young Children Born to HIV-Infected Mothers: A Meta-analysis. Pediatrics. 2018;141(2). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Gomez C, Archila ME, Rugeles C, Carrizosa J, Rugeles MT, Cornejo JW. [A prospective study of neurodevelopment of uninfected children born to human immunodeficiency virus type 1 positive mothers]. Rev Neurol. 2009;48(6):287–291. [PubMed] [Google Scholar]
- 4.le Roux SM, Donald KA, Brittain K, et al. Neurodevelopment of breastfed HIV-exposed uninfected and HIV-unexposed children in South Africa. AIDS. 2018;32(13):1781–1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kerr SJ, Puthanakit T, Vibol U, et al. Neurodevelopmental outcomes in HIV-exposed-uninfected children versus those not exposed to HIV. AIDS Care. 2014;26(11):1327–1335. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Nozyce ML, Huo Y, Williams PL, et al. Safety of In Utero and Neonatal Antiretroviral Exposure: Cognitive and Academic Outcomes in HIV-exposed, Uninfected Children 5–13 Years of Age. Pediatr Infect Dis J. 2014;33(11):1128–1133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Rice ML, Zeldow B, Siberry GK, et al. Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants. Pediatr Infect Dis J. 2013;32(10):e406–413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.le Roux SM, Donald KA, Kroon M, et al. HIV Viremia During Pregnancy and Neurodevelopment of HIV-Exposed Uninfected Children in the Context of Universal Antiretroviral Therapy and Breastfeeding: A Prospective Study. Pediatr Infect Dis J. 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Badell ML, Kachikis A, Haddad LB, Nguyen ML, Lindsay M. Comparison of pregnancies between perinatally and sexually HIV-infected women: an observational study at an urban hospital. Infectious diseases in obstetrics and gynecology. 2013;2013:301763. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Jao J, Kacanek D, Williams PL, et al. Birth Weight and Preterm Delivery Outcomes of Perinatally vs. non-Perinatally HIV-infected Pregnant Women in the U.S.: Results from the PHACS SMARTT Study and IMPAACT P1025 Protocol. Clin Infect Dis. 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Munjal I, Dobroszycki J, Fakioglu E, et al. Impact of HIV-1 infection and pregnancy on maternal health: comparison between perinatally and behaviorally infected young women. Adolesc Health Med Ther. 2013;4:51–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Connors SL, Levitt P, Matthews SG, et al. Fetal mechanisms in neurodevelopmental disorders. Pediatr Neurol. 2008;38(3):163–176. [DOI] [PubMed] [Google Scholar]
- 13.Bourgeois JP. Synaptogenesis, heterochrony and epigenesis in the mammalian neocortex. Acta Paediatr Suppl. 1997;422:27–33. [DOI] [PubMed] [Google Scholar]
- 14.Van Dyke RB, Chadwick EG, Hazra R, Williams PL, Seage GR 3rd. The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs. Front Immunol. 2016;7:199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Sirois PA, Huo Y, Williams PL, et al. Safety of perinatal exposure to antiretroviral medications: developmental outcomes in infants. Pediatr Infect Dis J. 2013;32(6):648–655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Bayley N. Bayley Scales of Infant and Toddler Development–Third Edition. San Antonio, TX: Harcourt Assessment; 2006. [Google Scholar]
- 17.Wechsler D. Wechsler Abbreviated Scale of Intelligence. San Antonio: The Psychological Corporation; 1999. [Google Scholar]
- 18.Aidala AHJ, Mellins CA, Dodds S, Whetten K, Martin D, Gillis L, & Ko P. Development and validation of the Client Diagnostic Questionnaire (CDQ): a mental health screening tool for use in HIV/AIDS service settings. Psychology, Health & Medicine. 2004;9(3):362–380. [Google Scholar]
- 19.Whitehead N, Potterton J, Coovadia A. The neurodevelopment of HIV-infected infants on HAART compared to HIV-exposed but uninfected infants. AIDS Care. 2014;26(4):497–504. [DOI] [PubMed] [Google Scholar]
- 20.Truong HM, Sim MS, Dillon M, et al. Correlation of immune activation during late pregnancy and early postpartum with increases in plasma HIV RNA, CD4/CD8 T cells, and serum activation markers. Clin Vaccine Immunol. 2010;17(12):2024–2028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Goeden N, Velasquez J, Arnold KA, et al. Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2016;36(22):6041–6049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Langridge AT, Glasson EJ, Nassar N, et al. Maternal conditions and perinatal characteristics associated with autism spectrum disorder and intellectual disability. PLoS One. 2013;8(1):e50963. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Hoare J, Fouche JP, Phillips N, et al. Structural brain changes in perinatally HIV-infected young adolescents in South Africa. AIDS. 2018;32(18):2707–2718. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Wood SM, Shah SS, Steenhoff AP, Rutstein RM. The impact of AIDS diagnoses on long-term neurocognitive and psychiatric outcomes of surviving adolescents with perinatally acquired HIV. AIDS. 2009;23(14):1859–1865. [DOI] [PubMed] [Google Scholar]
- 25.Smith R, Chernoff M, Williams PL, et al. Impact of HIV severity on cognitive and adaptive functioning during childhood and adolescence. Pediatr Infect Dis J. 2012;31(6):592–598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Nachman S, Chernoff M, Williams P, Hodge J, Heston J, Gadow KD. Human immunodeficiency virus disease severity, psychiatric symptoms, and functional outcomes in perinatally infected youth. Arch Pediatr Adolesc Med. 2012;166(6):528–535. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Koekkoek S, de Sonneville LM, Wolfs TF, Licht R, Geelen SP. Neurocognitive function profile in HIV-infected school-age children. Eur J Paediatr Neurol. 2008;12(4):290–297. [DOI] [PubMed] [Google Scholar]
- 28.Sirois PA, Chernoff MC, Malee KM, et al. Associations of Memory and Executive Functioning With Academic and Adaptive Functioning Among Youth With Perinatal HIV Exposure and/or Infection. J Pediatric Infect Dis Soc. 2016;5(suppl 1):S24–S32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Nichols SL, Chernoff MC, Malee KM, et al. Executive Functioning in Children and Adolescents With Perinatal HIV Infection and Perinatal HIV Exposure. J Pediatric Infect Dis Soc. 2016;5(suppl 1):S15–S23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav. 2012;106(1):29–39. [DOI] [PubMed] [Google Scholar]
- 31.Malee KM, Mellins CA, Huo Y, et al. Prevalence, incidence, and persistence of psychiatric and substance use disorders among mothers living with HIV. J Acquir Immune Defic Syndr. 2014;65(5):526–534. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Vesga-Lopez O, Blanco C, Keyes K, Olfson M, Grant BF, Hasin DS. Psychiatric disorders in pregnant and postpartum women in the United States. Arch Gen Psychiatry. 2008;65(7):805–815. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617–627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Aylward GP. Continuing issues with the Bayley-III: where to go from here. J Dev Behav Pediatr. 2013;34(9):697–701. [DOI] [PubMed] [Google Scholar]
- 35.Anderson PJ, De Luca CR, Hutchinson E, Roberts G, Doyle LW, Victorian Infant Collaborative G. Underestimation of developmental delay by the new Bayley-III Scale. Arch Pediatr Adolesc Med. 2010;164(4):352–356. [DOI] [PubMed] [Google Scholar]