HIV exposure in utero is associated with low birth weight (LBW), even in the absence of vertical transmission. To explore mechanism, we evaluated endothelial markers angiopoietin (Ang)-1 and Ang-2 among 294 uninfected Ugandan infants born to women with HIV (WWH). The median Ang-2/Ang-1 ratio was 0.051 [interquartile range (IQR) 0.023-0.19] among infants with LBW and 0.018 (IQR 0.010-0.037) among controls (P = 0.00011). Endothelial dysregulation may contribute to LBW among infants born to WWH.

OBJECTIVES:Antiretroviral therapy is critical for preventing perinatal HIV transmission during pregnancy; however, access is shaped by complex structural factors, including access to prenatal care, insurance status and provincial drug-coverage policies. Despite its importance, little is known about how out-of-pocket antiretroviral therapy costs during pregnancy differ within and across Canada. METHODS:We performed a secondary analysis of Quebec data from the Canadian Perinatal HIV Surveillance Program collected between 2019 and 2023, which included 225 pregnant women and pregnant people living with HIV. Out-of-pocket antiretroviral therapy costs were estimated using insurance information, medication prices, and provincial drug formularies. Additionally, we modelled hypothetical case scenarios to examine how antiretroviral therapy costs during pregnancy differed based on income level and province of residence. RESULTS:In the Quebec cohort, out-of-pocket antiretroviral therapy costs during pregnancy varied substantially by insurance coverage. Individuals without insurance faced median costs in pregnancy nearly 10 times higher (CAD $9380) than those with public (CAD $934) or private insurance (CAD $1196). Those insured under the Interim Federal Health Program incurred no costs (CAD $0). Simulated scenarios across provinces and territories revealed further disparities, with some jurisdictions providing full public coverage while others required out-of-pocket payments up to CAD $4296. CONCLUSIONS:Out-of-pocket costs for antiretroviral therapy during pregnancy remain high and inequitably distributed in Canada, with uninsured individuals facing the greatest burden in Quebec. These findings highlight the need for policy reforms to ensure free and equitable access to antiretroviral therapy during pregnancy, regardless of insurance coverage.

The incidence of congenital (CS) in Canada increased from 2.1 to 14.5 reported confirmed cases/100,000 live births from 2017 to 2023 (from 8 to 53 cases). We aimed to document prenatal characteristics and contributing factors to CS among mothers or birthing parents (M/BP) of infants with CS in Canada. Participants of the Canadian Paediatric Surveillance Program, which includes both paediatricians and paediatric subspecialists, were invited to report on CS cases meeting the study case definition between June 2021 and May 2023. A detailed questionnaire was completed by the reporting clinician. We used descriptive statistics in the assessment of prenatal risk factors among cases, including data on healthcare access, diagnosis, and treatment as well as on socio-demographic, socio-economic and socio-behavioural determinants. During the 24-month study period, 245 live-born cases of CS were reported, including 81 (33.1

INTRODUCTION:Integrase strand transfer inhibitors (INSTIs) are first-line antiretroviral medications used in pregnancy. Pre-clinical research suggests adverse effects in human stem cells associated with second- versus first-generation INSTIs. We compared perinatal and early infant outcomes after exposure to first- versus second-generation INSTIs. METHODS:Data were taken from the Canadian Perinatal HIV Surveillance Program. Infants born between January 1, 2010, and December 31, 2023, with in utero INSTI exposure were included. Univariate analysis compared perinatal and early infant outcomes between first- and second-generation INSTI exposures. Multivariable logistic regression was completed to identify independent associations between INSTI class and perinatal outcomes. RESULTS:A total of 1160 infants were included: 433 exposed to first-generation INSTIs and 727 to second-generation. There was a non-significant finding of fewer small-for-gestational-age (SGA) infants with exposure to second-generation INSTIs (odds ratio [OR] = 0.75; 95% confidence interval [CI] = 0.55-1.01, p = 0.058), which remained non-significant in multivariable analysis (OR = 0.72, 95% CI = 0.49-1.07, p = 0.105). There was a non-significant finding of increased preterm births with exposure to second-generation INSTIs (OR = 1.40, 95% CI = 0.97-2.00, p = 0.070), which remained non-significant in multivariable analyses (OR = 1.01, 95% CI = 0.62-1.66, p = 0.962). There was a non-significant increase in infant deaths in the second-generation INSTI group compared to the first-generation group (6 vs. 0, p = 0.089). No differences were observed in HIV transmission (p = 0.208). CONCLUSIONS:There were no significant associations between second-generation INSTIs and adverse perinatal outcomes compared to first-generation INSTIs. These findings support the ongoing use of second-generation INSTIs in pregnancy with continued careful surveillance of perinatal outcomes.

INTRODUCTION:Presumptive HIV therapy (PHT) is recommended for post-natal HIV prophylaxis (PNP) in situations at high risk of HIV vertical transmission (VT), for both prevention of transmission and as early treatment in cases of in utero transmission. The objective of this study was to describe the risk of VT and use PHT among newborns in Canada, and specifically, factors associated with the use of PHT. METHODS:Data were analysed for all mother-infant pairs (MIPs) in the Canadian Perinatal HIV Surveillance Program (1997-2020), collected annually from 22 perinatal HIV centres in Canada. Infants were categorized as high risk (delivery viral load [dVL] ≥1000 copies/ml or maternal combined antiretroviral [cART] <4 weeks prior to delivery), moderate risk (dVL detectable and <1000 copies/ml, and maternal cART ≥4 weeks prior to delivery) and low risk (dVL undetectable and maternal cART ≥4 weeks prior to delivery). Neonatal prophylaxis and HIV transmission risk were compared between groups. RESULTS:A total of 4743 MIPs were included in the analysis. Overall, 13.3% of newborns received PHT; the most prescribed PHT regimens included combinations using zidovudine, lamivudine and nelfinavir (48.5%) or nevirapine (41.9%). While the most significant risk factor for transmission on univariate analysis was a detectable dVL ≥1000 copies/ml versus undetectable (odds ratio [OR] 27.91 [11.20-69.54]), the risk remained significantly increased at dVL between 400 and 999 copies/ml (OR 31.71 [8.31-120.98], but not at dVL between 50 and 399 copies/ml (OR 3.03 [0.72-12.81]). At dVL 50-399 copies/ml, 29.8% of infants received PHT, increasing to 46.7% at dVL 400-999 copies/ml, and 64.4% of infants at dVL≥1000 copies/ml. The overall risk of transmission was 6% in the high-risk group, 0.5% in the moderate-risk group and 0.2% in the low-risk group. CONCLUSIONS:PHT has been widely used in Canada in situations at high risk of VT, with 25% of newborns in this risk group receiving PHT as PNP. While PHT may reduce the risk of VT in high-risk situations and may be of benefit in cases of VT, these data also highlight ongoing gaps in perinatal HIV prevention in Canada.

Background:Children who are HIV-exposed uninfected (CHEU) are at increased risk for neurodevelopmental impairments. Most studies report on neurodevelopmental outcomes in the first 2 years of life, with limited data available for school-aged CHEU. This interim study examined the intellectual and language outcomes in school-aged CHEU compared to children who are HIV-unexposed uninfected (CHUU). Setting:CHEU and CHUU aged 6-10 years recruited at two sites in Ontario, Canada. Methods:Intellectual and language abilities were measured using the WISC-V and CELF-5. Generalized linear models investigated associations of HEU-status with each neurodevelopmental outcome. An interaction term with sex was included to assess sex-specific effects. Gestational age, being small for gestational age (SGA), and household income were investigated as covariates. Results:65 CHEU (35 female, median age 9.00 years) and 42 CHUU (18 female, 8.96 years) were included. HEU-status was associated with significantly lower working memory and expressive language scores. In males, HEU-status was associated with lower scores on working memory, processing speed, overall intelligence, core, and expressive language abilities. No significant differences were observed in females by HEU-status. Household income was associated with all measures of intelligence and language. Lower working memory scores persisted in male CHEU after adjusting for covariates. Conclusion:Male CHEU and those with lower household income were the most vulnerable to cognitive and language deficits. Working memory deficits in CHEU indicates a specific cognitive vulnerability due to HEU exposure status. Our findings highlight the need for early interventions, including ensuring financial security and close neuropsychological follow-up.

There are known maternal and obstetrical risks following SARS-CoV-2 infection in pregnancy, but the impact on offspring is not well known. The objective of this study was to examine offspring risks of hospitalization and emergency department visits in the first year of life following SARS-CoV-2 infection in pregnancy. This was a retrospective cohort study in Ontario, Canada of infants born from March 1, 2020 to December 31, 2021 using health administrative databases. The exposure group was defined by a positive SARS-CoV-2 PCR test in pregnancy, while the comparator group included pregnancies without a positive test recorded. The primary outcomes included all-cause offspring hospitalizations and emergency department (ED) visits in the first year of life. Poisson regression was used to adjust for maternal sociodemographic factors, medical and obstetrical history, and health behaviours. The main secondary outcome was risk of infections (including respiratory, gastrointestinal and otitis media infections) in the first year of life. A sensitivity analysis was conducted in which individuals with a negative SARS-CoV-2 test served as the comparator group. There were 222,448 live births during the study period; following matching 45,958 pregnancies were included. Cases were matched on maternal age, geography, and last menstrual period date in a 10:1 ratio. The exposed group included 5,291 pregnancies and the comparator group included 40,667 pregnancies. There was no significant difference observed between groups in risk of hospitalization (aRR (95

Chronic systemic inflammation may affect linear growth and neurodevelopment in children who are HIV-exposed but uninfected (cHEU). We examined plasma concentrations of neutrophil activation marker chitinase-3-like protein 1 (CHI3L1) levels in 153 Ugandan cHEU. At 18 months of age, CHI3L1 levels were inversely correlated with height-for-age z scores (τB = -0.17, P = 0.0035) and a normalized developmental score (τB = -0.20, P = 0.00027). CHI3L1 appears to be a marker of adverse growth and development in cHEU.

BACKGROUND:Although cytomegalovirus (CMV) disease has been well described among severely immunocompromised children living with HIV (CLWH), the impact of CMV coinfection, is not well understood. The objective of this study was to characterize the clinical and immunologic effects of CMV coinfection in CLWH in Canada. METHODS:This is a substudy of the Early Pediatric Initiation, Canada Child Cure Cohort study, which enrolled CLWH in Canada between 2014 and 2018. CMV serostatus was determined at the first (baseline) study visit, and HIV-1 viral load (VL), CMV VL, and lymphocyte subsets were quantified every 3-6 months. For a subset of participants, CD4 + and CD8 + T cell subsets were analyzed using flow cytometry. The clinical outcomes were recorded retrospectively at the baseline visit and prospectively during the study period. RESULTS:Of the 225 participants, 85.3% were CMV seropositive (CMV + ) and 81% had suppressed HIV VL. While there were no significant differences in clinical outcomes between CMV + and CMV - children, CMV + children had lower frequencies of CD4 + T cells, higher frequencies of CD8 + T cells, and lower CD4/CD8 ratio at baseline than CMV - children. Children with CMV + children also demonstrated a higher frequency of CD4 + effector memory cells, lower CD8 + naïve T cells, and higher frequencies of CD8 + terminally differentiated effector memory cells. These differences remained significant even after adjusting for HIV viral control. CONCLUSIONS:CMV coinfection is common among CLWH and is associated with distinct immunological changes despite the effective control of HIV replication with antiretroviral therapy. The long-term implications of these immunologic perturbations require further investigation.

ImportanceDetection of congenital cytomegalovirus (cCMV) infection has previously relied on targeted screening programs or clinical recognition; however, these approaches miss most cCMV-infected newborns and fail to identify those infants who are asymptomatic at birth but at risk for late-onset sensorineural hearing loss.ObjectiveTo determine the feasibility of using routinely collected newborn dried blood spots (DBS) in a population-based cCMV screen to identify infants at risk for hearing loss and describe outcomes of infants screened.Design, Setting, and ParticipantsThis diagnostic study of a population-based screening program in Ontario, Canada, took place from July 29, 2019, to July 31, 2023. All newborns with a DBS sample collected as part of routine care were screened using polymerase chain reaction (PCR) analysis for cCMV as a risk factor for hearing loss. Infants with positive DBS PCR results for cCMV were referred for confirmation of infection by urine PCR (the gold standard), as well as complete medical and audiologic assessments for sequelae of cCMV infection. Infants with possible or confirmed symptomatic cCMV were referred to pediatric infectious disease specialists for evaluation for potential treatment with valganciclovir.ExposureDetection of cCMV by polymerase chain reaction assay on a newborn DBS.Main Outcomes and MeasuresNumber of infants with positive screening results successfully retrieved and confirmed to have cCMV and the timeliness of retrieval and symptomatic evaluation.ResultsOf 565 987 infants born in the screening period, 551 034 (97.4%) received cCMV screening on the DBS (45.7% female, 54.3% male). Of these infants, 689 (0.13%) screened positive for cCMV; 601 (87.2%) had cCMV infection confirmed and a complete assessment of sequelae of their congenital infection. Ninety-six infants with completed assessments (16.0%) were deemed to have cCMV symptoms, and 63 of these (65.6%) began valganciclovir treatment. Sensorineural hearing loss was confirmed in 34 of 96 infants (35.4%).Conclusions and RelevanceThis program found acceptable and feasible implementation of a population-based screening program using routinely collected DBS samples, suggesting that it may serve as a template for jurisdictions considering universal cCMV screening. The program had a much lower than expected prevalence of cCMV-positive screens but still identified many children who would otherwise not have been diagnosed and who would benefit from ongoing audiologic surveillance.

A latent HIV reservoir persists in children living with HIV (CLWH) despite treatment. We tested whether levels of expression of cytokines and co-inhibitory receptors in early life influenced size and persistence of the HIV reservoir. PBMC and plasma from CLWH (n = 64, aged 5–18 years) were analyzed for cell surface co-inhibitory receptor expression and levels of 33 cytokines, respectively. Frequencies of CD4+ and CD8+ T cells expressing PD-1 or TIGIT increased with age and positively correlated with frequency of cells with total HIV DNA and inducible HIV RNA. Specifically, CLWH <10 years exhibited elevated levels of 7 cytokines, including IL-7, IL-15, and TGF-β1/2, with high HIV DNA and inducible RNA linked to cytokine profiles driving CD4+ T cell effector differentiation (e.g., IFN-γ, IL-4). High levels of IL-17A, TNF-α, and M-CSF were linked to stable HIV DNA over two years, while their decrease corresponded with HIV DNA decay. Reduced TGF-b1/2, in CLWH >10 years, were significantly associated with high inducible HIV RNA. Our data demonstrate that increased levels of T helper differentiation cytokines despite high TGF-b in younger CLWH are associated with persistently high HIV DNA in PBMCs from ART-suppressed children. These cytokines and expression of immune checkpoint markers on T cells correlates with heightened HIV inducibility. Overall, the data suggest that effector differentiation of dysfunctional T cells during early childhood drives persistence of the HIV reservoir. NICHD P01-HD112217 Viral Immunology (VIR)

Antiretroviral therapy (ART) has dramatically reduced perinatal HIV transmission, leading to a growing population of children who are HIV-exposed but uninfected (CHEU). While the neuroanatomic developmental impacts of in utero HIV and ART exposure have been studied in young children, long-term effects on school-aged children are poorly understood, prompting this investigation. Fifty-eight CHEU and 38 children who are HIV-unexposed, uninfected (CHUU), 6–12 years old, were recruited through hospitals and community groups in Ontario, Canada. From T1-weighted magnetic resonance images, volume, cortical thickness, and gray-/white-matter tissue volume were extracted. Multiple linear regression models controlling for sex, age, household income, and total brain volume were fit to assess differences by in utero HIV exposure, with additional sex-stratified analyses to uncover sex-specific effects. Compared with CHUU, CHEU showed total brain volumes that were significantly smaller by 49.7cm3 (95

BACKGROUND:Bictegravir (BIC) was recently transitioned from insufficient data in pregnancy to an alternative antiretroviral therapy in pregnancy. Our study aimed to examine the perinatal and early infant outcomes after BIC exposure in pregnancy in Canada. METHODS:Data were obtained from the Canadian Perinatal HIV Surveillance Program for liveborn infants from July 28, 2018, to December 31, 2023. Using univariate analyses, BIC-exposed infants were compared with infants exposed to other antiretroviral regimens. To determine the independent association between preterm births and BIC, we completed a logistic regression analysis adjusting for relevant preterm birth risk factors. RESULTS:Among 1256 infants, 161 infants were exposed to BIC in pregnancy compared with 1095 infants exposed to non-BIC regimens. BIC exposure was categorized as preconception BIC with continued use in pregnancy (n = 81; 52%), preconception BIC with discontinuation in pregnancy (n = 34; 22%), and BIC started in pregnancy (n = 41; 26%). Infants exposed to BIC were more likely born to Indigenous mothers (38% vs. 21%; P < 0.001) linked with injection drug use (28% vs. 14%; P < 0.001). Infants exposed to BIC were more likely born preterm (19.4% vs. 12.9%; P = 0.025). After adjusting for ethnicity, maternal mode of HIV transmission, and viral load at delivery, preterm birth was not associated with BIC exposure (OR: 1.39; 95% CI: 0.78 to 2.49; P = 0.261). There were no between-group differences in maternal HIV viral load at delivery, mode of delivery, small for gestational age, perinatal HIV transmission, or congenital anomalies. CONCLUSIONS:BIC was not independently associated with adverse perinatal and early infant outcomes in the Canadian cohort, supporting recent guideline updates.

There have been growing ethical concerns about the widespread use of HIV-related molecular epidemiological public health surveillance and research—or what has come to be known as molecular HIV surveillance. The varied concerns of the practice originate due to lack of informed consent, lack of demonstrated benefit for communities, potential for eroded patient care relationships leading to poor health outcomes, and potential implications for information sharing and findings which could increase stigmatization and other negative impacts in contexts where HIV, drug use, sex work, migration, and poverty are criminalized. As people living with HIV, lawyers, clinicians, and social scientists, we are part of the growing movement calling for critical and ethical attention to the practice of molecular HIV surveillance and the public health logic which underwrites the practice. We urge Canadian public health actors and researchers working with molecular surveillance data to heed global guidance and recommendations for culturally informed ethical practices, to engage community members in HIV surveillance programs, and to ensure that people living with HIV are provided appropriate consent processes for uses of secondary data analysis. Furthermore, we urge researchers and Research Ethics Boards to interrogate assumptions of impracticality in seeking subsequent consent to use persons’ health information held in data repositories and explore new methods of informed consent.

Objective: To investigate the association between African ancestry and neutrophil counts among children living with HIV (CLWH). We also examined whether medications, clinical conditions, hospitalization, or HIV virologic control were associated with low neutrophil counts or African ancestry. Design: We conducted a secondary analysis of the Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) Study, a multicenter prospective cohort study of CLWH across eight Canadian pediatric HIV care centers. Methods: We classified CLWH according to African ancestry, defined as "African," "Caribbean" or "Black" maternal race. Longitudinal laboratory data (white blood cells (WBCs), neutrophils, lymphocytes, viral load, CD4 count) and clinical data (hospitalizations, AIDS-defining conditions, treatments) were abstracted from medical records. Results: Among 217 CLWH (median age 14, 55% female), 145 were of African ancestry and 72 were of non-African ancestry. African ancestry was associated with lower neutrophil counts, WBC counts, and neutrophil-lymphocyte ratios. Neutrophil count<1.5x10(9)/L was detected in 60% of CLWH of African ancestry, compared to 31% of CLWH of non-African ancestry (p<0.0001), representing a 2.0-fold higher relative frequency (95% CI 1.4-2.9). Neutrophil count was on average 0.74x10(9)/L (95%CI 0.45-1.0) lower in CLWH of African ancestry (p<0.0001). Neither neutrophil count<1.5x10(9)/L nor African ancestry was associated with medications, hospitalizations, AIDS-defining conditions, or markers of virologic control (viral load, sustained viral suppression, lifetime nadir CD4). Conclusion: In CLWH, African ancestry is associated with lower neutrophil counts, without clinical consequences. A flexible evaluation of neutrophil counts in CLWH of African ancestry may avoid unnecessary interventions.

Background: Chronic/latent viral infections may accelerate immunological aging, particularly among people living with HIV (PLWH). We characterized chronic/latent virus infections across their lifespan and investigated their associations with leukocyte telomere length (LTL). Methods: Participants enrolled in the CARMA cohort study were randomly selected to include n = 15 for each decade of age between 0 and >60 y, for each sex, and each HIV status. Cytomegalovirus (CMV), Epstein–Barr virus (EBV), human herpesvirus 8 (HHV-8), herpes simplex virus 1 (HSV-1), and HSV-2 infection were determined serologically; HIV, hepatitis C (HCV), and hepatitis B (HBV) were self-reported. LTLs were measured using monochrome multiplex qPCR. Associations between the number of viruses, LTL, and sociodemographic factors were assessed using ordinal logistic and linear regression modeling. Results: The study included 187 PLWH (105 female/82 male) and 190 HIV-negative participants (105 female/84 male), ranging in age from 0.7 to 76.1 years. Living with HIV, being older, and being female were associated with harbouring a greater number of chronic/latent non-HIV viruses. Having more infections was in turn bivariately associated with a shorter LTL. In multivariable analyses, older age, living with HIV, and the female sex remained independently associated with having more infections, while having 3–4 viruses (vs. 0–2) was associated with a shorter LTL. Conclusions: Our results suggest that persistent viral infections are more prevalent in PLWH and females, and that these may contribute to immunological aging. Whether this is associated with comorbidities later in life remains an important question.

Youth (aged 15 to 29 years) account for one quarter of new HIV cases in Canada. Of those, men-who-have-sex-with-men make up one third to one half of new cases in that age range. Moreover, Indigenous youth are over-represented in the proportion of new cases. The use of emtricitabine/tenofovir disoproxil fumarate as pre-exposure prophylaxis (PrEP) significantly reduces the risk of HIV acquisition in adults. Its use was expanded to include youth over 35 kg by the U.S. Food and Drug Administration in 2018. However, PrEP uptake remains low among adolescents. Prescriber-identified barriers include lack of experience, concerns about safety, unfamiliarity with follow-up guidelines, and costs. This article provides an overview of PrEP for youth in Canada, and its associated safety and side effect profiles. Hypothetical case vignettes highlight some of the many demographics of youth who could benefit from PrEP. We present a novel flow diagram that explains the baseline workup, prescribing guidelines, and follow-up recommendations in the Canadian context. Additional counselling points highlight some of the key discussions that should be elicited when prescribing PrEP.

Objective:Children who are HIV-exposed uninfected (CHEU) are at risk of neurodevelopmental impairments due to perinatal HIV and antiretroviral therapy exposure as well as additional health and psychosocial burdens. There is limited understanding of the impact of perinatal risk factors on long-term outcomes of CHEU. The present study investigated the association between perinatal risk factors and the intellectual and language abilities in CHEU and children who are HIV-unexposed uninfected (CHUU).Participants and Methods:CHEU and CHUU, 6 to 10 years, of age underwent neurodevelopmental assessments through the Kids Imaging and Neurocognitive Development (KIND) study at the Hospital for Sick Children in Toronto, Canada between January 2020 and August 2022. CHUU were recruited from the community with similar sociodemographic backgrounds based on residential area in Toronto and parental income levels. Measures of Full-Scale IQ (FSIQ), Verbal Comprehension (VCI), Visual Spatial skills (VSI), Fluid Reasoning (FRI), Working Memory (WMI), and Processing Speed (PSI) were evaluated with the Wechsler Intelligence Scale for Children - Fifth Edition. Core Language, Receptive Language, and Expressive Language skills were assessed with the Clinical Evaluation of Language Fundamentals - Fifth Edition. Perinatal risk factors included birthweight, birth complications (e.g., premature rupture of membranes, jaundice, etc.), maternal smoking and alcohol use during pregnancy, and NICU admission. Analyses of variance and chi-square tests were performed to investigate group differences and multiple regression analyses tested the relation between neurodevelopmental measures and birth factors. Significance was held at p <0.05.Results:36 CHEU (21 female, 8.74 ±1.56 years) and 26 CHUU (12 female, 8.53 ±1.50 years) children were included. For both groups, mean standardized scores of the cognitive abilities assessed were in the average range. CHEU had significantly lower birth weight than CHUU, but there were no differences between these groups with respect to maternal smoking and alcohol use, birth complications or NICU admission. There were no between group differences identified for the intellectual and language abilities. In the CHEU group, birthweight was significantly associated with lower VCI, WMI, and expressive language. In the CHUU group, prenatal alcohol and smoking exposure was associated with lower VCI scores. Birth complications were associated with lower WMI, PSI, and FSIQ scores.Conclusions:In this interim analysis, perinatal risk factors impacted neurodevelopmental outcomes of CHEU and CHUU differently. While the groups did not differ in frequency of birth complications and maternal smoking and alcohol use, these factors negatively impacted aspects of intellectual ability in the CHUU group. CHEU with lower birthweight are at greater risk of working memory and language difficulties, supporting the need for early interventions and close neuropsychological follow-up of this population throughout childhood.