Susan B. Brogly

In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children.

Background:There is equivocal evidence of in utero nucleoside reverse transcriptase inhibitor (NRTI) exposure and the occurrence of mitochondrial dysfunction (MD) in HIV-uninfected children born of HIV-infected women. Methods:The primary analysis included 1037 HIV-uninfected children born in 1991–2002 and enrolled in Pediatric AIDS Clinical Trials Group protocols 219/219C. Possible cases with unexplained signs of MD according to the Enquête Périnatale Française criteria were identified through retrospective review. Associations between overall in utero NRTI exposure, and trimester of first in utero NRTI exposure and possible MD were estimated with exact logistic regression. Results:Cases (n = 20) were significantly more likely to be male and to be born in earlier years than non-cases (n = 1017). There was no association between overall in utero NRTI exposure and MD. In unadjusted models there were higher odds of first in utero exposure in the third trimester to lamivudine (3TC) [odds ratio (OR), 3.76 versus 3TC unexposed; 95% confidence interval (CI), 1.09–11.78] and to zidovudine (ZDV) and 3TC in combination (ZDV/3TC) (OR, 3.29 vs. ZDV/3TC unexposed; 95% CI, 0.96–10.25) among cases than noncases. When adjusted for year of birth the odds of first exposure in the third trimester to 3TC (OR, 10.57; 95% CI, 1.93–75.61) and ZDV/3TC (OR, 9.84; 95% CI, 1.77–71.68) were significantly higher among cases than non-cases. Incomplete data precluded control of possible confounding by maternal viral load and psychoactive drug use. Conclusions:Our study suggests that first exposure to 3TC or ZDV/3TC in the third trimester may be associated with the occurrence of possible MD. Further studies that rigorously assess MD and better control confounding are needed.

Prenatal Protease Inhibitor Use and Risk of Preterm Birth among HIV-Infected Women Initiating Antiretroviral Drugs during Pregnancy

BACKGROUND Conflicting results have been reported among studies of protease inhibitor (PI) use during pregnancy and preterm birth. Uncontrolled confounding by indication may explain some of the differences among studies. METHODS In total, 777 human immunodeficiency virus (HIV)-infected pregnant women in a prospective cohort who were not receiving antiretroviral (ARV) treatment at conception were studied. Births <37 weeks gestation were reviewed, and deliveries due to spontaneous labor and/or rupture of membranes were identified. Risk of preterm birth and low birth weight (<2500 g) were evaluated by using multivariable logistic regression. RESULTS Of the study population, 558 (72%) received combination ARV with PI during pregnancy, and a total of 130 preterm births were observed. In adjusted analyses, combination ARV with PI was not significantly associated with spontaneous preterm birth, compared to ARV without PI (odds ratio [OR], 1.22; 95% confidence interval [CI], 0.70-2.12). Sensitivity analyses that included women who received ARV prior to pregnancy also did not identify a significant association (OR, 1.34; 95% CI, 0.84-2.16). Low birth weight results were similar. CONCLUSIONS No evidence of an association between use of combination ARV with PI during pregnancy and preterm birth was found. Our study supports current guidelines that promote consideration of combination ARV for all HIV-infected pregnant women.

Review of the assessment and management of neonatal abstinence syndrome

Neonatal abstinence syndrome (NAS) secondary to in-utero opioid exposure is an increasing problem. Variability in assessment and treatment of NAS has been attributed to the lack of high-quality evidence to guide management of exposed neonates. This systematic review examines available evidence for NAS assessment tools, nonpharmacologic interventions, and pharmacologic management of opioid-exposed infants. There is limited data on the inter-observer reliability of NAS assessment tools due to lack of a standardized approach. In addition, most scales were developed prior to the prevalent use of prescribed prenatal concomitant medications, which can complicate NAS assessment. Nonpharmacologic interventions, particularly breastfeeding, may decrease NAS severity. Opioid medications such as morphine or methadone are recommended as first-line therapy, with phenobarbital or clonidine as second-line adjunctive therapy. Further research is needed to determine best practices for assessment, nonpharmacologic intervention, and pharmacologic management of infants with NAS in order to improve outcomes.

Neurodevelopment and in utero antiretroviral exposure of HIV-exposed uninfected infants.

OBJECTIVE: Antiretroviral (ARV) drugs are routinely provided to HIV-infected pregnant women to prevent HIV mother-to-child transmission. Although ARV use has significantly reduced mother-to-child transmission to <2% in the United States, it remains crucial to monitor uninfected infants and children for adverse consequences of in utero ARV exposure. METHODS: We studied neurodevelopmental function in HIV-exposed uninfected children who were enrolled in Pediatric AIDS Clinical Trials Group 219/219C, a multisite, prospective, cohort study. Mental and motor functioning were assessed with the Bayley Scales of Infant Development (BSID), first and second editions. ARV exposure information was collected during pregnancy or within the first years of life. Linear regression methods were used to evaluate the association of in utero ARV exposure on Mental Developmental Index and Psychomotor Developmental Index at 2 years of age, controlling for demographic factors (age, gender, and race/ethnicity) and potential confounders: test version, primary language, primary caregiver, caregiver education level, low birth weight, geographic and urban/rural location, birth year, and maternal illicit drug use. RESULTS: Among 1840 infants who were born between 1993 and 2006, 1694 (92%) were exposed to ARV in utero and 146 (8%) were not exposed. After controlling for confounders, children who were exposed in utero to any ARV did not have lower Mental Developmental Index and Psychomotor Developmental Index scores than unexposed children. Among low birth weight infants, significantly higher BSID scores were observed for prenatally ARV-exposed than unexposed children. Maternal illicit drug use was reported for 17% of mothers but was not associated with BSID scores. CONCLUSIONS: Mental and motor functioning scores were not lower for infants with in utero ARV exposure compared with no exposure. Although these results are reassuring, continued evaluation of uninfected children with in utero ARV exposure for long-term adverse outcomes is important.

Birth defects among children born to human immunodeficiency virus-infected women: pediatric AIDS clinical trials protocols 219 and 219C.

Background: Some studies have detected associations between in utero antiretroviral therapy (ARV) exposure and birth defects but evidence is inconclusive. Methods: A total of 2202 human immunodeficiency virus (HIV)-exposed children enrolled in the Pediatric AIDS Clinical Trials Group 219 and 219 C protocols before 1 year of age were included. Birth defects were classified using the Metropolitan Atlanta Congenital Defects Program coding. Logistic regression models were used to evaluate associations between first trimester in utero ARV exposure and birth defects. Results: A total of 117 live-born children had birth defects for a prevalence of 5.3% (95% confidence interval [CI]: 4.4, 6.3). Prevalence did not differ by HIV infection status or overall ARV exposure; rates were 4.8% (95% CI: 3.7, 6.1) and 5.8% (95% CI: 4.2, 7.8) in children without and with first trimester ARV exposure, respectively. The defect rate was higher among children with first trimester efavirenz exposure (5/32, 15.6%) versus children without first trimester efavirenz exposure (adjusted odds ratio [aOR] = 4.31 [95% CI: 1.56, 11.86]). Protective effects of first trimester zidovudine exposure on musculoskeletal defects were detected (aOR = 0.24 [95% CI: 0.08, 0.69]), while a higher risk of heart defects was found (aOR = 2.04 [95% CI: 1.03, 4.05]). Conclusions: The prevalence of birth defects was higher in this cohort of HIV-exposed children than in other pediatric cohorts. There was no association with overall ARV exposure, but there were some associations with specific agents, including efavirenz. Additional studies are needed to rule out confounding and to evaluate newer ARV agents.

Satellite needle distribution among injection drug users: Policy and practice in two Canadian cities

Summary: Access to clean needles and syringes through needle exchange programs (NEPs) has reduced both high‐risk behaviors and the transmission of blood‐borne infections among injection drug users (IDUs). However, policies regarding “needle‐for‐needle” exchange versus unrestricted needle distribution remain controversial. The objective of this study was to compare sources of needles, trends in needle distribution, and the practice of satellite needle distribution (SND) among IDUs in Vancouver and Montreal. SND was defined as receiving a new syringe from another individual through trading, purchasing, borrowing, or being given the syringe outright, or supplying a syringe to another individual through trading, selling, lending, or giving a syringe outright. This was practiced by 46% of IDUs in Vancouver and 50% of IDUs in Montreal. SND was associated with borrowing used injection equipment (adjusted OR [AOR], 2.62; 95% CI: 1.85‐3.71), conducting bulk needle exchanges (AOR, 1.85; 95% CI: 1.34‐2.54), being married or in a common‐law relationship (AOR, 1.85; 95% CI: 1.34‐2.54), and regular visits to the NEP (> weekly) (AOR, 1.54; 95% CI: 1.17‐2.13). In Vancouver, SND was also associated with borrowing used needles (AOR, 2.07; 95% CI: 1.22‐3.52). In these two cities, despite different distribution policies, almost half of the participants reported SND, and this was associated with high risk sharing. The practice of SND appears to be an important mechanism for needle acquisition, especially for those at highest risk for HIV and hepatitis C transmission.

Prenatal Buprenorphine Versus Methadone Exposure and Neonatal Outcomes: Systematic Review and Meta-Analysis

Increasing rates of maternal opioid use during pregnancy and neonatal withdrawal, termed neonatal abstinence syndrome (NAS), are public health concerns. Prenatal buprenorphine maintenance treatment (BMT) versus methadone maintenance treatment (MMT) may improve neonatal outcomes, but associations vary. To summarize evidence, we used a random-effects meta-analysis model and estimated summary measures of BMT versus MMT on several outcomes. Sensitivity analyses evaluated confounding, publication bias, and heterogeneity. Subjects were 515 neonates whose mothers received BMT and 855 neonates whose mothers received MMT and who were born from 1996 to 2012 and who were included in 12 studies. The unadjusted NAS treatment risk was lower (risk ratio=0.90, 95% confidence interval (CI): 0.81, 0.98) and mean length of hospital stay shorter (-7.23 days, 95% CI: -10.64, -3.83) in BMT-exposed versus MMT-exposed neonates. In treated neonates, NAS treatment duration was shorter (-8.46 days, 95% CI: -14.48, -2.44) and morphine dose lower (-3.60 mg, 95% CI: -7.26, 0.07) in those exposed to BMT. BMT-exposed neonates had higher mean gestational age and greater weight, length, and head circumference at birth. Fewer women treated with BMT used illicit opioids near delivery (risk ratio=0.44, 95% CI: 0.28, 0.70). Simulations suggested that confounding by indication could account for some of the observed differences. Prenatal BMT versus MMT may improve neonatal outcomes, but bias may contribute to this protective association. Further evidence is needed to guide treatment choices.

Prevalence of Congenital Anomalies in Infants with in Utero Exposure to Antiretrovirals

Background: Although use of efficacious interventions, including antiretrovirals (ARVs), has dramatically reduced the rate of mother-to-child transmission of human immunodeficiency virus, the safety of in utero ARV exposure remains of concern. Methods: Data regarding 1112 infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group protocol P1025 born between 2002 and 2007 were analyzed for this study. Congenital anomalies were classified based on the Metropolitan Atlanta Congenital Defects Program guidelines. Associations between congenital anomalies and timing of first in utero exposure to ARVs were evaluated by logistic regression analysis. Results: Congenital anomalies were identified and confirmed in 61 of the 1112 infants, resulting in a prevalence of 5.49/100 live births (95% confidence interval, 4.22–6.99). Among the 80 anomalies identified, the organ systems involved included cardiovascular (n = 33), musculoskeletal (n = 15), renal (n = 9), genitourinary (n = 6), craniofacial (n = 4), and central nervous system (n = 2). First trimester exposure to efavirenz was associated with a significantly increased risk of congenital anomalies (odds ratio, 2.84; 95% confidence interval, 1.13–7.16). No significant associations were observed between exposure to other individual ARVs or classes of ARVs started at any time during pregnancy and infant congenital anomalies. Conclusions: The observed rate of congenital anomalies in this cohort is higher than previously reported for the general population, but it is consistent with rates observed in other recent studies of children born to human immunodeficiency virus–infected women. Cardiovascular anomalies occurred most frequently. With the exception of a known teratogen (efavirenz), no statistically significant associations between in utero exposure to ARVs and congenital anomalies were identified.

Towards More Effective Public Health Programming for Injection Drug Users: Development and Evaluation of the Injection Drug User Quality of Life Scale

The psychometric properties of the Injection Drug User Quality of Life Scale (IDUQOL) were assessed in 61 Montreal IDUs in 2001, 85% of whom were reinterviewed within four weeks. The reliability of the IDUQOL was acceptable (ICC = 0.71) and concordance between the IDUQOL and the Flanagan Quality of Life Scale was moderate (Pearson coefficient = 0.57). Quality of life was negatively associated with injection cocaine and emergency department use with both instruments; these results were more striking for the IDUQOL. The IDUQOL is a culturally relevant quality of life instrument with good psychometric properties. The IDUQOL may be useful in the development and evaluation of interventions for IDUs.

Malignancy in perinatally human immunodeficiency virus-infected children in the United States

Objectives: To determine the incidence of and factors associated with malignancy in perinatally human immunodeficiency virus (HIV)-infected children in the United States. Methods: Included were 2969 children followed in the Pediatric AIDS Clinical Trials Group (PACTG) 219/219C cohort from 1993 through 2003. Cancer incidence by sex, race, age, histology and highly active antiretroviral therapy (HAART) era (pre-HAART, 1993–1997; HAART, 1998–2003) was estimated, and the standardized incidence ratio contrasting infected and uninfected children was determined. Poisson regression was used to further investigate the relation between HAART use (≥3 drugs of ≥2 classes, 1 of which was a protease inhibitor), CD4+% and cancer. Results: There were 37 cancers (17 prevalent and 20 incident) diagnosed in 2969 children for a prevalence of 0.6% [95% confidence interval (CI), 0.3, 0.9] and an incidence of 1.56/1000 person-years (95% CI 0.95, 2.41). Compared with uninfected children, the standardized incidence ratio was 10.08 (95% CI 5.87, 16.14). Incidence did not significantly differ by sex, race, age or HAART era. Of the cases, 35% were immunocompetent (CD4+ ≥25%), 25% were moderately immunosuppressed (15%≤ CD4+ ≤24%) and 40% were severely immunosuppressed (CD4+ <15%) at diagnosis. In multivariate regression, the cancer rate was 3.09 (95% CI 1.22, 7.85) times higher in children with ≤2 years of HAART use than in children with >2 years of HAART and 3.20 (95% CI 1.32, 7.76) times higher in children with CD4+ <15% at cohort enrollment than in children with CD4+ ≥15%. Conclusion: Cancer incidence in this U.S. pediatric cohort was lower than that of European cohorts but was markedly higher than that of HIV-uninfected children. Cancer incidence was highest in children who were severely immunosuppressed and in children who received HAART for ≤2 years.