Nearly 9000 HIV-exposed but uninfected (HEU) infants are born in the US each year, and from 85% to nearly 97% were exposed in utero and/or in early infancy to antiretroviral drugs [1,2]. In-utero antiretroviral exposure has been associated with significant changes in echocardiographic parameters of left-ventricular structure and function in HEU children within the first 2 years of life in the highly active antiretroviral therapy (HAART) era . Antiretroviral-exposed HEU infants need to be followed to monitor the long-term safety of these exposures including cardiac health .
Cardiac biomarkers which have proven useful in evaluating cardiac status in children with a variety of conditions may be similarly useful in HIV-infected or HEU children [5,6]. In children, serum measurements of cardiac troponins T (cTnT) and I (cTnI) are sensitive and specific for detecting myocardial injury in a variety of settings [7–12]. Elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are sensitive markers of asymptomatic left-ventricular systolic and diastolic dysfunction, as determined by echocardiography [13,14]. Serum high-sensitivity C-reactive protein (hsCRP) is a general inflammatory marker produced in response to infection or inflammation associated with a variety of cardiovascular conditions [15–17].
Echocardiographic screening and monitoring of the thousands of HEU children born annually in the US is not affordable or practical. Cardiac biomarkers could potentially identify which HEU patients might benefit from a more comprehensive clinical assessment including echocardiography. Using data from a cohort of HEU children, we tested two hypotheses: first, that there would be associations between specific maternal antiretroviral regimens and abnormal cardiac biomarker levels and, second, that there would be a significant association between levels of cardiac biomarkers and echocardiographic measurements.
The Surveillance Monitoring for ART Toxicities Study (SMARTT) of the Pediatric HIV/AIDS Cohort Study (PHACS) is a prospective study of the potential adverse outcomes of maternal antiretroviral drug use on HEU infants and children using longitudinal demographic, anthropomorphic, clinical, and laboratory data collected at 22 US pediatric centers. The study protocol was reviewed and approved by the institutional review boards at all sites. Written informed consent was obtained from the children's parent or legal guardian and assent from child participants as appropriate. Details of the SMARTT study design have been described previously .
Children underwent a single echocardiogram and blood draw between the ages of 3 and 5 years. Cardiac biomarker evaluation was initiated prior to performing an echocardiogram on all children, and only a subset of children had biomarker assays performed within 3 months of the echocardiogram. Biomarker assays were performed using the repository specimen closest in time to the echocardiogram for participants who had an echocardiogram; the most recently obtained specimen was used for participants who did not have an echocardiogram.
Cardiac biomarker assays
For consistency, all specimens were analyzed for cardiac biomarkers at the Clinical Chemistry Laboratory at Boston Children's Hospital: high-sensitivity cTnT, with a detection limit of 3 pg/ml and normal value defined as 3 pg/ml or less; hsCRP, with normal defined as 1 mg/l or less; and NT-proBNP, with normal defined as 100 pg/ml or less [10,19,20]. cTnT and NT-proBNP were measured by a quantitative sandwich enzyme immunoassay technique on the Roche E Modular system (Roche Diagnostics, Indianapolis, Indiana, USA). The concentration of hsCRP was determined using an immunoturbidimetric assay on the Roche P Modular system (Roche Diagnostics). These biomarkers are stable in cryopreserved specimens [7,21–25].
Child and maternal factors and maternal antiretroviral use
Child demographic, anthropometric factors, and birth characteristics [preterm birth (<37 weeks) and low birth weight (<2500 g)] were considered. Maternal factors included young age at delivery (<25 years), low household income (<$20 000), less than a high school education, viral load above 1000 copies/ml, CD4+ T-lymphocyte (CD4) cell count below 250 cells/μl, and illicit substance use during pregnancy. Intrauterine exposures to individual antiretroviral drugs, antiretroviral drug classes, and HAART were examined overall and by trimester. Antiretroviral drug classes included nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors. HAART was defined as at least three antiretroviral drugs from at least two antiretroviral drug classes.
Echocardiographic assessment of cardiac structure and function
An M-mode echocardiogram including 2-D and tissue Doppler imaging was performed by PHACS trained sonographers. Echocardiographic measures were centrally re-measured at the echocardiographic core lab at Boston Children's Hospital to improve measurement reliability.
Using normative data from a reference cohort of healthy children from Boston Children's Hospital Echocardiographic Laboratory, echocardiographic parameter Z-scores were calculated. This population was not known to be HIV-infected or antiretroviral-exposed and was not matched to the study cohort for race, ethnicity, or socioeconomic status . Reporting the data as Z-scores adjusts for the effects of variation in age and body surface area.
We calculated the percentage of children with elevated levels of each cardiac biomarker, along with exact 95% confidence intervals (CIs) based on a binomial distribution. Logistic regression models were used to assess the association of maternal and infant characteristics and of in-utero antiretroviral exposure with abnormal biomarker levels. Child characteristics considered included age at biomarker measurement, sex, race, ethnicity, prematurity, low birth weight, and BMI Z-score. Maternal characteristics included age at delivery of child, household income, educational level, maternal CD4 cell count and viral load, and use of illicit drugs, alcohol or tobacco during pregnancy. Univariate logistic regression models were first fit for each covariate and those with P less than 0.20 were considered for inclusion in a multivariate model. The multivariate model was reduced to those covariates with P less than 0.15 to develop a separate core model for each biomarker. Adjusted logistic regression models were then fit for intrauterine exposure to HAART and for each drug class overall and by trimester, adjusting for potential confounders. Similar analyses evaluating associations between individual antiretroviral agents and elevated cardiac biomarkers were also conducted, restricting to children with intrauterine exposure to HAART to reduce residual confounding. Because prematurity and/or low birth weight may be on the causal pathway between in-utero antiretroviral exposure and abnormalities in cardiac biomarkers, sensitivity analyses were also conducted excluding these birth characteristics from models.
The association between cardiac biomarkers with echocardiographic Z-scores was based on a subset of participants (the echocardiogram group) aged 3–5 years who also had an echocardiogram conducted within 3 months of their blood draw and was evaluated in two ways. First, Spearman rank-based correlation coefficients were calculated between cardiac biomarker measurements and each targeted echocardiographic parameter. Secondly, the mean echocardiographic Z-scores were compared between those with elevated versus those with normal biomarker levels in linear regression models adjusting for potential confounders, including age sex, ethnicity, and BMI Z-score. Two-sided P values less than 0.05 were considered statistically significant. Because SMARTT is a safety study, we did not adjust for multiple comparisons in order to minimize the type II error rate (e.g. the probability of failing to detect true associations). SAS version 9.2 (SAS Institute, Cary, North Carolina, USA) was used to conduct all analyses, based on data submitted as of 1 October 2010.
We evaluated 338 children enrolled between March 2007 and June 2009 who had cardiac biomarker measurements obtained at a mean age of 4.3 years (Table 1). Ninety-four of these patients also had an echocardiogram within 3 months of the biomarker measurements. The group was 50% female, 66% non-White, and 43% Hispanic. Almost all participants (96%) received neonatal prophylaxis with zidovudine for the first 6 weeks of life, whereas a small number (n = 10, 3%) received zidovudine in combination with at least one other antiretroviral drug as prophylaxis. There were no significant differences between those with versus those without an echocardiogram for any child or maternal characteristic.
Prevalence of elevated cardiac biomarkers
For the 338 children with biomarker measurements, the median level of NT-proBNP was 57.6 pg/ml [interquartile range (IQR) = 29.8, 94.8], 87% of cTnT results were at or below the limit of detection of 3.0 pg/ml, and the median level of hsCRP was 0.22 mg/l (IQR = 0.11, 0.97). No child had an NT-proBNP level in the cardiomyopathy (>100 pg/ml) or heart failure range (>400 pg/ml) . Two children had cTnT measurements which exceeded the 10 pg/ml level (10.9 and 72.4 pg/ml, respectively), the limit of detection of the older, less-sensitive cTnT assay; no child had cTnT measurements in the unstable angina range of 100–200 pg/ml or the acute myocardial infarction range of above 200 pg/ml. However, 42 of 338 children (12%) had a cTnT between 3 and 10 pg/ml, a low-level elevation of unclear clinical significance. Elevated biomarker levels ranged from 13 to 24% (Fig. 1). At least one elevated biomarker value was found in 51% of children.
Association of cardiac biomarkers with child demographic and maternal factors
Elevated levels of hsCRP were associated with older age at biomarker draw [adjusted odds ratio (aOR) 1.42, 95% CI 1.03, 1.94, P = 0.03], whereas children born prematurely had reduced odds of elevated hsCRP (aOR 0.46, 95% CI 0.22, 0.97, P = 0.04). Elevated NT-proBNP levels were associated with maternal tobacco use (aOR 2.28, 95% CI 1.13, 4.58, P
= 0.02); female sex (aOR 1.73, 95% CI 0.94, 3.18, P = 0.08), Hispanic ethnicity (aOR 1.83, 95% CI 0.99, 3.40, P = 0.05), maternal viral load above 1000 copies/ml (aOR 2.10, 95% CI 0.99, 4.46, P = 0.05), and marginally with low birth weight (aOR 1.86, 95% CI 0.92, 3.76, P = 0.08). Increased odds of elevated cTnT were associated with younger age of the child (aOR 0.56, 95% CI 0.38, 0.85, P = 0.01), and marginally associated with younger age of the mother at delivery (aOR 0.46, 95% CI 0.20, 1.07, P = 0.07). Maternal alcohol use during pregnancy was associated with more than three-fold odds of an elevated level of cTnT (aOR 3.56, 95% CI 1.30, 9.74, P = 0.01).
Association of maternal antiretroviral drug exposures and cardiac biomarkers
Most (84%) participants had intrauterine exposure to HAART, 97% had exposure to NRTIs (primarily zidovudine and lamivudine), 23% had exposure to NNRTIs (primarily nevirapine), and 69% had exposure to protease inhibitors (primarily nelfinavir) (Table 2). With one exception, no significant associations were found between in-utero HAART exposures or specific drug classes, either overall or during the first trimester, and elevated cardiac biomarkers. Overall exposure to NRTIs was associated with decreased odds of elevated NT-proBNP levels (aOR 0.08, 95% CI 0.01, 0.85, P = 0.04); however, only 3% of participants were unexposed to NRTIs. The only individual antiretroviral drugs for which intrauterine exposure showed associations with elevated cardiac biomarkers after adjustment for maternal and child covariates were abacavir and stavudine. Abacavir exposure was associated with increased odds of elevated cTnT levels (aOR 2.33, 95% CI 1.03, 5.26, P = 0.04). Stavudine was significantly associated with decreased odds of elevated NT-proBNP (aOR 0.13, 95% CI 0.02, 0.99, P = 0.05). In sensitivity analyses excluding birth characteristics (prematurity and low birth weight) from models for NT-proBNP and hsCRP due to the possibility of these measures being part of the causal pathway between in-utero ART exposure and elevated cardiac biomarkers, the above findings remained unchanged.
Association between cardiac biomarkers and echocardiographic parameters
For the 94 children with an echocardiogram within 3 months of a biomarker assay, the mean echocardiographic Z-scores were 0.00 for left-ventricular fractional shortening (a load-dependent measure of left-ventricular systolic performance), and 0.09 for left-ventricular contractility (a load-independent measure of left-ventricular systolic performance that reflects the health of the cardiomyocytes), consistent with cardiac functioning in the reference population. However, mean Z-scores for left-ventricular thickness-to-dimension ratio (a measure of potential left-ventricular remodeling which is left-ventricular structural changes of the left-ventricular wall thickness and dimension in response to a cardiac injury or insult) (−0.52), and end-diastolic septal thickness (a measure of ventricular structure) (−0.23) were significantly below 0 (P < 0.0001 and P = 0.011, respectively).
Table 3 summarizes the association of cardiac biomarkers with echocardiographic parameter Z-scores, based on both linear regression models comparing mean echocardiographic Z-scores between children with abnormal versus normal biomarker levels and on Spearman correlation coefficients for biomarker levels with echocardiographic Z-scores. The adjusted mean Z-scores for children with abnormal cTnT levels were significantly higher than those for children with normal cTnT levels for left-ventricular end-diastolic (LVED) posterior wall thickness (a measure of ventricular structure) (mean Z = 0.33 versus −0.21, respectively, P = 0.04) and left-ventricular thickness-to-dimension ratio (mean Z = −0.10 versus −0.61, respectively; P = 0.04). Mean end-systolic septal thickness Z-scores were significantly lower in children with elevated NT-proBNP than children with normal NT-proBNP (mean Z = −0.89 versus −0.39; P = 0.03). In addition, left-ventricular contractility Z-scores for children with abnormal hsCRP levels were significantly lower than for those with normal hsCRP (mean Z = −0.37 versus 0.21; P = 0.04).
Using continuous measures of biomarker levels, hsCRP was inversely associated with ED septal thickness (correlation coefficient r = −0.22, P = 0.03); NT-proBNP was positively associated with LVED dimension (a measure of ventricular structure) (r = 0.20, P = 0.05); and cTnT was positively associated with LVED thickness-to-dimension ratio (r = 0.21, P = 0.04).
The first study aim was to determine if maternal antiretroviral regimens or specific antiretroviral agents were associated with cardiac biomarkers in HEU infants and children exposed in utero to these agents. No association between elevated cardiac biomarkers and maternal HAART or antiretroviral drug class was found. Analysis of individual antiretroviral agents revealed that abacavir was associated with significantly increased odds of elevated cTnT, suggesting injury or death of cardiomyocytes. Abacavir has been associated with cardiac toxicity, including increased risk of myocardial infarction in HIV-infected adults, although recent reports have challenged this association [27–30]. Although these results are not definitive, they highlight the need for further evaluation of the potential cardiotoxicity of in-utero exposure to abacavir. Using cardiac biomarkers, we found no evidence of cardiotoxicity after in-utero exposure to other antiretroviral drugs using observations at a single time point.
We found an association of maternal alcohol use during pregnancy with elevated cTnT levels. Maternal alcohol use during pregnancy has been associated with structural heart defects, long QT syndrome, and heart muscle disease in human, animal, and in-vitro studies [31–36]. Maternal tobacco use was associated with significantly increased NT-proBNP levels. Prenatal tobacco exposure is associated with inhibition of cardiac DNA synthesis, impaired vascular smooth muscle structure and function, and structural cardiac defects .
The second study aim was to determine if elevated serum cardiac biomarker levels were associated with echocardiographic parameters in HEU infants and children. Higher hsCRP levels were associated with significantly lower end-diastolic septal thickness and left-ventricular contractility. The NHLBI-funded Cardiovascular Status of HAART Therapy in HIV-Exposed Infants and Children (CHAART-1) study of HEU children found that decreased septal thickness and left-ventricular mass were associated with in-utero exposure to antiretroviral drugs . The same study found an association between specific cardiac biomarkers and left-ventricular echocardiographic parameter changes . The CHAART-1 study found that in-utero antiretroviral exposure was associated with increased left-ventricular contractility at age 2 years. We found that HEU children in the SMARTT cohort had significantly decreased left-ventricular contractility in those with elevated hsCRP who were aged 3–5 years, suggesting the possibility that perhaps HEU children with ongoing generalized inflammation, as indicated by elevated hsCRP, are at risk for decreased left-ventricular function as they age. This has implications for recommendations for cardiac screening and follow-up of this group. It has been reported that generalized inflammation in the neonatal period is associated with myocardial injury as measured by cTnT . If such generalized inflammation persists, the expected consequence in later childhood may be decreased septal thickness and perhaps decreased left-ventricular contractility. We have previously found that generalized inflammation is associated with echocardiographic abnormalities, myocardial injury, and poorer clinical status in children with heart failure [13,14]. Ongoing generalized inflammation has been associated with restrictive cardiomyopathy in anthracycline-exposed long-term survivors of childhood cancer [38–40].
Detectable serum cTnT suggests the possibility of active myocardial injury or cardiomyocyte apoptosis [7,41–49]. In this study we found that 12% of SMARTT HEU children had detectable serum cTnT raising concerns that active myocardial injury occurred. We are concerned that these low level cTnT elevations are significantly associated with a higher left-ventricular thickness-to-dimension ratio suggesting that low-level cTnT elevations may relate to subclinical changes in left-ventricular structure. Although two of 338 (0.6%) of SMARTT children had cTnT levels above 10 pg/ml, none of them had cTnT levels at the higher levels seen with unstable angina (∼100 pg/ml) or myocardial infarction (≥200 pg/ml) in adults. In a previous study of apparently HIV or ART-unexposed pediatric outpatients , we reported elevated levels of cTnI above 0.05 ng/ml in 7.8% of 193 acutely ill children and 4.4% of well children. Four of the five children with elevated cTnI, who also had cTnT measured (level of detection = 0.01 ng/ml or 10 pg/ml), had highly elevated cTnT levels in the range seen in adults with unstable angina or myocardial infarction. Previously, it had been shown that cTnI accurately shows myocardial injury similar to cTnT [50,51]. Compared to the previous report of cardiac troponin levels in non-HIV or ART exposed children in an outpatient setting , the HEU children described in this current report had reassuringly lower rates of active myocardial injury as defined by serum cardiac troponin concentrations. On the basis of our results, we cannot determine whether elevated cTnT levels in our HEU population are related to HIV or ART exposure, acute febrile illnesses, or other conditions. We do not consider evidence of dead or dying cardiomyocytes, as indicated by measureable cardiac troponin blood concentrations, in healthy children in this age range to be normal.
In active myocardial injury with myocytolysis related to inflammatory heart disease, such as myocarditis, cardiac biopsy specimens often demonstrate a mononuclear intramyocardial infiltrate . This infiltrate is accompanied by interstitial edema with a thicker left-ventricular wall by cardiac imaging [53,54]. Therefore, for the subset of children in this study with a measureable cTnT, the association with a thicker left-ventricular wall could be consistent with active myocardial inflammation, although similar levels have been reported in 4% of healthy children in one study. Further investigation would be needed to establish the significance of this finding .
The association of a greater left-ventricular dimension with increased NT-proBNP is consistent with left-ventricular neurohormonal activation due to left-ventricular stress (cardiomyocyte release of NT-pro BNP in response to increased left-ventricular volume or pressure) . The finding of a significant correlation between left-ventricular dimension and NT-proBNP, coupled with overall mean decrease in left-ventricular thickness-to-dimension ratio and septal thickness for the 94 children with both echocardiographic and biomarker measurements noted above, could be suggestive of early left-ventricular remodeling (left-ventricular structural changes of the left-ventricular wall thickness and dimension in response to a cardiac injury or insult). We have previously reported that in children with heart failure that a 10-fold increase in NT-proBNP serum levels was associated with cardiac symptoms and indices of left-ventricular systolic dysfunction and remodeling .
Our results suggest that there may be several pathophysiologic processes occurring in some of these patients. An acute and active myocardial injury process may explain the detectable serum cTnT. Acute myocardial hypertrophy may be the result of an inflammatory cardiac process such as myocarditis with an infiltrate and interstitial edema. There also may be a chronic inflammatory process resulting in decreased septal thicknesses and a decrease in the left-ventricular thickness-to-dimension ratio consistent with left-ventricular remodeling even at 3–5 years of age. The significantly reduced left-ventricular thickness-to-dimension ratio overall is consistent with active left-ventricular remodeling being present in this population.
The first limitation of this study is that only a subset (28%) of the children with biomarker measurements had temporally matched cardiac echocardiographic measurements. This affects the power of the study to detect significant associations between these parameters. Secondly, using only a single time point for both cardiac biomarker measurements and echocardiography limits the ability to assess temporal trends and evaluate causal associations. Next, the large number of comparisons between echocardiographic parameters, cardiac biomarker levels, and maternal antiretroviral drug use means that statistically significant associations could be a result of chance. Analyses were not adjusted for multiple comparisons in order to detect safety signals.
The findings of left-ventricular structural and functional abnormalities are, however, consistent with other studies and the associations with cardiac biomarkers are biologically plausible. Finally, the clinical significance of these findings is unclear; as is the optimal postnatal time to conduct these measurements to best identify those HEU infants and children who should receive additional longitudinal cardiac follow-up.
In conclusion, we observed no potentially adverse significant associations between specific intrauterine antiretroviral exposures and elevated cardiac biomarkers of abnormal cardiac structure or function, with the exception of a positive association between maternal abacavir use and measurable serum cTnT. Our results highlight the need for further evaluation of the potential for in-utero exposure to abacavir to cause adverse cardiac effects in HEU children. HIV strains that are resistant to zidovudine or lamivudine are generally sensitive to abacavir. The largest maternal risk from abacavir use is a hypersensitivity reaction in less than 10% of patients . Hypersensitivity testing has been determined to be cost-effective . The maternal or child health effects of removing abacavir from HAART regimens for pregnant mothers are unknown. The child health cardiac effects of prenatal abacavir exposures need to be further studied.
We observed associations between elevations of specific biomarkers and echocardiographic parameters consistent with an acute and/or chronic cardiac inflammatory response. The results of this study suggest that there may be a role for cardiac biomarkers to monitor HEU children for increased risk of deleterious cardiac effects that merit echocardiographic evaluation. The cost of these three biomarkers, or a similar panel, is less than $100 while the cost of an echocardiogram is $1000 or more. Future longitudinal studies of these and other, possibly more sensitive and specific, cardiac biomarkers or biomarker combinations in a larger population of HEU infants with echocardiograms could better define the utility of cardiac biomarkers to screen for cardiac changes in this population.
J.D.W. designed the study, interpreted the data, and wrote the article. P.L.W. designed the study, analyzed and interpreted the data, and wrote the article. E.L. and B.Z. analyzed the data and wrote the manuscript. W.T.S., S.D.C., G.K.S., L.B.D., G.B.S., and K.C.R. interpreted the data and wrote the manuscript. S.E.L. designed the study, interpreted the data, and wrote the manuscript.
We thank the children and families for their participation in the PHACS protocol ‘Surveillance Monitoring of ART Toxicities’ (SMARTT), and the individuals and institutions involved in the conduct of PHACS SMARTT. The following institutions, clinical site investigators and staff participated in conducting PHACS SMARTT in 2010, in alphabetical order: Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Emma Stuard, Anna Cintron; Children's Diagnostic & Treatment Center: Ana Puga, Dia Cooley, Doyle Patton, Deyana Leon; Children's Hospital of Philadelphia: Richard Rutstein, Carol Vincent, Nancy Silverman; Children's Memorial Hospital: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Molly Nozyce; New York University School of Medicine: William Borkowsky, Sandra Deygoo, Helen Rozelman; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera; SUNY Downstate Medical Center: Hermann Mendez, Ava Dennie, Susan Bewley; SUNY Stony Brook: Sharon Nachman, Margaret Oliver, Helen Rozelman; Tulane University Health Sciences Center: Russell Van Dyke, Karen Craig, Patricia Sirois; University of Alabama, Birmingham: Marilyn Crain, Newana Beatty, Dan Marullo; University of California, San Diego: Stephen Spector, Jean Manning, Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Emily Barr, Robin McEvoy; University of Florida/Jacksonville: Mobeen Rathore, Kristi Stowers, Ann Usitalo; University of Illinois, Chicago: Kenneth Rich, Delmyra Turpin, Renee Smith; University of Maryland, Baltimore: Douglas Watson, LaToya Stubbs, Rose Belanger; University of Medicine and Dentistry of New Jersey: Arry Dieudonne, Linda Bettica, Susan Adubato; University of Miami: Gwendolyn Scott, Claudia Florez, Elizabeth Willen; University of Southern California: Toinette Frederick, Mariam Davtyan, Maribel Mejia; University of Puerto Rico Medical Center: Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio. PHACS 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 on Allergy and Infectious Diseases, the Office of AIDS Research, National Institute of Mental Health, the National Institute of Neurological Diseases and Stoke, the National Institute of Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with Harvard School of Public Health and Tulane School of Medicine. Data management services were provided by Frontier Science and regulatory services and logistical support by Westat. The conclusions and opinions expressed are those of the authors and do not necessarily reflect those of the NIH or DHHS.
Conflicts of interest
There are no conflicts of interest.
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