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The purpose of this study is to assess for increased risk of attention deficit hyperactivity problem in young children with prenatal methamphetamine exposure from the multicenter, longitudinal Infant Development, Environment, and Lifestyle (IDEAL) study.
IDEAL enrolled 412 mother-infant pairs at four sites (Tulsa, OK; Des Moines, IA; Los Angeles, CA; and Honolulu, HI). Methamphetamine exposed subjects (n=204) were identified by self-report and/or gas chromatography/mass spectrometry confirmation of amphetamine and metabolites in infant meconium. Matched subjects (n=208) denied methamphetamine use and had a negative meconium screen. This analysis includes a subsample of 301 subjects that were administered the Conners’ Kiddie Continuous Performance Test (K-CPT) at age 5.5 years (153 exposed, 148 comparison). Hierarchical linear models adjusted for covariates tested exposure effects on K-CPT measures. Using the same covariates, logistic regression was used to determine the effect of exposure on the incidence of a positive ADHD confidence index score, defined as greater than 50%.
There were no differences between the groups in omission or commission errors or reaction time for correct trials. However, methamphetamine exposure was associated with subtle differences in other outcomes predictive of ADHD, including increased slope of reaction time across blocks (p<0.001), increased variability in reaction time with longer interstimulus intervals (p<0.01), and increased likelihood of greater than 50% on the ADHD confidence index (OR 3.1, 95% CI 1.2–7.8; p=0.02).
Prenatal methamphetamine exposure was associated with subtle differences in K-CPT scores at age 5.5 years. Even at this relatively young age, these children exhibit indicators of risk for ADHD and warrant monitoring.
Methamphetamine (MA) abuse among women continues to be a significant problem in the United States. In 2009, 0.2% of reproductive-aged women stated they had used methamphetamine in the prior month1. Also that year, women accounted for 46% of patients treated for MA abuse in treatment centers2. Further, prevalence of MA abuse during pregnancy tripled in 2006, rising to 24% of all pregnant women admitted to federally funded treatment centers3. Similarly, this burden is shared globally, with international data from 2004 revealing amphetamine abuse by 23% of substance-abusing mothers4.
MA is associated with neurochemical and structural alterations in areas of the brain known to affect attention and behavior. Positron emission tomography (PET) studies have shown a decrease in dopamine transporter and receptor density in the striatum in MA using adults5. Proton magnetic resonance spectroscopy has documented frontal white matter neurochemical abnormalities among MA exposed children ages 3–4 years6 and volumetric magnetic resonance imaging assessments in exposed children have shown smaller subcortical volumes in areas that impact attention and memory, including the putamen, globus pallidus, and hippocampus7. Further, recent neuroimaging reports have demonstrated that MA exposure is associated with reductions in striatal and caudate volume8.
Little is known regarding the neurobehavioral effects of prenatal MA exposure in school aged children. A longitudinal study of prenatal amphetamine exposure in Sweden found slightly lower general IQ in exposed preschoolers9, as well as increased aggressive behavior and problems with peers in exposed 8-year-olds10. However, this study lacked a control group, utilized a small sample size, and did not control for additional prenatal drug use. A more recent report linked in utero MA exposure with deficits in executive function and spatial performance during elementary school11, as well as delays in math and language in early adolescence12. However, these findings were retrospective, also utilized a small sample, and did not control for the impact of attention deficit disorder medication, which enhances cognitive abilities.
The multisite Infant Development, Environment, and Lifestyle (IDEAL) study is a prospective, longitudinal study of children exposed prenatally to MA. Previous findings from the IDEAL network have described a subtle neurobehavioral profile in infancy associated with MA exposure, including increased stress, poorer quality of movement, and lower arousal13;14, despite controlling for maternal depression15. Additionally, the IDEAL study has reported behavior problems in exposed children, with increased emotional reactivity and anxiety/depression at ages 3 and 5, as well as increased externalizing behavior and ADHD issues at age 516. The current study reports the effect of prenatal MA exposure on attention and impulsivity in 5.5-year-old children assessed by Conners’ Kiddie Continuous Performance Test (K-CPT). The K-CPT is a useful measure of inattention and impulsivity designed to assess 4- and 5-year-old children. The objective of this study was to assess for increased risk of inattention and impulsivity among 5.5-year-old children exposed prenatally to MA utilizing the K-CPT.
The IDEAL study is a multi-site, longitudinal study investigating the effects of prenatal MA exposure on childhood outcome. We have previously reported recruitment methods for the IDEAL study in detail17. Briefly, from September 2002 – November 2004, subjects were recruited at the time of delivery from seven hospitals in four geographically diverse, collaborating centers in the following areas: Los Angeles, CA; Des Moines, IA; Tulsa, OK; and Honolulu, HI. During the recruitment period, 34,833 mother-infant pairs were screened. Of the screened population, 26,999 were available to be approached, of which 17,961 (67%) were eligible for the study. Of the eligible population, 21% (3705) mother-infant pairs were consented for participation. Meconium tests were performed on all consented infants. MA exposure was determined by self-reported use during this pregnancy and/or a positive meconium screen and gas chromatography/mass spectroscopy (GC/MS) confirmation. Comparison subjects were defined as denial of MA use during this pregnancy and a negative GC/MS for amphetamine and metabolites.
A postpartum mother was excluded if she was <18 years of age; used opiates, lysergic acid diethylamide, phencyclidine or cocaine-only during her pregnancy; was institutionalized for retardation or emotional disorders; was overtly psychotic or had a documented history of psychosis; or was non-English speaking. Exclusion criteria for the infants included: critically ill and unlikely to survive, multiple birth, major life threatening congenital anomaly, documented chromosomal abnormality associated with mental or neurological deficiency, overt clinical evidence of an intrauterine infection, and sibling previously enrolled in the IDEAL study.
The Institutional Review Boards at all participating sites approved the study and all subjects signed an informed consent. Confidentiality of information regarding the mothers’ drug use was assured by obtaining a National Institute on Drug Abuse Certificate of Confidentiality, which superseded mandatory reporting of illegal substance use.
The longitudinal follow-up sample included all MA exposed infants and mothers (n=204) and comparison dyads (n=208) matched on maternal race, birth weight, type of insurance, and education. Of the 412 enrolled subjects, 301 (153 exposed, 148 comparison) remained in the study through the 5.5-year assessment and were included in this analysis.
After consent was obtained, a medical chart review and a recruitment Lifestyle Interview18;19 were performed to acquire information about prenatal substance use, maternal characteristics and newborn characteristics. Heavy MA use was defined as use ≥3 times/week throughout pregnancy. Socioeconomic status (SES) was determined using Hollingshead scale, an index that ranks SES based on occupation and years of education20. Meconium was collected in the nursery on all infants of consented mothers. Information on the collection procedures and analysis of the meconium samples has been previously published17.
The K-CPT assessment was administered to the subjects at 5.5 years of age by certified examiners masked to MA exposure status. The K-CPT is a computerized, visual exam that analyzes performance measures associated with ADHD, with a published 91% sensitivity and 73% specificity21. This assessment was derived from the Conners’ Continuous Performance Test II (CPT II), which is used for children ages 6 and older, in order to allow for earlier identification of attention deficits in young children. As opposed to the CPT II, which runs for 15 minutes and utilizes letters as the stimuli, the K-CPT run time is 7.5 minutes and uses a stimulus that is familiar to young children, including a ball, horse, house, scissors and a sailboat. During the K-CPT, the child is asked to press the spacebar each time a picture appears, unless the picture is of a ball. The pictures are presented in five blocks, first in 1.5-second interstimulus intervals (ISIs) followed by 3-second ISIs within each block.
The child’s performance is scored based on eleven measures: Omission, the number of pictures that the child incorrectly did not respond to; Commission, the number of times the child incorrectly responded to the picture of the ball; Hit Reaction Time, the overall response time recorded in milliseconds (ms); Hit Reaction Time Standard Error, the within-child variability of standard errors of reaction times from one block to another; Attentiveness, how well the child discriminated between the target and nontarget pictures; Perseverations, the number of times the child responded in less than 100 ms indicating impulsivity; Hit Reaction Time Block Change, the slope of change in reaction times over the five time blocks; Hit Standard Error Block Change, the slope of change in reaction time standard errors over the five time blocks; Hit Reaction Time ISI Change, the slope of change in reaction times over the two ISIs (1.5 and 3 seconds); and Hit Standard Error ISI Change, the slope of change in reaction time standard errors over the two ISIs. In general, these measures collectively detect inattention and impulsivity. For example, high omission rates indicate distractibility; in contrast, high commission error rates with a fast reaction time indicate impulsivity while high commission error rates with a slow reaction time indicate inattention. Finally, an ADHD Confidence Index score, which corresponds to the likelihood that the child displays a clinical profile consistent with ADHD, is then calculated based on the child’s scores on these measures. The developers of the K-CPT suggest that a Confidence Index score greater than 50% corresponds to an ADHD clinical profile21.
Covariates were selected based on conceptual reasons, published literature, and maternal and newborn characteristics that differed between groups if not highly correlated with other covariates. Previous reports have described the effect of prenatal alcohol, tobacco, and marijuana exposure on continuous performance tests in children22–25, resulting in the inclusion of prenatal exposure to alcohol, tobacco, and marijuana as covariates. Other covariates included study site, child’s age at assessment; gender; SES; caregiver IQ; caregiver change; caregiver depressive symptoms; maternal education; partner status; HOME score; and mother’s current alcohol, tobacco and marijuana use. Caregiver IQ was measured by the Peabody Picture Vocabulary Test at the 5.5 years assessment. Hollingshead SES was averaged from birth to 66 months (5.5 years), caregiver change included any change in the 66 months, caregiver depressive symptoms were averaged from 1, 12 and 36 month assessments, and the HOME score was determined at the 30-month assessment. There were 48 (15.9%) missing values for the HOME. Multiple imputation was used to impute HOME scores (SAS Proc MI, version 9.1.3, SAS Institute, Cary, North Carolina) for each of the K-CPT measures separately. Ten imputed data sets were generated for each analysis. The results of each dataset were combined for the estimation of regression parameters (SAS Proc MIANALYZE). Sensitivity analyses were performed on the data with and without the imputed values and the results were similar. Reported results are from the analyses with the imputed data to retain the full sample. Continuous covariates were grand mean centered.
Maternal and infant characteristics were examined by prenatal MA exposure status. Significance levels for differences in MA exposure were assessed using ANOVA to compare means and chi-square tests to compare proportions for categorical variables.
Hierarchical linear models (SAS Proc Mixed) were used to test associations between exposure effects (any use; heavy use, N=28; or some use, N=120) on K-CPT measures with adjustment for covariates. Study site was included to address the nesting structure of children in study sites.
Logistic regression was used to determine the effect of exposure on the incidence of a positive ADHD confidence index score, defined as greater than 50%. In all analyses, significance was accepted at p<0.05.
A comparison of the dyads included and not included at the 5.5-year evaluation is shown in Table 1. Of note, there were no significant differences in race; presence of a partner at birth; education; maternal age; any or heavy prenatal MA use; prenatal tobacco, alcohol, and marijuana use; gender; gestational age; or birth growth parameters. The only difference between the two groups was in their average Hollingshead Index of Social Position (ISP) score, with the included group having a higher score.
The maternal characteristics are presented in Table 2. There were no differences between the groups in race, maternal age, and current alcohol or marijuana use. The MA-abusing mothers had a lower Hollingshead ISP score and were less likely to have a partner at the time of delivery relative to the comparison group. Furthermore, the methamphetamine group was more likely to abuse tobacco, alcohol and marijuana prenatally, and was more likely to use tobacco at the time of the 5.5-year assessment.
The neonatal characteristics are shown in Table 3. We found no differences in gender, birth weight, or birth head circumference between the MA-exposed and comparison newborns. However, while the exposed infants were generally born at term, their gestational age was slightly shorter than the comparison infants. Lastly, the exposed neonates had a shorter birth length than their comparisons. Of note, in this sample, 11 (7.2%) of 153 in the MA exposed group were also exposed to cocaine prenatally. Prenatal cocaine exposure was tested in the models and there were no significant effects.
After adjusting for covariates, we found differences between the MA-exposed and comparison children (Table 4) in their Hit Reaction Time Block Change (P<0.001) and Hit Standard Error ISI Change measures (P=0.002). No differences between the exposed and comparison children were found regarding errors of Omission, Commission, Hit Reaction Time or Perseverations. Moreover, while neither group averaged greater than 50%, the exposed children had higher ADHD Confidence Index scores than their comparisons (P=0.014). In adjusted analyses, caretaker change was associated with a decrease in Hit Reaction Time Block Change and Hit Standard Error ISI Change (P<0.05 for all). Gender was associated with an increase in Hit Standard Error ISI Change and a higher ADHD Confidence Index score (P<0.05 for all). Partner status was associated with a higher ADHD Confidence Index score (P=0.003, P=0.024). These findings persisted even when we evaluated the children exposed to heavy use and some use separately (Table 4). Additionally, the incidence of scoring greater than 50% on the ADHD confidence index was higher in MA exposed children than their comparisons (41 (26.8%); 22 (14.9%); P=0.011). After adjusting for covariates, MA exposure was associated with an increased likelihood of greater than 50% on the ADHD confidence index (OR 3.1, 95% CI 1.2–7.8; p=0.02).
This is the first prospective investigation reporting the effects of prenatal MA exposure on the incidence of inattention and impulsivity. We found MA-specific differences in the Hit Reaction Time Block Change and Hit Standard Error ISI Change, measures of vigilance and attention, respectively, as defined by the K-CPT. This suggests that the MA-exposed subjects were more likely to exhibit slowing, as well as less consistent reaction times, as the test progressed. Additionally, the exposed children had a higher ADHD Confidence Index Score, suggesting a greater risk of developing ADHD. These K-CPT findings remained significant despite analyzing the heavily exposed children separately, suggesting that these discrepancies were associated with any amount of MA exposure.
Our results compliment previous findings of alterations in neurobehavior associated with prenatal MA exposure, including aggressive behavior, problems with peers, and deficits in executive function and spatial performance23;25. Interestingly, the work of Piper’s group did not find any differences in CPT performance between methamphetamine exposed and unexposed 7- to 9-year-old children; however, they did report a four-fold higher frequency of ADHD in the exposed children, with the majority having received drug therapies prior to behavioral testing in their investigation. Moreover, our results parallel the previously reported IDEAL findings of behavioral problems in exposed 3- and 5-year old children. At both ages the methamphetamine exposed children were described as having increased emotional reactivity and anxious/depressed symptoms, with externalizing and attention-deficit/hyperactivity issues by age 5 years16.
Our findings of increased risk for inattention are consistent with other prenatal drug exposures. Continuous performance tests have been employed in studies of in utero exposure to tobacco, alcohol, and marijuana, correlating prenatal marijuana and alcohol exposure with increased errors of commission, as well as prenatal tobacco exposure with increased errors of omission22;23;25. Conners’ K-CPT, specifically, has been used to demonstrate adverse attention-related outcomes among 5-year-old children exposed prenatally to organophosphate pesticides26. In addition, Conners’ Continuous Performance Tests have shown attention deficits at 3-, 5- and 7-year old children in reports of intrauterine cocaine exposure, with increased errors of omission22;25;27;28. However, as opposed to our findings, studies have also linked intrauterine cocaine exposure with impulsivity, reporting errors of commission as well22.
The strengths of this study include that it is a longitudinal, multisite, NIH funded investigation and is the first of its kind to evaluate the K-CPT with a MA exposed population. However, our results should be interpreted with caution, as there are limitations to our study. This report employs Conners’ K-CPT to assess for ADHD. While Conners’ CPT-II has been a reliable instrument used in numerous studies of drug exposed older children27;28, the K-CPT has not been utilized as consistently in these high risk populations. In fact, despite a growing number of preschoolers presenting to clinicians for assessment of attention problems, the majority of tools developed to measure attention in this age group is described only in experimental literature29. Therefore, the validity and dependability of this test may not be as strong as the CPT-II. While we inquired about parental medication use, we did not include parental ADHD as a covariate. Another limitation of our study was the exclusion of subjects in the enrollment process who were critically ill or had other major medical impairments. Therefore, our sample is biased toward healthier children and, as a result, our outcome measures may have been underestimated.
In conclusion, we found persistent neurobehavioral effects to prenatal MA exposure, with patterns of abnormal attention processing at 5.5 years of age. These findings were not dose-dependent and imply a modestly increased risk for developing ADHD associated with MA exposure. Longitudinal studies will determine if these findings amplify as these preschoolers approach school age. In order to minimize the neurological sequelae of MA exposure, these increased issues with attention suggest methamphetamine exposed children require close follow-up and behavioral screening.
This study was supported by NIDA Grant# 1RO1DA014948 and in part by the National Center on Research Resources Grant# 1UL1-TR000124 and 5P20 RR11091.
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Conflicts of Interest and Source of Funding
The authors have no conflicts of interest relevant to this article to disclose.