February 2014 Journal Watch

Behavioral & Developmental Pediatrics

O’Leary CM, Taylor C, Zubrick S, et al. Prenatal Alcohol Exposure and Educational Achievement in Children Aged 8-9 Years. Pediatrics. 2013; 132: e468-e475.
This study looked at the effects and patterns of fetal alcohol exposure on children’s psychometric testing results in children aged 8-9 years. The study was conducted on 4056 Australian children. The investigators classified maternal alcohol consumption during pregnancy as low (1-2 standard drinks/occasion and <7per week), moderate (3-4 standard drinks/occasion and no more than 7 per week), binge drinking (50+g per occasion, less frequently than weekly), and heavy drinking (>7standard drinks per week, including binge drinking weekly or more frequently). The 8-9 year olds that participated in the study took standardized testing in school that evaluated reading, writing, spelling and numeracy. The study concluded that the pattern (dose and timing) of alcohol exposure during pregnancy effects academic testing results in children 8-9 years old. The study results demonstrated that heavy prenatal alcohol exposure in the first trimester resulted in students with low performance in reading on standardized testing. The study also showed occasional binge drinking late in pregnancy was associated with lower scoring in writing on standardized testing. There was no effect on psychometric testing in this cohort in children with low or moderate fetal alcohol exposure. The information this study provides is helpful for pediatricians who have patients with known fetal alcohol exposure. We should be mindful of a child’s potential academic limitations as an effect of in utero exposures including alcohol. In children with known exposures it may be beneficial to give them access to resources early so that they can achieve their full academic potential.
Submitted by: Lindsey Forur
Comment: These study results are potentially reassuring to women who consumed small amounts of alcohol early in pregnancy prior to pregnancy awareness. However, these results should not serve to “normalize” alcohol intake during pregnancy - the American College of Obstetrics and Gynecology is very clear: no alcohol use is safe in pregnancy, and that is the pediatrician’s working mantra also. Of note, recommendations for alcohol intake during pregnancy changed in Australia in 2009 from low to no intake; public compliance with this recommendation has thus far been low (Anderson BMC Public Health 2012). Lydia Furman, MD

Kotte A, Joshi G, et al. “Autistic Traits in Children With and Without ADHD.” Pediatrics. 2013; 132 (3): 612-622.
Children diagnosed with ADHD often exhibit features of other psychopathologies such as ODD, depression, anxiety, etc. Some studies have found that as many as 25-30% of children with ADHD also show “autistic traits” of impaired empathy and social communication. Implications for this overlap with ASD are unclear. In this study, children with ADHD with and without autistic traits (as scored by the Child Behavior Checklist-CBCL) and without ADHD were studied to determine the prevalence and potential implications of autistic traits in children with ADHD. Broadly, autistic traits were considerably more common in children with ADHD than without: 18% vs. 0.87%; P< 0.001. Additionally, of the children with ADHD, those exhibiting autistic traits tended to have more severe dysfunction. While all children with ADHD were more likely to require extra assistance in school, such as a tutoring or repeating a grade, those with autistic traits were twice as likely (22.8% vs. 50%) to be placed in a dedicated special needs classroom. Similarly, all children with ADHD had a higher prevalence of mood and behavior disorders, but the prevalence was yet higher in the ADHD with autistic traits group. Finally, children with ADHD with autistic traits had worse social functioning (68% vs. 34% as measured by the Social Adjustment Inventory for Children and Adolescents) and more significantly impaired cognitive function demonstrated by lower full-scale IQ, increased distractibility, etc. on the WISC-R Full IQ test. Whether seeing children with ADHD in the setting of a general pediatrics practice or a developmental and behavioral pediatrics clinic, this article shows the importance of screening for co- morbidities, namely autistic characteristics, among children with ADHD. Since these children seem far more impaired than even their counterparts with ADHD without autistic features, correctly identifying them and referring them for more intensive treatment such as behavioral therapy in addition to medication alone seems to be of great importance.
Submitted by: Kailey Littleton
Comment: This is very interesting data, and, as the authors point out, it is consistent with previous studies. It can serve as a reminder to screen for co-morbid conditions in children with ADHD because, as Dr. Littleton points out, the therapy can then be individualized and optimized. Laura Caserta, MD

Winarni TI, Chonchaiya W, Adams E, Au J, Mu Y, Rivera SM, Nguyen DV, Hagerman RJ. Sertraline May Improve Language Developmental Trajectory in Young Children with Fragile X Syndrome: A Retrospective Chart Review. Autism Research and Treatment. 2012.
This article is a retrospective chart review of 45 patients with fragile X syndrome (FXS) and concurrent autism spectrum disorder (ASD) with language delay, which showed significant improvement in both expressive and receptive language at 20 and 40 months of age compared to controls when treated with sertraline in the first 5 years of life. The authors hypothesized that this effect was either due to decreasing anxieties and inhibitions, thus allowing the children to learn more effectively, or due to the direct effect on synaptic modulation since there is evidence that serotonin is involved in the rapid synaptogenesis that occurs in the first 5 years of life. This study had several limitations including variability in how long children were treated for, dosing, and follow-up. However, it should be followed with a prospective study to observe whether there is a true effect of sertraline treatment on language development. At this point, there is not enough evidence to recommend SSRI treatment for language deficits; however I will be more proactive about addressing anxieties in children with ASD.
Submitted by: Divya Parikh
Comment: I agree with Dr. Parikh’s take home point. The control group did not receive sertraline for several reasons, including being seen prior to routine use, parental refusal and a < 1 month trial that was not effective (n=2); the authors acknowledge the clinical and selection bias associated with this retrospective review. A prospective study would indeed be needed to recommend sertraline to promote language development. Lydia Furman, MD


“Oxygen Saturation Normogram in Newborns Screened for Critical Congenital Heart Disease.” Jegatheesan, Priya et al. Pediatrics. 2013; Volume 131: e1803-e1809.
More than 13,000 asymptomatic newborns born at ≥34 weeks gestation and admitted to the newborn nursery, were screened for congenital heart disease by performing pre-ductal (right hand/wrist) and post-ductal (either lower extremity) oxygen saturations at 24 hours after birth. Infants were considered to have passed the screening test if both the pre- and post-ductal saturations were ≥95% and the difference between the two was ≤3%. Infants required a repeat screening test 4 hours later if either saturation was 90-94% or if there was ≥ 3% difference in the two scores. Infants failed if either saturation was <90%, and were required to undergo a pre-discharge echocardiogram. This study found a mean pre-ductal sat of 98.3% and mean post-ductal sat of 98.6% at 24 hours. Pre-ductal values were slightly higher in infants delivered by c-section versus those born by vaginal delivery. There was no significant difference among other identified subgroups. Of all infants screened, only 91 newborns required a repeat screen, of which 90% passed and 2 were found to have CCHD. This intervention showed consistency across three different centers, was low cost through using reusable pulse oximeters and required minimal nursing time per infant screened. Although larger numbers are required, this study provided a model for consistent, low-cost screening, and contributed to establishing a definitive normogram for screening CCHD in asymptomatic late pre-term and term newborns. This study made me aware of the growing amount of data supporting the use pre- and post-ductal screening for CCHD. This article may lead me to use the methods presented in this article to screen the healthy late pre-term and term infants in my practice at 24 hours of age for CCHD.
Submitted by: Alyssa Stachowiak
Comment: This study validates the usefulness of pre/postductal saturation screening for critical congenital heart disease (CCHD) in a large population of term and late preterm infants. The authors stress that adherence to protocol is key and must be carefully monitored, and in fact adherence was very good (99.7%). Of the 8 asymptomatic infants who had a saturation <90% on first screen who should have had an automatic echocardiogram, 6 actually had a repeat screen which was passed, suggesting a possible role for re-screening to decrease further unnecessary echocardiograms (in a potential future revision of the protocol). Lydia Furman, MD


Lotstein et al. Transition From Pediatric to Adult Care for Youth Diagnosed with Type 1 Diabetes in Adolescence. Pediatrics. Volume 131, Number 4, April 2013. ppe1063-e1069
This study looked at the transition of adolescents diagnosed with type 1 diabetes to adult care. Diabetes requires lifelong management and better control correlates to healthier outcomes, and this transfer of care is crucial. As with many chronic diseases, patterns of transfer vary by location, patient, and family. This study explored the change in diabetes care providers in a 6-site study. Of 185 youth interviewed, the mean age for transition was 20.1 years (95% CI, 19.8-20.4). 47% had transitioned at 18-20 years of age, and 77% had transitioned by 21 years. Of note, those with higher hemoglobin A1c levels were less likely to leave a pediatric provider (a 27% decrease for every 1 unit increase in A1c, p=0.13). One likely explanation is that transitioned patients have already been shown to have worse glycemic control, and pediatric providers might be worried about worsening control in already poorly controlled patients. In addition, these patients may need more psychosocial resources, which are more readily available in the pediatric setting. Also, higher parental education was associated with reduced odds of transitioning care (OR=.34, 95%CI 0.14-0.82). The transition of pediatric patients both with and without chronic illness is coming into focus as a widespread issue that many sub-specialties handle with variable success. The earlier we are able to identify barriers to this process, the earlier we can amend them and ease the transition. There are clearly not enough measures in place, and this study shows that young adults transitioning to adult care actually may require more resources and planning.
Submitted by: Anat Cohen
Comment: This certainly is an important issue that is gaining more attention currently. Most alarming was the disparity found between certain ethnic groups with non-white patients having significantly worse glycemic control at follow-up. Laura Caserta, MD

Urinary Phthalates and Increased Insulin Resistance in Adolescents. Leonardo Trasande, Adam J. Spanier, Sheela Sathyanarayana, Teresa M. Attina, and Jan Blustein. Pediatrics. 2013; 132:3 e646-e655.
Di-2-ethylhexylphthalate (DEHP) is a chemical commonly found in processed foods. Exposure early in life to phthalate compounds has previously been associated with adverse endocrine processes. Phthalate exposures is associated with increased insulin resistance in adults, but has not been studied in adolescents or children. This is a cross-sectional study using data from 2003-2008 NHANES to evaluate associations between phthalate metabolites and categorical measures of insulin resistance in 766 fasting adolescents aged 12-19. The study authors controlled for demographic and behavioral factors in the study, such as diet, age, BMI, and creatinine clearance. The authors calculated the homeostatic model assessment of insulin resistance (HOMA-IR) and then categorized the outcome to determine level of insulin resistance. Phthalate levels were measured in 1 spot urine sample. Results of the study indicated that there was a 0.27 increase in insulin resistance levels for each log (threefold) increase in urinary phthalate levels in the study group (95% confidence interval 0.14–0.40; P < 0.001). Association between urinary phthalate levels and insulin resistance prevailed even after controlling for bisphenol A levels, which is another endocrine-producing hormone found in processed foods. The authors identified a cross-sectional association of urinary phthalate levels and rising levels of insulin resistance. It would be helpful to see a more longitudinal study conducted over time to see if this association persists. Processed foods have been found to contain high levels of calories and salt without much nutrition. This study also introduces data that these products may be associated with insulin resistance, and subsequently increase the risk of type II diabetes. This will be another interesting data point to add to my discussions with patients and families on healthy eating choices.
Submitted by: Amanda Gogol-Tagliaferro
Comment: The authors point out that there are some limitations in this study (especially given that the phthalate level was only measured on one spot urine sample), and that more studies would be needed to clarify the association. However, since processed foods are often higher in calories and sodium, it is definitely worth counseling patients to limit their intake anyway. Laura Caserta, MD


Shelby, Grace D. PhD, et al. Functional Abdominal Pain in Childhood and Long-term Vulnerability to Anxiety Disorders. Pediatrics. 2013:132:475-481.
This is a prospective study of pediatric patients with functional abdominal (FAP) to determine their rates of psychiatric disorders. This study evaluated for the diagnostic criteria for psychiatric disorders and if their FAP persisted. They were compared to a control group of children without functional abdominal pain into adolescence or young adulthood. They looked at 491 participants, 332 with FAP and 159 controls. The Anxiety Disorders Interview Schedule-IV: Adult Lifetime and Child and Parent Versions (ADIS) were used to assess current and lifetime DSM-IV psychiatric disorders. The odds ratio for any lifetime anxiety disorder was 4.59 times higher for FAP compared with controls. Depressive disorders were significantly higher in the FAP group as well. Even the patients who no longer met criteria for FAP at follow up had higher lifetime rates of anxiety disorders. This study notes that these subjects were followed in a GI clinic and does not include other patients with FAP that are followed by their primary care physician. As a primary care physician, I think it would be useful to inform patients with FAP about the increased rates of depression and anxiety disorders so that it is something their family is aware of and can monitor. They would also benefit from regular screening for depressive/anxiety disorders.
Submitted by: Megan Knowles
Comment: This is certainly important data and highlights the need for screening for depression/anxiety in patients with FAP. Laura Caserta, MD

Infectious Disease

Atwell JE, Van Otterloo J, Zipprich J, Winter K, Harriman K, Salmon DA, Halsey NA and Omer SB. Nonmedical Vaccine Exemptions and Pertussis in California, 2010. Pediatrics. 2013; 132:624-630.
This is a study that used Kulldorff’s scan statistics and census tracts to determine if the clusters of children entering Kindergarten who did not get a pertussis vaccination were correlated with the location of pertussis outbreaks. The study looked at clusters of pertussis outbreaks in 2010 and vaccination records from Kindergartens from 2005 to 2010. If the pertussis vaccination was not given for any reason other than a medical contraindication, it was labeled as a nonmedical exemption (NME). Many officials attributed the outbreak in California (where the study was done) to waning immunity of acellular pertussis vaccines as well as genetic changes of the latest strains and while this article agrees with those reasons, it explores the possibility that NMEs are also correlated to outbreaks. Through multiple different statistical methods, an odds ratio of 2.47 with a 95% confidence interval of 2.22-2.75 was determined and showed that a NME cluster was more likely to be in a pertussis case cluster than census tracts outside of a NME cluster. The association remained significant even when controlled for population characteristics such as population density and ethnicities. This article showed that communities with large numbers of intentionally unvaccinated children can lead to pertussis outbreaks and that herd immunity is only effective if all of the patients who can get the vaccine get it so that the children who medically cannot will be protected. This article points out that while the pertussis outbreak in California in 2010 was likely caused by many different factors including waning immunity, another cause was the lack of vaccination due to nonmedical reasons. I feel that this article reinforces to us as pediatricians the importance of vaccination and stressing to parents the need for vaccination. We could use this article to cite a very concrete reason as to why it is important to vaccinate. Also of note is that we are also having a pertussis outbreak here in Ohio currently.
Submitted by: Diana Yan
Comment: The strength of this article is its careful use of statistical methodologies to assess the impact of parental choice not to vaccinate on pertussis outbreaks. So, without hand waving or fanfare, we can non-judgmentally say, YES, choice not to vaccinate does increase disease risk for both the individual child and the community. The Immunization Action Coalition site (www.immunize.org) is an excellent internet-based resource for parents seeking clear and accurate information about vaccines. Lydia Furman, MD


Esther García-Esquinas, Lauren F. Loeffler, Virginia M. Weaver, Jeffrey J. Fadrowski and Ana Navas-Acien. “Kidney Function and Tobacco Smoke Exposure in US Adolescents.” Pediatrics. 2013;131;1415-1423.
This article describes a cross-sectional study over 11 years in which creatinine and cotinine levels (a metabolite of nicotine) were measure from 7516 adolescents. Active smokers, and those exposed to second-hand smoke, were classified using a self-reported questionnaire and cotinine levels. eGFR was then calculated from the serum creatinine level using the Schwartz equation and CKiD equation. eGFR was then compared among active smokers, those exposed to second hand smoke, and those who were not exposed. The median eGFR was higher in subjects not exposed to tobacco; eGFR was estimated at 99.1mL/min per 1.73^2 as compared to 96.8 in those exposed to second hand smoke and 90.1 in active smokers (P=0.1). When a dose-response analysis was done, eGFR levels decreased progressively with increasing serum cotinine. A multivariate analysis showed that in males, an increase in cotinine levels was associated with a steeper decreased in eGFR than in females. This study gives evidence that even second hand smoke effects kidney function and a known exposure to tobacco smoke should cause a pediatrician to pause when evaluating creatinine levels. The outcomes are relevant to the general pediatric population. It can be used as another reason to assess for tobacco use in adolescents and counsel parents about quitting or not smoking around their children.
Submitted by: Meg Oberle
Comment: With smoking a documented risk factor for chronic kidney disease in adults, it makes sense that the toxic effect on the kidney begins when smoke exposure begins. Additional clinician education about supporting smoking cessation would likely be very helpful as knowledge about the many adverse health effects of smoking continues to expand. Lydia Furman, MD


Childhood Interstitial Lung Disease: An 18 Year Retrospective Analysis. Pediatrics. 2013; 132; 684.
This article was a retrospective review of 18 years at a single institution (Vanderbilt University) to assess the frequency and various classifications of interstitial lung disease; a group of rare disorders previously described only at major referral centers. Their aim was to establish the frequency at a moderately-sized children’s hospital so that their results and conclusions might be more applicable to most children’s hospitals regarding this rare disease. They found 93 cases between 1994 and 2011; and were able to classify them according to diseases that occur more frequently in infants (higher morbidity/mortality) and those that do not. Through their analysis, they were able to provide classification of cases that were previously undetermined in origin. For example, a portion of the cases (9.7%) were Neuro-Endocine Cell Hyperplasia of Infancy; 3 of which were identified historically, and 5 of which were identified only by retrospective review of charts, CT scans, and previously inconclusive lung biopsies. Additionally, there was a spectrum of disorders that is similar to other ILD reports from larger centers. The authors determined that finding a broad spectrum of ILD classifications in a moderately sized children’s hospital, as well as the ability to identify previously undiagnosed cases via retrospective review argued for broader participations in these types of retrospective analyses by other children’s hospitals. This type of broader participation might identify previously undiagnosed cases of ILD as well as help to refine the current classification system. This study underscores that rare disorders are not limited to tertiary care/referral centers. The study demonstrates that thoughtful reflection (analysis) of historical clinical data can be a useful tool in answering current questions.
Submitted by: PJ Tate
Comment: The authors of this study hope that their findings can be used in the future to help classify ILD using less invasive techniques. Laura Caserta, MD

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