April 2014 Journal Watch

Behavioral & Developmental Pediatrics

Garg S, Green J, Leadbitter K, et al. Neurofibromatosis Type 1 and Autism Spectrum Disorder. Pediatrics. 2013;132:e1642-1648.

An epidemiological study was performed on a neurofibromatosis registry in the United Kingdom to assess the prevalence of autism spectrum disorders (ASD) among children aged 4-16 years. Defects in the Nf1 gene are known to cause abnormalities in the Ras pathway. Abnormalities in the Ras pathway which occur in Fragile X Syndrome and Tuberous Sclerosis have been linked to autism in these patients, thereby providing a possible genetic connection between NF1 and autism. The prevalence of ASDs among the NF1 population studied was 24.9% with an additional 20.8% showing features of autism (less than 1% was previously diagnosed). This is significantly higher than a prevalence of 1-2% among the general population. There was no difference in IQ, age, socioeconomic status, NF1 inheritance type, or NF1 physical severity among the groups. Those with autism were found to have an increase in repetitive behaviors, functional impairment, and were more likely to be male. Neurofibromatosis Type 1 (NF1) is one of the most common neurologic single-gene disorders with a prevalence of 1:4,560 and birth incidence of 1:2699, making it a disorder that is likely to be seen among pediatricians. Cognitive and behavioral difficulties with attention, language, and executive function in these children are often thought to be secondary to the primary disease (NF1), but it is important to consider an ASD as a cause of these symptoms. Pediatricians should have a low threshold to test children with NF1 and behavioral difficulties for ASDs.

Submitted by: Amanda Lansell
Comment: This is very interesting information. The authors suggest heightened awareness of possible ASD and ADHD in children with NF1 and instituting appropriate therapies as soon as possible. Laura Caserta MD

Child Abuse/Advocacy

Newgard, Craig D., MD, Nathan Kuppermann, MD, James F. Holmes, MD, Jason S. Haukoos, MD, Brian Wetzel, NP, Renee Y. Hsia, MD, N. Ewen Wang, MD, and Eileen M. Bulger, MD. Gunshot Injuries in Children Served by Emergency Services. Pediatrics 132.5 (2013):862-70.

Emergency services are often the first to care for victims of gunshot injuries, which represent an important preventable cause of harm and death in the pediatric population. This study wanted to describe the incidence, injury severity, resource use, mortality and costs for children with gunshot injuries compared with other mechanisms of injury. The study design was a population-based, retrospective cohort study from January 2006 to December 2008 of all injured children who called 9-1-1 from 47 EMS agencies transporting to 93 hospitals in 5 regions of the western United States. This included 49,983 children. The outcomes studied included population-adjusted incidence, injury severity score, major surgery, blood transfusion, mortality and average per patient acute care costs. The population- adjusted annual incidence varied 16-fold between geographic regions. Those injured by gun violence in comparison to other mechanisms of injury had the highest proportion of serious injuries, major surgery and costs. This studies how deadly and costly gun violence is to our society. With gun laws and research being a recent controversial topic, this study highlights the need for pediatricians to advocate for our patients safety since gun violence is truly a topic of public health and health policy. We should advocate for our patients when it comes to gun control laws and research and when in the clinical practice setting, we should ensure to ask all families about weapons and encourage safety.

Submitted by: Sheila Bigelow
Comment: Following the 1993 NEJM publication of, “Gun ownership as a risk factor for homicide in the home,” the NRA (National Rifle Association) campaigned successfully to prohibit gun control research at the CDC via the so-called Dickey amendment to the 1996 Omnibus Budget Bill. Since then, although not specifically disallowed, gun control research has essentially been un-fundable at the CDC (see full history at https://www.apa.org/science/about/psa/2013/02/gun-violence.aspx). Ongoing research can only benefit our patients and families; it is sad when politics rules. Lydia Furman MD

Fieldston E, Zaniletti I. Community Household Income and Resource Utilization for Common Inpatient Pediatric Conditions. Pediatrics. 2013. 132: 1592-1601.

This is a retrospective study of 32 freestanding children’s hospitals for five diagnoses including asthma, diabetes, RSV bronchiolitis, pneumonia, and urinary tract infections that included over 110,000 hospitalizations with analysis of inpatient cost relative to zip code-based median annual household income. Three out of the five common pediatric conditions had significant differences in cost across hospitalization cost by zip code income. Though these findings will not affect my day-to-day practice, the public health implications of this and similar studies are immense. Given the changing health care climate with the Affordable Care Act, hospital compensation will increasingly been linked to diagnoses which will adversely affect those caring for medically underserved populations with multifaceted socioeconomic needs.

Submitted by: Anya Kleinman
Comment: I agree with Dr. Kleinman. This data has important health policy implications. The authors postulate that lower income families may have longer hospital stays and health care utilization due to difficulties in care coordination and complex disease management. Helping to bridge this gap can be an important goal for the future. Laura Caserta MD


Hart CN, Carskadon MA, Considine RV, et al. Changes in Children’s Sleep Duration on Food Intake, Weight, and Leptin. Pediatrics. 2013;132:e1473-1480.

Children between the ages of 8-11 years who reported approximately 9.5 hours of sleep per typical night were monitored during one week of their normal sleeping pattern, one week of sleeping an extra 1.5 hours nightly, and one week of sleeping 1.5 hours less nightly. Sleep times were adjusted by bedtime with constant wake times. Compared to the decreased sleep condition, children reported decreased caloric intake (134 kcal/day), had lower fasting leptin values, and had a lower weight by an average of 0.22 kg in the increased sleep condition. Most extra caloric intake occurred later in the day, especially during the 3 additional hours of wake time. Decreases in weight correlated with decreases in leptin, but not with caloric intake. There were no differences found in fasting ghrelin levels. The CDC estimates that 18% of United States youth are obese and pediatricians are facing overweight patients more frequently. This study suggests that increased sleep time results in lower body weight due to decreased caloric intake. Leptin, a hormone that inhibits appetite, was lower when these children had increased sleep times and lower caloric intake, indicating that their appetite was less suppressed, yet these children ate less. Recommending increased sleep time for our overweight patients gives them less time to eat. Additionally, the extra caloric intake during the decreased sleep condition occurred later in the evening, so having an earlier bedtime provides fewer hours where the child may be more susceptible to acting on his or her hunger.

Submitted by: Amanda Lansell
Comment: This study adds to the long list of benefits of a good night's sleep, and can serve as a reminder to ask about sleep at all Well-Child Care visits. Maintaining a healthy body weight can be one more reason to promote good sleep hygiene in children. Laura Caserta MD

Infectious Disease

Payne DC, Vinje J, et al. Norovirus and Medically Attended Gastroenteritis in U.S. Children. N Engl J Med 2013; 368:1121-30.

This was a surveillance study throughout 3 counties between New York, Tennessee, and Ohio over two years. The settings were between inpatient hospital admissions, emergency room visits, and outpatient visits. They included cases of children younger than 5 years old with symptoms of acute gastroenteritis and controls of healthy children younger than 5 at well child visits. They were able to demonstrate rates of emergency room visits, hospitalizations and outpatient visits attributable to norovirus infection by multiplying the proportions of patients with positive test results for norovirus by the number of patients presenting to these settings with acute gastroenteritis. They compared these rates to rates of acute gastroenteritis attributable to rotavirus estimated by the same method. This study showed that 21% of cases of acute gastroenteritis were attributable to norovirus, while only 12% were attributable to rotavirus. The authors showed that the predominant culprit in acute gastroenteritis in all settings is norovirus; on the rise since the advent of rotavirus vaccine. Of children under 5 in the US, 1 in 278 will be hospitalized, 1 in 14 will go to the ER, and 1 in 6 will go to the clinic because of norovirus, totaling a cost of more than $273 million per year. This article underscores that highly infectious causes of disease find opportunity in niches left behind by now-vaccinated-against agents. These niches still represent large amounts of cost for the medical system at large and significant burden for families, despite the success of well established vaccine-programs.

Submitted by: PJ Tate
Comment: Although it is clear that Norovirus has “stepped up,” the good news is that overall gastroenteritis-related hospitalizations for children under age 5 years have decreased following implementation of rotavirus vaccination, from a hospitalization rate of 74/10,000 (pre) to 50-51/10,000 (post) (Desai et al Clin Infect Dis 2012). Lydia Furman MD

General Pediatrics

Paul, Ian M., MD, Jessica S. Beiler, MPH, Tonya S. King, PhD, Edelveis R. Clapp, DO, Julie Vallati, LPN, and Cheston M. Berlin, MD. Vapor Rub, Petrolatum, and No Treatment for Children with Nocturnal Cough and Cold Symptoms. Pediatrics 126 (2010): 1-8. Pediatrics.aappublications.org. Web. 22 Nov. 2013.

The topic of whether or not to recommend vapor rub for children with viral upper respiratory infection symptoms came up during my time on OBRE. This study was performed to provide evidence for or against vapor rub products containing a combination of camphor, menthol and eucalyptus oils. They administered surveys to parents on 2 consecutive days, the day the child presented with symptoms, and the following day after which they had used vapor rub at night on their child. They compared vapor rub ointment, petrolatum ointment and no treatment according to a partially double-blinded randomization design. Their study group included 138 children from 2 to 11 years of age. They looked at significant differences in improvement in cough, congestion and sleep difficulty. Vapor rub performed better than no treatment for all symptoms except rhinorrhea and performed better than petrolatum for cough severity, child and parent sleep difficulty and combined symptoms score. Petrolatum wasn’t better than no treatment at all for any outcome. Irritating side effects were more common among vapor rub treated participants than all others. In the age group of less than six years old, there are not many options to offer parents and patients to relieve their irritating upper respiratory symptoms. This study helps give some credence to vapor rub and allows us to offer an evidence based option to pediatric patients. I think it is important to reiterate to parents that should be used sparingly and not in children that may try to ingest it. However, it does seem to be a beneficial topical over the counter medication for our pediatric patients.

Submitted by: Sheila Bigelow
Comment: Thank you for reviewing this article, Dr. Bigelow. We all likely recall the good news about treatment with honey for cough in children over 1 year of age (Cohen et al Pediatrics 2012) and this is similarly good information, both scientifically and for parents! Lydia Furman MD

Grimshaw KEC, Maskell J, Oliver EM, Morris RCG, Foote KD, Mills C, Roberts G and Margetts BM. Introduction of complementary foods and the relationship to food allergy. Pediatrics (2013) 132: e1529-e1538.

There is debate over the WHO’s recommendation that all infants be exclusively breastfed for 26 weeks. In undeveloped countries, this provides safe milk for the baby especially when sanitation is of concern. However in developed countries, the benefit of exclusive breastfeeding for this period of time is less clear. This is a nested case-control within a cohort study that addresses this debate. Infants from the PIFA study (a prospective study of 1140 infants) who developed food allergies were matched to other infants in the study. Parents kept food diaries and it was noted when exclusive breastfeeding ceased and when semi-solid or solid foods were introduced. When possible food allergy cases came up, a physical exam, skin prick testing, and blood testing were done. Following positive tests, the infant would get a DBFCFC. If this was positive, food allergies were diagnosed. 41 infants developed food allergies and were compared to 82 matched controls. The median age at start of food allergy symptoms was 24 weeks and at diagnosis was 56 weeks of age. The most common causative foods were hen’s egg followed by cow’s milk. The study showed an association between solid food introduction before 17 weeks of age and food allergies and a negative association between food allergies and concurrent breast milk feeding with other foods. Therefore the study supported current allergy prevention recommendations that solids should not be introduced before 17 weeks of age and the feeding recommendation that breastfeeding should continue while solids are being introduced. I feel that this is more evidence for our parents to continue to breastfeed for as long as they can and for us, as pediatricians, to encourage this. The article unfortunately did not have enough power to make recommendations of breastfeeding duration to prevent allergies. However the article does note that the WHO recommends parents to breastfeed up to 2 years of age.

Submitted by: Diana Hou
Comment: This is a very interesting study, and does support current feeding recommendations. Laura Caserta MD


Wang, et al. Hydroxyurea is Associated With Lower Costs of Care of Young Children With Sickle Cell Anemia. Pediatrics 2013; 132; 677-83.

The BABY HUG trial was a multi-center randomized double-blinded NIH supported study of hydroxyurea use in very young children with sickle cell anemia. The study demonstrated that hydroxyurea, which is an inhibitor of ribonucleotide reductase and increases fetal hemoglobin levels in red blood cells, decreases hospitalizations, need for exchange transfusions, and frequency of pain crises and acute chest syndrome. With use of hydroxyurea expected to rise in the pediatric population, this study investigated costs of care in children treated with hydroxyurea with sickle cell disease and those untreated with sickle cell disease. The study actually re-utilized the same database for the BABY HUG trial and compared those receiving hydroxyurea to those receiving placebo. The study analyzed outpatient expenses based on a visit schedule required in the BABY HUG trial verses a “standard” schedule typical of 1-3 year olds with sickle disease. Inpatient costs were also analyzed based on length of stay with consideration given to episodes of acute chest, splenic sequestration, or transfusion. For results, there were 232 hospitalizations in the hydroxyurea group and 324 in the placebo group. Outpatient expenses were greater in the hydroxyurea group from the BABY HUG trial but inpatient expenses for the placebo group outnumbered these expenses. The total annual cost estimated for the hydroxyurea group, $11,072, was less than the placebo group costs, $13,962, by 21% (p=.038). The results of this study demonstrate that use of hydroxyurea in infants with sickle cell disease is cost-effective, providing additional support for its routine use. Cost-effectiveness likely will increase with age since the study population was young and hydroxyurea is expected to decrease adverse outcomes like pain crises, ACS, and splenic sequestration over time.

Submitted by: Amanda Gogol-Tagliaferro
Comment: This article is a “sometimes the good guys win” story—it makes sense that a medically effective treatment that reduces episodes of pain and improves outcome should also be the right choice economically. Lydia Furman MD


Bethell, et al. Complementary and Conventional Medicine Use Among Youth With Recurrent Headaches. Pediatrics. 2013;132:e1173-e1183.

This is a cross-sectional study using national databases including over 5000 adolescents ages 10 to 17. Overall prevalence of headache was nearly 11 percent. Among those experiencing headache, 30 percent had used complementary and alternative medicine (CAM) in the past 12 months. The most common CAM types used were biologically based (avoiding certain foods or taking herbs or supplements) and mind-body therapies (including hypnosis, meditation, and biofeedback). The rate of CAM use among adolescents with headaches was 2.1 times higher than in those without headaches, after controlling for age, gender, race, household income, and geographic region. CAM use was especially prevalent in teens experiencing multiple chronic conditions or those who also had difficulty with daily activities, emotions, school attendance, and concentration or behavior. While on neurology elective, I saw multiple adolescents with headaches, including some with a significant psychological component due to depression, anxiety, and stress. We frequently refer these patients to Dr. Howard Hall in psychology for biofeedback, hypnosis, relaxation techniques, etc. However, I don’t often ask about CAM use and was surprised by the prevalence in this article. I think it would be helpful to ask about CAM use for patients with headaches and to recommend CAM in addition to conventional therapies, especially biofeedback, relaxation, and stress management, for patients with or without other underlying psychological diagnoses.

Submitted by: Katy Swearingin
Comment: I also found it interesting that the use of CAM for headaches was much more prevalent in patients with higher family income level and private insurance. The authors point out that this may be a health policy issue, since some CAM modalities have proven success for headaches (such as relaxation and biofeedback). Laura Caserta MD

Sports Medicine

Mitchell J. Rauh, PhD, Jeanne F. Nichols, PhD, and Michelle T. Barrack, PhD. Relationships Among Injury and Disordered Eating, Menstrual Dysfunction, and Low Bone Mineral Density in High School Athletes: A Prospective Study. Journal of Athletic Training. 2010;45(3):243–252.

This article describes a prospective cohort study evaluating the relationship between disordered eating, menstrual dysfunction, and low bone mineral density and musculoskeletal injury among female high school athletes. Daily injury reports, the Eating Disorder Examination Questionnaire, bone density scan, and lean tissue mass, anthropometric measurements, and a questionnaire about menstrual history. 163 athletes which were post-menarche females aged 13 to 18 or pre-menarche females aged 15 to 18 participating in 8 interscholastic sports. 37% had a total of 90 sports-related injuries. Overuse or chronic injuries accounted for 69% of reported injuries. Athletes who had an overall bone marrow density z-score of less than or equal to -1.0 SD were 3.6 times more likely to have a musculoskeletal injury than those with normal BMD z-scores. Although not statistically significant (P=0.08), athletes who reported more dietary restraint were more likely to have musculoskeletal injury. Athletes who reported oligomenorrhea or amenorrhea had a nearly 3 times increase in injury risk compared to those who reported regular menses (P=.004). I think the biggest take-away point from this article that even z-scores less than or equal to -1 and athletes reporting oligomenorrhea or amenorrhea are associated with an increased likelihood of injury. Taking a menstrual history is a point which I will add to my evaluation of female athlete patients. This will help me assess their risk of injury as well as counseling the female athlete on nutritional needs and bone health.

Submitted by: Meg Oberle
Comment: This interesting article has many take home points, and I certainly agree with Dr. Oberle’s. And I would add that in the injured female athlete, we need to have increased vigilance for eating and menstrual disorders—it is way too easy to focus on the pain and injury rather than attending to the whole young woman. Lydia Furman MD

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