Positional plagiocephaly/brachycephaly is associated with later cognitive and academic outcomes

Positional plagiocephaly/brachycephaly is associated with later cognitive and academic outcomesTranslating Best Evidence into Best Care
EDITOR’S NOTE: Studies for this column are identified using the Clinical Queries feature of PubMed, “hand” searching JAMA, JAMA Pediatrics, Pediatrics, The Journal of Pediatrics, and The New England Journal of Medicine, and from customized EvidenceAlerts.
EBMPEARL: COX PROPORTIONAL HAZARDS REGRESSION (CPH): CPH is a semiparametric method to estimate the effect of multiple variables on the outcome of interest for a specific time period. A semiparametric method does not assume a specific distribution of outcomes, but does assume a specific relationship between the variables and the outcome. Typi- cally, CPH is used to estimate the hazard rate controlling for independent variables that are known to influence or suspected of influencing the hazard rate. CPH assumes an important condition: each variable’s effect on the outcome (hazard rate) is constant (constant proportion) over time. CPH can handle censored data—data that is incomplete—for example, patients lost to follow- up, and can accommodate both continuous and bivariate data. CPH was used in the study by al-Haddad et al reviewed below.
CRITICAL STATISTICAL DISTINCTION PEARL: RELATIVE RISK (RR), ODDS RATIO (OR), AND HAZARD RATIO (HR): This instalment features 3 statistics terms that may be confused with one another, especially RR and HR. RR is the event- (or outcome) occurrence rate (or percent) in the experimental group divided by the event-occurrence rate in the control group at the completion of a study, A/(A+B)/C/(C+D) (Table). OR is the event/no event proportion in an exposed group divided by the event/no event proportion in an unexposed group, (A/B)/(C/D). HR is the event-occurrence rate in the exposed (or experimental) group divided by the event-occurrence rate in the unexposed (or control) group, A/ (A+B)/C/(C+D), during a specific time period.
Table. 2-Group Study
Exposed (or Experimental) A B Unexposed (or Control) C D
—Jordan Hupert, MD
Maternal infection associated with autism and depression in their offspring
Al-Haddad BJS, Jacobsson B, Chabra S, Modzelewska D, Olson EM, Bernier R, et al. Long-term Risk of Neuropsychi- atric Disease After Exposure to Infection In Utero. JAMA Psychiatry 2019, in press.
Question What is the association of maternal infection dur- ing pregnancy, with development of autism, depression, bi- polar disorder, and psychosis in their offspring?
Design Cohort study of the Swedish population-based birth registry, linked to hospital inpatient, demographic, educa- tion, and death registries.
Setting Sweden.
Participants All children born between January 1, 1973, and December 31, 2014.
Intervention Maternal infection during pregnancy.
Outcomes Autism, depression, bipolar disorder, or psycho- sis among offspring over the 41 years covered by the database.
Main Results A total of 1 791 520 children contributed 32 125 813 person-years. Fetal exposure to maternal infection increased the child’s risk for autism and depression, but not bipolar disease, hazard ratio (HR), 1.79 (95% CI, 1.34-2.40) and HR, 1.24 (95%CI, 1.08-1.42) for autism and depression, respectively, but not bipolar disease or psychosis.
Conclusions Maternal infection is associated with development of autism and depression in their offspring.
Commentary al-Haddad et al highlight the potential signif- icance of maternal infection during pregnancy by showing associations with offspring neuropsychiatric disorders. Re- searchers and clinicians should consider several limitations when reviewing the study. First, the authors used inpatient records to identify both risks and outcomes. Therefore, the range of severity used to assess a “dose–dependent” relation is quite limited. Additionally, inpatient care for the studied outcomes may indicate general illness rather than severity of disorder. Second, sensitivity analyses revealed that misclas- sification of outcomes must be considered. Third, although some measured covariates were included in adjusted models, maternal psychiatric disorders and socio-demographic
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characteristics were not included. Future research would benefit from the use of outpatient records, the inclusion of placental pathology markers of subclinical inflammation, and a more precise indication of chorioamnionitis.1 Further, a genetically-informed design, such as a cousin- or sibling- comparison, would advance our knowledge as the current study cannot exclude familial confounding.2 Although more research is needed, pregnant women should continue to take measures to reduce infections during pregnancy.
Quetzal A. Class, PhD University of Illinois at Chicago
Chicago, Illinois
References
1. Higgins RD, Saade G, Polin RA, Grobman WA, Buhimschi IA,
Watterberg K, et al. Chorioamnionitis workshop participants. Evaluation
andmanagement ofwomen andnewbornswith amaternal diagnosis of cho-
rioamnionitis: Summary of a workshop. Obstet Gynecol 2016;127:426-36.
2. D’Onofrio BM, Class QA, Rickert ME, Sujan AC, Larsson H,
Kuja-Halkola R, et al. Translational epidemiologic approaches to under-
standing the consequences of early-life exposures. Behav Gen 2016;46:
315-28.
Positional plagiocephaly/brachycephaly is associated with later cognitive and academic outcomes
Collett BR,Wallace ER, Kartin D, CunninghamML, Speltz ML. Cognitive Outcomes and Positional Plagiocephaly. Pedi- atrics 2019;143. pii: e20182373.
Question Among school-aged children, what is the associa- tion of a history of positional plagiocephaly/brachycephaly (PPB), compared with children without a history of PPB, with cognitive and academic outcomes?
Design Prospective cohort.
Setting Seattle Children’s Craniofacial Center.
Participants 187 school-aged children with a history of PPB and 149 controls.
Intervention PPB or none.
Outcomes Cognitive and academic outcomes as measured by the Differential Ability Scales, Second Edition and the Wechsler Individual Achievement Test, Third Edition, respec- tively.
Main Results Children with a history of PPB scored lower than controls on most scales of both tests. A “dose response” was noted: children with moderate to severe PPB were signif- icantly different from controls, whereas those with mild PPB were not.
Conclusions A history of moderate to severe PPB was asso- ciated with cognitive and academic outcomes.
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Commentary PPB has become a common reason for parents to seek a pediatrician’s advice. Although there is growing ev- idence suggesting that infants with PPB display mild develop- mental delays, there is little evidence about long-term developmental trajectories. This well-designed and executed study compares cognitive and academic functioning of chil- dren with PPB to non-affected peers at school age using a prospective, longitudinal design. Overall, findings are reas- suring for parents of children with mild PPB, suggesting that mild PPB is not associated with increased risk of general cognitive and academic difficulties at school age. However, the authors recommend close developmental monitoring for infants with moderate to severe forms of PPB as this group performed significantly lower on both cognitive and academic measures. Importantly, as most of the children in the study performed in the age-appropriate range when compared with test norms, results suggest that any cognitive or academic difficulties for children with PPB (and no other risk factors) are likely to be modest. The authors caution that results do not infer that skull deformation causes cognitive or academic difficulties but rather that moderate/severe PPB may be a marker for developmental risk. Future work should consider other aspects of neuropsychological functioning not evaluated in the current study, including attention, memory, executive function, mood, and behavioral regulation.
Sarah Knight, PhD The University of Melbourne
Victoria, Australia
iBsafe app enhances safety skills and knowledge among young children Dixon CA, Ammerman RT, Johnson BL, Lampe C, Hart
KW, Lindsell CJ, et al. A randomized controlled field trial of iBsafe-a novel child safety game app. Mhealth 2019;5:3.
Question Among young children, what is the therapeutic ef- ficacy of a device-based bicycle and dog-related safety- learning app, compared with control, in safety knowledge and skills performance?
Design Single-blinded, randomized, controlled trial.
Setting Outpatient safety simulation lab, University of Cin- cinnati.
Participants Sixty, 5- and 6-year-old children.
Intervention Apple-iPod-touch-based iBsafe game app vs control (nutritional pamphlets).
Outcomes Child bicycle and dog-related safety knowledge and skills performance (using real props—a safety street, bi- cycles, and live dogs).
Main Results Children randomized to iBsafe had statistically higher bicycle and dog-related safety knowledge scores and exhibited more safety skills compared with control children.
Conclusions Under laboratory conditions, the iBsafe app enhanced and improved child safety knowledge and safety skills, respectively.
Commentary Like it or not, today’s children spend hours on mobile devices. It seems wise, therefore, to incorporate pedi- atric injury prevention into mobile apps. Dixon et al evalu- ated iBsafe, a theory-based interactive app to teach 5- and 6-year-olds bicycle and dog safety.1 Results from the pilot offer promise—children’s knowledge and skills both improved among the randomly-assigned intervention chil- dren compared with the control group, and improvements were seen both on dog and bicycling safety—but results must be interpreted cautiously. Details of how the app func- tions to teach children are sparse, as are methodological lo- gistics of the skills assessment. Children nearly reached ceiling level on the knowledge measure, even at baseline, so improvements among the intervention group were positive but modest. Also concerning was the sample, which was fairly small and consisted primarily of white children of highly- educated parents. Despite these limitations, iBsafe offers exciting potential. It reaches children “where they are” (mo- bile apps) and could be expanded to other child injury pre- vention domains, as well as other developmental stages.
David C. Schwebel, PhD University of Alabama at Birmingham
Birmingham, Alabama
Reference
1. Dixon CA, Ammerman RT, Dexheimer JW, Meyer B, Jung H,
Johnson BL, et al. Development of iBsafe: A collaborative, theory-based
approach to creating a mobile game application for child safety. AMIA
Annu Symp Proc 2014;2014:477-85.
Cyclosporine and coronary outcomes in Kawasaki disease
Hamada H, Suzuki H, Onouchi Y, Ebata R, Terai M, Fuse S, et al. Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormal- ities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglob- ulin (KAICA): A randomized controlled, open-label blinded endpoints, phase 3 trial. Lancet 2019;393:1128-37.
Question Among children with Kawasaki disease and at high risk for intravenous immunoglobulin (IVIG) resistance, what is the therapeutic benefit of IVIG plus cyclosporine, compared with IVIG alone, in reducing coronary artery ab- normalities (CAAs)?
Design Randomized, controlled, open-label blinded endpoint, phase 3 trial.
Setting 22 hospitals in Japan.
Participants 175 high-risk patients with Kawasaki disease aged 4 months to 12 years.
Intervention IVIG + Cyclosporine (5 mg/kg/day p.o. x 5 days) or IVIG alone.
Outcomes Primary outcome: CAA incidence over 12 weeks by Japanese Ministry of Health (JMH) criteria.
Main Results CAA incidence at Week 2 was reduced in the cyclosporine group, absolute risk reduction (ARR), 12.6% (95% CI, 4.0% - 21.2%). The fold-change in CRP level was greater in the group that received cyclosporine at Day 3 (P < .0001) and Day 5 (P = .0051). However, there was no dif- ference in median coronary artery Z score between the groups except for the left anterior descending artery at Week 4 (P = .014), the percentage of patients requiring addi- tional IVIG (44-45%), or the fold-change in CRP at Day 8-85. Also, although cyclosporine improved overall CAA incidence (detection of CAAs by JMH criteria at any point in the study), ARR 17.2% (95% CI, 4.9% - 29.3%), by the end of the study at 12 weeks, there was no statistical difference in CAA prev- alence, although the study was underpowered to detect a prevalence difference.
Conclusions Intensification of initial therapy with cyclo- sporine was well-tolerated and improved CAA 4-week and overall incidence, but not CAA prevalence at 12 weeks in high-risk Japanese patients with acute Kawasaki disease.
Commentary There are many reasons to postulate that cyclosporine would be a useful drug for the treatment of acute Kawasaki disease. Cyclosporine is a specific T cell in- hibitor and blocks the calcium-driven calcineurin-NFAT pathway that leads to transcription of many pro-inflamma- tory cytokines that are known to be players in the acute inflammation of Kawasaki disease. Polymorphisms in cal- cium pathway and calcium channel genes are risk factors for Kawasaki disease susceptibility, which underscores the importance of the calcineurin-NFAT pathway.1 Autopsy studies have shown that cytotoxic CD8+T cells infiltrate the arterial wall after the initial influx of neutrophils and macrophages. Elegant gene expression studies of these au- topsy tissues show an increase in transcripts related to these cytotoxic T cells.2 Taken together, these data suggest that cyclosporine would be an ideal drug to prevent progression of inflammation in the arterial wall. Two aspects of the cur- rent study deserve comment. First, the clinical risk score used to select subjects at risk for IVIG-resistance has poor performance in non-Japanese populations. Because the pri- mary goal of treatment is to block coronary artery inflam- mation, a better trial design for Western populations would be to enroll patients with an initial coronary artery Z score ³2.5 because studies have shown that 80% of pa- tients who will go on to develop CAAs have a Z score above this threshold on their initial echocardiogram.3 Close exam- ination of the results demonstrates a rebound in Z scores after cyclosporine discontinuation (after 5 days) on the Week 1 echocardiogram. A longer treatment period may have yielded better outcomes. This study paves the way
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for future randomized studies, in other countries, of cyclo- sporine in patients with acute Kawasaki disease with diverse genetic backgrounds at high risk of CAAs based on the Z scores on the initial echocardiogram.
Jane C. Burns, MD University of California San Diego
San Diego, California
References
1. Onouchi Y. The genetics of Kawasaki disease. Int J RheumDis 2018;21:26-
30.
2. Rowley AH, Wylie KM, Kim KY, Pink AJ, Yang A, Reindel R, et al. The
transcriptional profile of coronary arteritis in Kawasaki disease. BMC Ge-
nomics 2015;16:1076.
3. Dominguez SR, Anderson MS, El-Adawy M, Glode MP. Preventing cor-
onary artery abnormalities: a need for earlier diagnosis and treatment of
Kawasaki disease. Pediatr Infect Dis J 2012;31:1217-20.
Children older than 12 months and with commercial insurance at risk for delayed treatment of UTI
Hum SW, Shaikh N. Risk Factors for Delayed Antimicro- bial Treatment in Febrile Children with Urinary Tract Infec- tions. J Pediatr 2019;205:126-9.
Question Among children diagnosed with a first or second urinary tract infection (UTI), what are the factors associated with delayed antibiotic treatment (which is associated with renal scarring)?
Design Secondary analysis of a randomized controlled trial and a prospective cohort study.
Setting Multiple sites across the US.
Participants 2 to 71 months of age presenting with a first or second UTI.
Intervention Time to antibiotic initiation.
Outcomes Risk factors (eg, age, insurance, race).
Main Results Multivariate analysis identified age >12 months, and commercial insurance were associated with an
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average delayed treatment of 26.2 and 12.6 hours, respec- tively. Race, ethnicity, primary caregiver’s education level, and income were not associated with delayed treatment.
ConclusionsOlder age and commercial insurance were asso- ciated with delayed antibiotic treatment and may be associ- ated with renal scarring.
Commentary Delayed antimicrobial treatment in febrile children with UTI is associated with increased risk of renal scarring. In this sizable cohort of young children, delay was significantly longer beyond infancy and in those with commercial insurance. The mean time prior to initi- ation of antimicrobial therapy was 68.5 hours for toddlers and 72.6 hours for older children, nearing and exceeding the “safe” upper limit of 72 hours, respectively.1 Despite the focus on infants, the reaffirmed American Academy of Pediatrics’ clinical practice guideline includes children up to 24 months of age2 and provides the framework for older children, who often present with non-specific symptoms and deserve prompt treatment. Commercial insurance may pose hurdles in providing prompt treat- ment due to flaws in the acute setting or unfavorable characteristics of families served. The underlying factors for these intriguing associations
merit future exploration in order to design targeted interven- tions.
Alexandra Soldatou, MD, PhD University of Athens
Athens, Greece
References
1. Karavanaki KA, Soldatou A, Koufadaki AM, Tsentidis C, Haliotis FA,
Stefanidis CJ. Delayed treatment of the first febrile urinary tract infection
in early childhood increased the risk of renal scarring. Acta Paediatr
2017;106:149-54.
firmation of AAP Clinical Practice Guideline: The Diagnosis and
Management of the Initial Urinary Tract Infection in Febrile Infants
and Young Children 2–24 Months of Age. Pediatrics 2016;138:
Maternal infection associated with autism and depression in their offspring
References
iBsafe app enhances safety skills and knowledge among young children
Reference
References
Children older than 12 months and with commercial insurance at risk for delayed treatment of UTI
References