Childhood Seizures After Phototherapy

In this retrospective cohort study of nearly half a million births, we confirm an association reported from Denmark that newborn phototherapy is associated with childhood epilepsy in boys. BrightcoveDefaultPlayer10.1542/6138642839001PEDS-VA_2018-0648 Video Abstract BACKGROUND AND OBJECTIVES: In a recent Danish study, researchers found an increased risk of childhood epilepsy after phototherapy but only in boys. We investigated this association in a Kaiser Permanente Northern California cohort. METHODS: From 499 642 infants born at ≥35 weeks’ gestation in 1995–2011 followed for ≥60 days, we excluded 1773 that exceeded exchange transfusion thresholds and 1237 with seizure diagnoses at <60 days. We ascertained phototherapy, covariates, and outcomes from electronic records and existing databases. Our primary outcome was ≥1 encounter with a seizure diagnosis plus ≥1 prescription for an antiepileptic drug. We used Cox and Poisson models to adjust for bilirubin levels and other confounding variables. RESULTS: A total of 37 683 (7.6%) infants received any phototherapy. The mean (SD) follow-up time was 8.1 (5.2) years. The crude incidence rate per 1000 person-years of the primary outcome was 1.24 among phototherapy-exposed children and 0.76 among those unexposed (rate ratio: 1.63; 95% confidence interval [CI]: 1.44 to 1.85). The adjusted hazard ratio (aHR) was 1.22 (95% CI: 1.05 to 1.42; P = .009). Boys were at higher risk of seizures overall (aHR = 1.18; 95% CI: 1.10 to 1.27) and had a higher aHR for phototherapy (1.33; 95% CI: 1.10 to 1.61) than girls (1.07; 95% CI: 0.84 to 1.37), although effect modification by sex was not statistically significant (P = .17). The adjusted 10-year excess risks per 1000 were 2.4 (95% CI: 0.6 to 4.1) overall, 3.7 (95% CI: 1.2 to 6.1) in boys, and 0.8 (95% CI: −1.7 to 3.2) in girls. CONCLUSIONS: Phototherapy in newborns is associated with a small increased risk of childhood seizures, even after adjusting for bilirubin values, and the risk is more significant in boys.

[1]  C. McCulloch,et al.  Efficacy of Subthreshold Newborn Phototherapy During the Birth Hospitalization in Preventing Readmission for Phototherapy , 2018, JAMA pediatrics.

[2]  Eileen M. Walsh,et al.  Phototherapy and Risk of Type 1 Diabetes , 2016, Pediatrics.

[3]  Eileen M. Walsh,et al.  Risk of Autism Associated With Hyperbilirubinemia and Phototherapy , 2016, Pediatrics.

[4]  C. McCulloch,et al.  Neonatal Phototherapy and Infantile Cancer , 2016, Pediatrics.

[5]  Eileen M. Walsh,et al.  Retrospective Cohort Study of Phototherapy and Childhood Cancer in Northern California , 2016, Pediatrics.

[6]  J. Tyson,et al.  Phototherapy and the Risk of Photo-Oxidative Injury in Extremely Low Birth Weight Infants. , 2016, Clinics in perinatology.

[7]  Dina N. Greene,et al.  Association Between Laboratory Calibration of a Serum Bilirubin Assay, Neonatal Bilirubin Levels, and Phototherapy Use. , 2016, JAMA pediatrics.

[8]  H. Aly,et al.  Jaundice, phototherapy and DNA damage in full-term neonates , 2016, Journal of Perinatology.

[9]  Gregory H Gorman,et al.  Association of Autism Spectrum Disorders With Neonatal Hyperbilirubinemia , 2015, Global pediatric health.

[10]  E. Ribeiro,et al.  Maple syrup urine disease in Brazil: a panorama of the last two decades. , 2015, Jornal de pediatria.

[11]  M. McCarthy,et al.  Using sex differences in the developing brain to identify nodes of influence for seizure susceptibility and epileptogenesis , 2014, Neurobiology of Disease.

[12]  H. Scharfman,et al.  Sex differences in the neurobiology of epilepsy: A preclinical perspective , 2014, Neurobiology of Disease.

[13]  K. Michelsson,et al.  Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates—a 30 year prospective follow-up study , 2014, PeerJ.

[14]  J. Olsen,et al.  Neonatal hyperbilirubinemia and the risk of febrile seizures and childhood epilepsy , 2016, Epilepsy Research.

[15]  A. Taştekin,et al.  Phototherapy causes a transient DNA damage in jaundiced newborns , 2013, Drug and chemical toxicology.

[16]  Pablo Lema,et al.  Early-Life Stress Is Associated with Gender-Based Vulnerability to Epileptogenesis in Rat Pups , 2012, PloS one.

[17]  Wei Tao,et al.  PS2-44: VDW Data Sources: Kaiser Permanente Northern California , 2012, Clinical Medicine & Research.

[18]  Y. Palancı,et al.  Prevalence and risk factors of epilepsy among school children in eastern Turkey. , 2012, Pediatric neurology.

[19]  W. Baine,et al.  The Agency for Healthcare Research and Quality , 2006, Italian Journal of Public Health.

[20]  J. Olsen,et al.  Breastfeeding and risk of epilepsy in childhood: a birth cohort study. , 2011, The Journal of pediatrics.

[21]  Tristram H. Smith,et al.  Is Neonatal Jaundice Associated with Autism Spectrum Disorders: A Systematic Review , 2011, Journal of autism and developmental disorders.

[22]  J. Olsen,et al.  Neonatal Jaundice, Autism, and Other Disorders of Psychological Development , 2010, Pediatrics.

[23]  E. C. Neto,et al.  The influence of phototherapy on serum cytokine concentrations in newborn infants. , 2010, American journal of perinatology.

[24]  C. McCulloch,et al.  Numbers Needed to Treat With Phototherapy According to American Academy of Pediatrics Guidelines , 2009, Pediatrics.

[25]  A. Aygun,et al.  Use of Phototherapy for Neonatal Hyperbilirubinemia Affects Cytokine Production and Lymphocyte Subsets , 2008, Neonatology.

[26]  A. Karadağ,et al.  Phototherapy increases DNA damage in lymphocytes of hyperbilirubinemic neonates. , 2008, Mutation research.

[27]  O. Erel,et al.  Phototherapy causes DNA damage in peripheral mononuclear leukocytes in term infants. , 2008, Jornal de pediatria.

[28]  Ozcan Erel,et al.  Estado oxidante/antioxidante total em recém-nascidos ictéricos antes e depois da fototerapia , 2007 .

[29]  A. Sola.  Turn off the lights and the oxygen, when not needed: phototherapy and oxidative stress in the neonate. , 2007, Jornal de pediatria.

[30]  O. Erel,et al.  Total oxidant/antioxidant status in jaundiced newborns before and after phototherapy. , 2007, Jornal de pediatria.

[31]  Şebnem Soysal,et al.  Prevalence of some risk factors in children with epilepsy compared to their controls , 2007, Seizure.

[32]  M. Weinstock.  Gender Differences in the Effects of Prenatal Stress on Brain Development and Behaviour , 2007, Neurochemical Research.

[33]  K. Joseph,et al.  Relation of Pregnancy and Neonatal Factors to Subsequent Development of Childhood Epilepsy: A Population-Based Cohort Study , 2006, Pediatrics.

[34]  Subcommittee on Hyperbilirubinemia.  Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. , 2004, Pediatrics.

[35]  G. Gathwala,et al.  Phototherapy induces oxidative stress in premature neonates. , 2002, Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology.

[36]  M. Hadders‐Algra,et al.  Are Moderate Degrees of Hyperbilirubinemia in Healthy Term Neonates Really Safe for the Brain? , 2001, Pediatric Research.

[37]  G. Gathwala,et al.  Oxidative stress, phototherapy and the neonate , 2000, Indian journal of pediatrics.

[38]  L. Sirota,et al.  Phototherapy for neonatal hyperbilirubinemia affects cytokine production by peripheral blood mononuclear cells , 1999, European Journal of Pediatrics.

[39]  H. Adami,et al.  Prenatal and neonatal risk factors for childhood myeloid leukemia. , 1995, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[40]  H. Stähelin.  Guidelines , 1994, Communicating Science.

[41]  M. Klebanoff,et al.  Neonatal hyperbilirubinemia and long-term outcome: another look at the Collaborative Perinatal Project. , 1993, Pediatrics.

[42]  G. Papageorgiou,et al.  A Spectrum Response Study on Single Strand DNA Breaks, Sister Chromatid Exchanges, and Lethality Induced by Phototherapy Lights , 1981, Pediatric Research.

[43]  P. Scheidt,et al.  Toxicity to bilirubin in neonates: infant development during first year in relation to maximum neonatal serum bilirubin concentration. , 1977, The Journal of pediatrics.

[44]  A. Morris,et al.  Screening using compressed digital retinal images successfully identifies retinopathy. , 2003, Diabetes care.

[45]  G. Dahlquist,et al.  Indications that phototherapy is a risk factor for insulin-dependent diabetes. , 2003, Diabetes care.

[46]  H. Rosenkranz,et al.  Phototherapy for neonatal hyperbilirubinemia--a potential environmental health hazard to newborn infants: a review. , 1979, Environmental mutagenesis.