Neonatal Jaundice, Autism, and Other Disorders of Psychological Development

Full text


Psychological Development

WHAT’S KNOWN ON THIS SUBJECT: Little and inconclusive evidence has been published regarding the association between neonatal jaundice and autistic disorders.

WHAT THIS STUDY ADDS: With this study, the authors confirm a positive association between neonatal jaundice and autistic disorders, as well as possibly disorders of psychological development in general. Gestational age, parity, and season of birth play important roles in this association.


OBJECTIVES:The goals were to study the association between neona-tal jaundice and disorders of psychological development in a national, population-based cohort and to study whether gestational age, parity, and season of birth influenced that association.

METHODS:A population-based, follow-up study of all children born alive in Denmark between 1994 and 2004 (N⫽733 826) was performed, with data collected from 4 national registers. Survival analysis was used to calculate hazard ratios (HRs).

RESULTS:Exposure to jaundice in neonates was associated with in-creased risk of disorders of psychological development for children born at term. The excess risk of developing a disorder in the spectrum of psychological development disorders after exposure to jaundice as a neonate was between 56% (HR: 1.56 [95% confidence interval [CI]: 1.05–2.30]) and 88% (HR: 1.88 [95% CI: 1.17–3.02]). The excess risk of infantile autism was 67% (HR: 1.67 [95% CI: 1.03–2.71]). This risk for infantile autism was higher if the child was conceived by a parous woman (HR: 2.71 [95% CI: 1.57– 4.66]) or was born between October and March (HR: 2.21 [95% CI: 1.24 –3.94]). The risk for infantile autism dis-appeared if the child was conceived by a primiparous woman (HR: 0.58 [95% CI: 0.18 –1.83]) or was born between April and September (HR: 1.02 [95% CI: 0.41–2.50]). Similar risk patterns were found for the whole spectrum of autistic disorders.

CONCLUSIONS:Neonatal jaundice in children born at term is associ-ated with disorders of psychological development. Parity and season of birth seem to play important roles.Pediatrics2010;126:872–878

AUTHORS:Rikke Damkjær Maimburg, MPH, PhD,a,bBodil

Hammer Bech, MD, PhD,aMichael Væth, PhD,cBjarne

Møller-Madsen, MD, DMSci,dand Jørn Olsen, MD, PhDa,e

Departments ofaEpidemiology andcBiostatistics, School of

Public Health, Aarhus University, Aarhus, Denmark; Departments ofbObstetrics and Gynecology anddOrthopedic Surgery, Aarhus

University Hospital, Aarhus, Denmark; andeDepartment of

Epidemiology, School of Public Health, University of California, Los Angeles, California


jaundice, hyperbilirubinemia, autistic disorders, neurodevelopment, psychological development

ABBREVIATIONS HR—hazard ratio CI—confidence interval

DMBR—Danish Medical Birth Register DNHR—Danish National Hospital Register

ICD-10—International Classification of Diseases,10th Revision DPCR—Danish Psychiatric Central Register


Accepted for publication Jul 22, 2010

Address correspondence to Rikke Damkjær Maimburg, MPH, PhD, Aarhus University, School of Public Health, Department of Epidemiology, Bartholins Allé 2, 8000 Aarhus C, Denmark. E-mail:

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2010 by the American Academy of Pediatrics


Neonatal jaundice usually is a result of elevated bilirubin production caused by increased breakdown of fetal eryth-rocytes and a low hepatic excretory ca-pacity resulting from general immatu-rity of the liver. Visual jaundice is seen for 60% of term neonates and 80% of preterm neonates.1,2 For most

neo-nates, this is a normal transitional phenomenon that resolves itself within the first week of life.2However, it is the

most common condition requiring medical attention in newborns and is the main reason for readmission in the neonatal period.3–5

Exposure to high serum bilirubin lev-els, hyperbilirubinemia, is of concern because unconjugated bilirubin is neu-rotoxic and can cause death in new-borns or lifelong sequelae, such as mental retardation, cerebral palsy, and kernicterus, in those who survive.6

It was suggested recently that expo-sure to moderate serum bilirubin lev-els is associated with impaired child development, especially autistic disor-ders classified as pervasive develop-mental disorders.7We reported

previ-ously on a positive association between neonatal jaundice and au-tism,8as did Jangaard et al9and

Buch-mayer et al.10Croen et al11 found no

significant association, but they in-cluded relatively few cases with mod-erate/high levels of bilirubin in their study. Moreover, the study was con-ducted in a restricted geographical area.11

The cause of autistic disorders is not known. Genetic factors play a role but prenatal exposure to thalidomide, val-proic acid, or viral infections also may play a role.12,13Season of birth and

par-ity are environmental factors that of-ten are studied in autism research and also are relevant in studies of neonatal jaundice. Exposure to daylight is a con-tributing factor in decreasing bilirubin levels, and children born to primipa-rous women experience different

ex-posure to antibodies in fetal life than do children born to multiparous women. In a previous case-control study, we found an almost fourfold higher risk for infantile autism (sus-pected to be limited to term-born chil-dren) if the child developed hyperbil-irubinemia in the neonatal period.8In

the present study, we investigated (1) the association between neonatal jaundice and autistic disorders, and other disorders of psychological devel-opment, in a national cohort and (2) the role of gestational age, parity, and season of birth in autistic disorders.


Study Population

This study was designed as a national, population-based, follow-up study of all children born in Denmark between January 1, 1994, and December 31, 2004. The cohort was established from the Danish Medical Birth Register (DMBR),14which includes information

on⬎99% of all deliveries in Denmark. The data stored in the register have been validated and are considered re-liable.15From the DMBR, we obtained

information on parent’s age, mother’s citizenship, maternal smoking in early pregnancy, birth weight (in grams), gestational age, irregular fetal presen-tation, congenital malformations, and Apgar score. Additional data on expo-sures and outcomes were obtained from the Danish National Hospital Reg-ister (DNHR),16the Danish Psychiatric

Central Register (DPCR)17(through the

DNHR), and the Cause of Death


Exposure and Outcomes

We determined jaundice exposure sta-tus and diagnoses of disorders of psy-chological development on the basis of theInternational Classification of Dis-eases, 10th Revision (ICD-10).7

Expo-sure status (neonatal jaundice) was defined on the basis of ICD-10 codes

P57.0 to P59.9, and data were retrieved from the DNHR. Neonatal jaundice caused by hemolytic diseases was not included (ICD-10 codes P55–P56). No information on phototherapy or serum bilirubin levels is available in the reg-ister. The outcome diagnoses (disor-ders of psychological development) were defined on the basis of ICD-10 codes F80.0 to F89.9, and data were re-trieved from the DPCR through the DNHR.

The outcome diagnoses were divided into the following subgroups: specific developmental disorders of speech and language (ICD-10 codes F80 – F80.9), specific developmental disor-ders of scholastic skills (ICD-10 codes F81–F81.9), specific developmental disorders of motor function (ICD-10 codes F82–F82.9), mixed specific devel-opmental disorders (ICD-10 codes F83–F83.9), pervasive developmental disorders (also referred to as autistic disorders; ICD-10 codes F84 –F84.9), and other and unspecified disorders of psychological development (ICD-10 codes F88 –F89.9). The subgroup of pervasive developmental disorders was further restricted to infantile au-tism (ICD-10 code F84.0). Information on mental retardation (ICD-10 codes F70 –F79.9) also was retrieved. The out-come diagnoses were obtained from the DPCR, which was established in 1938 and computerized in 1969 to in-clude all inpatient admissions to psy-chiatric hospitals and wards. Since January 1, 1995, information from all contacts with psychiatric outpatient clinics has been included. In Denmark, children are referred to a specialist in child psychiatry by general practitio-ners, schools, or psychologists if men-tal impairment problems are sus-pected. Only child psychiatrists assign a diagnostic code, and all diagnoses are recorded in the DPCR. Denmark provides universal tax-paid health care coverage, and no private


DPCR are thought to capture the vast majority of children with severely im-paired development. Information on children’s vital status and time of death was obtained from the Cause of Death Register.

The information from the different reg-isters was linked through the unique identification numbers that are as-signed to all live-born children and new residents in Denmark and are used whenever a person is in contact with the Danish health care system. This number allows for the accurate linkage of information between regis-tries at the individual level.

Statistical Analyses

We estimated the relative risks of neo-natal jaundice and disorders of psy-chological development as hazard

ra-tios (HRs) with 95% confidence

intervals (CIs), with Cox regression models with right censoring. For all children, the follow-up time began at birth and continued until the first oc-currence of 1 of the following events: date of relevant diagnosis, time of death, or end of the follow-up period on April 30, 2008. No attempts were made to adjust for emigration, which has a low rate of ⬍1% in Denmark.18 Both

crude and adjusted HRs were com-puted. The potential confounders in-cluded in the analysis were selected from the already known risk factors for jaundice or disorders of psycholog-ical development and included moth-er’s smoking status, irregular fetal presentation, gender, birth weight, gestational age, Apgar score, parents’ ages, mother’s citizenship, and con-genital malformations.

In the analysis, we considered all dis-orders of psychological development (ICD-10 codes F80 –F89.9), followed by the analysis of 6 diagnostic subgroups (ICD-10 codes F80 –F80.9, F81–F81.9,

obtained separate estimates of the as-sociations between neonatal jaundice and the outcomes for term and pre-term births.

For term-born children, further analy-ses (crude and adjusted) were made for autistic disorders and the re-stricted subgroup of infantile autism. These analyses included stratification according to the gender of the child, the season of birth (April to September versus October to March), parity (pri-miparous versus parous women), and mental retardation (children with or without a diagnosis of mental retar-dation). To clarify the importance of gestational age, we also performed a series of supplementary analyses with 10 gestational age categories. In these analyses, the outcome was the main group of psychological develop-ment disorders and the 2 subgroups of autistic disorders and infantile autism.

Likelihood ratio tests were used to test for effect measure modification by gestational age (term versus preterm) in the entire cohort with a full range of diagnoses and within the diagnostic subgroups. Similarly, in the analysis of term-born children, we assessed whether the associations between neonatal jaundice and outcomes de-pended on the gender of the child, the season of birth, parity, and mental re-tardation. We used Stata 9 (Stata Corp, College Station, TX) for data analysis. The study was approved by the Danish Data Protection Agency.


Study Group

A total of 733 826 children were in-cluded in the cohort. There were 35 766 children (4.9%) with a diagnosis of neonatal jaundice in the register. Of those cases, 0.09% were ascribed to hemolytic disease and the remaining

trum of disorders of psychological de-velopment during the follow-up period, and 4257 children died.

Crude and Adjusted Analyses Table 1 shows the distribution of the cohort according to exposure status, gender, birth weight, gestational age, parents’ ages, and malformations. Larger proportions of children ex-posed to jaundice in the neonatal pe-riod were seen for boys, children born preterm, children with low birth weights, and children with malforma-tions. Table 2 presents the association between exposure to neonatal jaun-dice and the risk of receiving a diagno-sis within the spectrum of disorders of psychological development. Data were stratified for term (ⱖ37 weeks of ges-tation) versus preterm (⬍37 weeks of gestation) birth. Overall, children ex-posed to jaundice had an almost 90% greater risk of diagnosis of a psycho-logical development disorder, com-pared with unexposed children. With adjustment, the association between neonatal jaundice and disorders of psychological development was atten-uated but remained statistically signif-icant (HR: 1.29 [95% CI: 1.06 –1.56]). With stratification for gestational age, the association was found only for term-born children (tests for no inter-action were statistically significant only for the main group [ICD-10 codes F80 –F89.9];P⫽.001). Term-born chil-dren exposed to jaundice as neonates had 56% to 88% greater risks of a dis-order within the spectrum of psycho-logical development disorders, com-pared with children not exposed to jaundice as neonates (Table 2).


spec-trum of psychological development disorders (ICD-10 codes F80 –F89.9) was higher for children born at 40 to 42 weeks of gestation. Similar pat-terns were found for the 2 autistic subgroups (ICD-10 codes F84 –F84.9 and F84.0) (Fig 1).

Stratified Analyses for Term-Born Children

Table 3 shows the association between neonatal jaundice among term-born children and the 2 autistic subgroups, presented in separate categories for

gender, parity, season of birth, and di-agnosis of mental retardation. No sig-nificantly elevated risks for autistic disorders were found for children with or without a diagnosis of mental retar-dation. The risk of an autism diagnosis increased if the child was born be-tween October and March and disap-peared if the child was born between April and September. However, we found no statistically significant inter-action. Similarly, we found an associa-tion between jaundice and autistic dis-orders if the child was born of a parous woman, and the risk disap-peared if the child was born of a pri-miparous woman. For parity, the inter-action was statistically significant for pervasive developmental disorders (P ⫽ .02) and infantile autism (P ⫽ .01).


In this study, we included all children born in Denmark in 1994 –2004; there-fore, the study is unlikely to be affected by selection bias. According to Statis-tics Denmark, the Danish population is characterized as being stable, with lit-tle migration. Data for the cases were obtained from the DPCR through the DNHR. The completeness and validity of the diagnostic data for autistic disor-ders obtained from the DPCR seems to be high,19but we did not validate the

other diagnostic codes in the spec-trum of psychological development disorders. Exposure data and informa-tion on confounders were obtained from the DNHR and the DMBR, respec-tively. The DMBR contains data on

⬎99% of all births in Denmark, and the information stored in the register is considered reliable.15 Data on

expo-sure status with respect to neonatal jaundice were obtained from the DNHR, which means that we captured only the most-severe cases. Our data on exposure are most likely affected by nondifferential exposure misclassifi-cation, which may make our result

un-TABLE 1 Characteristics of 733 826 Children and Their Parents in Danish Cohort

Characteristics n(%)

All (N⫽733 826)

With Jaundice (N⫽35 766)

Without Jaundice (N⫽698 060)


Male 376 662 (51.3) 20 617 (57,6) 356 045 (51,0) Female 357 164 (48.7) 15 149 (42.4) 342 015 (49.0) Birth weight

ⱕ2499 g 37 103 (5.1) 11 956 (33.4) 25 147 (3.6) 2500–2999 g 81 690 (11.1) 6927 (19.4) 74 763 (10.7) 3000–3499 g 223 403 (30.4) 7766 (21.8) 215 637 (30.9) 3500–3999 g 244 741 (33.4) 5950 (16.6) 238 791 (34.2)

ⱖ4000 g 140 660 (19.1) 2903 (8.1) 137 757 (19.7)

Data missing 6229 (0.8) 264 (0.7) 5965 (0.9)

Gestational age

ⱕ36 wk 46 348 (6.3) 15 455 (43.2) 30 893 (4.4) 37–41 wk 622 350 (84.8) 19 252 (53.8) 603 098 (86.4)

ⱖ42 wk 59 459 (8.1) 789 (2.2) 58 670 (8.4)

Data missing 5669 (0.8) 270 (0.8) 5399 (0.8)

Fetal presentation

Regular 601 191 (81.9) 25 100 (70.2) 576 091 (82.5) Irregular 126 418 (17.2) 10 445 (29.2) 115 973 (16.6)

Data missing 6217 (0.8) 221 (0.6) 5996 (0.9)

Apgar score

0–5 2166 (0.3) 215 (0.6) 1951 (0.3)

6–10 464 319 (63.3) 22 329 (62.4) 441 990 (63.3) Data missing 267 341 (36.4) 13 222 (37.0) 254 119 (36.4) Malformation

Yes 28 740 (3.9) 2760 (7.7) 25 980 (3.7)

No 705 086 (96.1) 33 006 (92.3) 672 080 (96.3)

Mental retardation

Yes 1239 (0.2) 127 (0.4) 1112 (0.2)

No 732 587 (99.8) 35 639 (99.6) 696 948 (99.8)

Season of birth

April through September 380 724 (51.9) 17 952 (50.2) 362 772 (52.0) October through March 353 102 (48.1) 17 814 (49.8) 335 288 (48.0) Mother’s age

ⱕ25 y 153 329 (20.9) 8265 (23.1) 145 064 (20.8) 25–35 y 504 803 (68.7) 23 505 (65.7) 481 298 (68.9)

ⱖ35 y 75 671 (10.3) 3996 (11.2) 71 675 (10.3)

Data missing 23 (0.0) 0 23

Father’s age

ⱕ25 y 74 338 (10.1) 4072 (11.4) 70 266 (10.1)

25–35 y 473 547 (64.5) 22 751 (63.6) 450 796 (64.6)

ⱖ35 y 171 352 (23.4) 8104 (22.7) 163 248 (23.4) Data missing 14 589 (2.0) 839 (2.3) 13 750 (1.9) Parity

Primiparous 313 422 (42.7) 15 198 (42.5) 298 224 (42.7) Parous 403 687 (55.0) 19 757 (55.2) 383 930 (55.0) Data missing 16 717 (2.3) 811 (2.3) 15 906 (2.3) Mother’s smoking

Yes 55 401 (7.5) 2639 (7.4) 52 762 (7.6)

No 678 425 (92.5) 33 127 (92.6) 645 298 (92.4)


derestimated. Potential confounders were selected on the basis of the liter-ature for already known confounders for jaundice, autistic disorders, and developmental disorders.

An increased risk of psychological de-velopment disorders, including autis-tic disorders, was observed for chil-dren exposed to jaundice as neonates. In the stratified analysis, the

associa-ment was limited to term-born infants.

This is in accordance with observa-tions made in our previous study of hy-perbilirubinemia and infantile autism8

and in a recently published Swedish

study.10The difference in risk for term

and preterm children might suggest that brain development undergoes a sensitive period with special vulnera-bility to bilirubin exposure at ⬃40 weeks of gestation. The difference also might be explained by confounding by treatment; preterm infants are hospi-talized and receive routine treatment

as soon as they are exposed to biliru-bin. Unfortunately, in the Danish na-tional registers, there is no informa-tion on treatment with phototherapy or on measured serum bilirubin levels.

Therefore, we were unable to calculate hyperbilirubinemia risk estimates and dose-response estimates in this study.

In addition, we found that children born at term from parous women had a greater risk of autism than did chil-dren born at term from primiparous

women. This may indicate that parous women have accumulated higher lev-els of antibodies during more preg-nancies and that hemolytic disease rarely affects firstborn children.20 It

also may reflect the differences of ac-cess to health care in the first days after delivery. In Denmark, parous women with healthy term newborns

are normally discharged from the hos-pital shortly after delivery. Children born of primiparous women are dis-charged 3 to 4 days after delivery, which makes it more likely that

first-born children with high serum biliru-bin levels would receive diagnoses be-fore leaving the hospital. Recently, a Danish study found that the incidence of hyperbilirubinemia was constant

for children in hospitals, whereas the incidence of hyperbilirubinemia

Disorders and Subgroups n Crude HR (95% CI)

P Adjusted HR (95% CI)a


Disorders of psychological development (ICD-10 codes F80–F89.9)

1721 1.87 (1.58–2.21) .001 1.29 (1.06–1.56) .011

Term 1518 1.82 (1.45–2.28) .001 1.60 (1.26–2.01) .001 Preterm 203 1.00 (0.75–1.34) .999 0.88 (0.64–1.21) .437 Specific developmental disorders of speech and

language (ICD-10 codes F80–F80.9)

537 1.59 (1.15–2.20) .005 1.39 (0.96–2.00) .082

Term 485 1.65 (1.08–2.50) .02 1.56 (1.01–2.40) .046 Preterm 52 0.94 (0.53–1.68) .837 1.04 (0.55–1.97) .902 Specific developmental disorders of scholastic

skills (ICD-10 codes F81–F81.9)

58 1.10 (0.35–3.53) .867 0.55 (0.16–1.97) .362

Term 49 2.16 (0.67–6.94) .197 2.00 (0.61–6.57) .252

Preterm 9

Specific developmental disorders of motor function (ICD-10 codes F82–F82.9)

208 2.60 (1.69–3.95) .001 1.36 (0.82–2.26) .238

Term 167 2.11 (1.11–3.99) .022 1.89 (0.95–3.74) .068 Preterm 41 1.00 (0.53–1.91) .991 0.86 (0.44–1.70) .669 Mixed specific developmental disorders (ICD-10

codes F83–F83.9)

365 2.73 (1.99–3.74) .001 1.51 (1.04–2.21) .031

Term 311 2.16 (1.36–3.44) .001 1.88 (1.17–3.02) .009 Preterm 54 1.62 (0.95–2.75) .075 1.10 (0.61–1.98) .747 Pervasive developmental disorders (ICD-10

codes F84–F84.9)

577 1.52 (1.11–2.09) .001 1.26 (0.89–1.80) .198

Term 532 1.84 (1.26–2.69) .002 1.56 (1.05–2.30) .028 Preterm 45 0.79 (0.41–1.50) .473 0.87 (0.44–1.70) .675 Other or unspecified disorders of psychological

development (ICD-10 codes F88–F89.9)

66 1.99 (0.86–4.60) .109 0.94 (0.33–2.64) .905

Term 57 1.21 (0.29–4.95) .795 0.96 (0.23–4.00) .955 Preterm 9 1.56 (0.42–5.80) .510 1.19 (0.25–5.80) .828

Term indicatesⱖ37 gestational weeks and preterm⬍37 gestational weeks.

aAdjusted for smoking, irregular fetal presentation, gender, Apgar score, parents’ ages, mother’s citizenship, birth weight, and congenital malformations, as shown in Table 1.













33 34 35 36 37 38 39 40 41 42 Gestational weeks


IA 95% CI



among children admitted from home had increased threefold.21

The seasonal variation of birth has been studied in relation to neuropsy-chiatric disorders, but the results have been inconclusive.22,23Exposure to

day-light is a contributing factor in de-creasing the levels of bilirubin.24It is

possible that children born in months with less exposure to daylight have prolonged exposure to bilirubin. Therefore, we stratified our analyses for autistic disorders and infantile au-tism in term-born children into a

6-month summer period and a

6-month winter period, and we found

that the risk was higher in the winter period. These results may reflect the different exposures to daylight but also the fact that children born in the winter period are more exposed to other contributing agents, such as in-fections. In a previous study, we found no association between prenatal fever or infections and infantile autism.25A

recent meta-analysis reviewing data on obstetric risk factors and autism found inconclusive results for prenatal infections and autism.26 However,

Rosen et al27found a modestly elevated

risk of infection in the first 30 days of life for children with autistic

disor-ders, and recent animal studies indi-cated that viral infections in mice were associated with changes in brain de-velopment in the offspring that bore a resemblance to changes seen for chil-dren with schizophrenia and au-tism.28,29Finally, prenatal and

postna-tal vitamin D deficiency has been associated with impaired brain devel-opment.30,31 It is known that prenatal

vitamins containing 400 IU of vitamin

D3 have little effect on

25-hydroxyvitamin D concentrations, es-pecially during the winter months,32

and populations with high skin pig-mentation and low sun exposure have a profoundly higher prevalence of vita-min D deficiency.30Several studies of

autistic disorders found higher risks among children of immigrants.25,26,33


Accumulating evidence suggests an association between exposure to neo-natal jaundice and autistic disorders, as well as perhaps other disorders of psychological development. Gesta-tional age, parity, and season of birth seem to play important roles in this association. Additional evidence to dis-tinguish the genetic and environmen-tal components is needed to explain the association between neonatal jaundice and autistic disorders.


This study was supported by the Uni-versity of Aarhus Research Foundation and the Augustinus Foundation.


1. Cohen SM. Jaundice in the full-term new-born.Pediatr Nurs. 2006;32(3):202–208 2. Shapiro SM. Bilirubin toxicity in the

develop-ing nervous system.Pediatr Neurol. 2003; 29(5):410 – 421

3. Escobar GJ, Greene JD, Hulac P, et al. Rehos-pitalisation after birth hosRehos-pitalisation: pat-terns among infants of all gestations.Arch Dis Child. 2005;90(2):125–131

4. Oddie SJ, Hammal D, Richmond S, Parker L. Early discharge and readmission to

hospi-tal in the first month of life in the northern region of the UK during 1998: a case cohort study.Arch Dis Child. 2005;90(2):119 –124

5. Liu S, Wen SW, McMillan D, Trouton K, Fowler D, McCourt C. Increased neonatal readmis-sion rate associated with decreased length of hospital stay at birth in Canada.Can J Public Health. 2000;91(1):46 –50

6. Maimburg RD, Bech BH, Bjerre JV, Olsen J, Moller-Madsen B. Obstetric outcome in Dan-ish children with a validated diagnosis of

kernicterus. Acta Obstet Gynecol Scand. 2009;88(9):1011–1016

7. World Health Organization.International Classification of Diseases. 10th ed. Geneva, Switzerland: World Health Organization; 1993

8. Maimburg RD, Vaeth M, Schendel DE, Bech BH, Olsen J, Thorsen P. Neonatal jaundice: a risk factor for infantile autism? Paediatr Perinat Epidemiol. 2008;22(6):562–568 9. Jangaard KA, Fell DB, Dodds L, Allen AC. Out-TABLE 3 HRs for Neonatal Jaundice and Pervasive Developmental Disorders for Children Born

at Term

n Crude HR (95% CI)

P Adjusted HR (95% CI)a


Autistic disorders (ICD-10 codes F84.0–F84.9)

All 532 1.84 (1.26–2.69) .002 1.56 (1.05–2.30) .028 Boys 413 1.66 (1.09–2.58) .018 1.54 (1.00–2.39) .051 Girls 119 1.76 (0.72–4.32) .214 1.63 (0.66–4.04) .292 From April to September 252 1.29 (0.66–2.51) .454 1.03 (0.50–2.10) .938 From October to March 280 2.28 (1.43–3.64) .001 1.97 (1.23–3.17) .005 From primiparous women 234 1.18 (0.58–2.38) .649 0.82 (0.82–1.76) .611 From parous women 287 2.47 (1.57–3.89) .001 2.29 (1.44–3.63) .001 With mental retardation 74 1.03 (0.41–2.54) .955 1.31 (0.51–3.33) .572 Without mental retardation 458 1.75 (1.15–2.67) .009 1.49 (0.97–2.30) .070 Infantile autism (ICD-10 code F84.0)

All 317 2.11 (1.33–3.36) .002 1.67 (1.03–2.71) .038 Boys 255 1.89 (1.14–3.13) .014 1.63 (0.96–2.78) .070 Girls 62 2.05 (0.64–6.54) .225 1.87 (0.58–6.08) .298 From April to September 149 1.46 (0.65–3.31) .362 1.02 (0.41–2.50) .973 From October to March 168 2.63 (1.50–4.64) .001 2.21 (1.24–3.94) .007 From primiparous women 137 1.00 (0.37–2.71) .996 0.58 (0.18–1.83) .352 From parous women 174 3.10 (1.83–5.28) .001 2.71 (1.57–4.66) .001 With mental retardation 54 1.13 (0.41–3.13) .811 1.56 (0.54–4.47) .407 Without mental retardation 263 2.01 (1.19–3.38) .009 1.57 (0.91–2.70) .108

Data do not sum up because of missing values.

aAdjusted for smoking, irregular fetal presentation, gender, Apgar score, parents’ ages, mother’s citizenship, birth weight, and congenital malformations, as shown in Table 1.


els ofⱖ325␮mol/L (ⱖ19 mg/dL) who were born in Nova Scotia, Canada, between 1994 and 2000.Pediatrics. 2008;122(1):119 –124 10. Buchmayer S, Johansson S, Johansson A,

Hultman CM, Sparén P, Cnattingius S. Can association between preterm birth and au-tism be explained by maternal or neonatal morbidity?Pediatrics. 2009;124(5). Avail-able at: full/124/5/e817

11. Croen LA, Yoshida CK, Odouli R, Newman TB. Neonatal hyperbilirubinemia and risk of au-tism spectrum disorders.Pediatrics. 2005; 115(2). Available at: cgi/content/full/115/2/e135

12. Rapin I. Autism.N Engl J Med. 1997;337(2): 97–104

13. Rutter M. Incidence of autism spectrum disorders: changes over time and their meaning.Acta Paediatr. 2005;94(1):2–15 14. Knudsen LB, Olsen J. The Danish Medical

Birth Registry.Dan Med Bull. 1998;45(3): 320 –323

15. Kristensen J, Langhoff-Roos J, Skovgaard LT, Kristensen FB. Validation of the Danish Birth Registration.J Clin Epidemiol. 1996; 49(8):893– 897

16. Andersen TF, Madsen M, Jorgensen J, Mel-lemkjoer L, Olsen JH. The Danish National Hospital Register: a valuable source of data for modern health sciences.Dan Med Bull. 1999;46(3):263–268

Bull. 1997;44(1):82– 84

18. Lauritsen MB, Pedersen CB, Mortensen PB. The incidence and prevalence of pervasive d e v e l o p m e n t a l d i s o r d e r s : a D a n i s h population-based study.Psychol Med. 2004; 34(7):1339 –1346

19. Lauritsen MB, Jørgensen M, Madsen KM, et al. Validity of childhood autism in the Danish Psychiatric Central Register: findings from a cohort sample born 1990 –1999.J Autism Dev Disord. 2010;40(2):139 –148

20. Hollister JM, Laing P, Mednick SA. Rhesus incompatibility as a risk factor for schizo-phrenia in male adults.Arch Gen Psychiatry. 1996;53(1):19 –24

21. Bjerre JV, Petersen JR, Ebbesen F. Surveil-lance of extreme hyperbilirubinaemia in Denmark: a method to identify the newborn i n f a n t s . A c t a P a e d i a t r. 2 0 0 8 ; 9 7 ( 8 ) : 1030 –1034

22. Bolton P, Pickles A, Harrington R, Mac-donald H, Rutter M. Season of birth: issues, approaches and findings for autism.J Child Psychol Psychiatry. 1992;33(3):509 –530 23. Landau EC, Cicchetti DV, Klin A, Volkmar FR.

Season of birth in autism: a fiction revisited. J Autism Dev Disord. 1999;29(5):385–393 24. Cremer RJ, Perryman PW, Richards DH.

In-fluence of light on the hyperbilirubinaemia of infants.Lancet. 1958;1(7030):1094 –1097 25. Maimburg RD, Vaeth M. Perinatal risk

fac-26. Gardener H, Spiegelman D, Buka SL. Prena-tal risk factors for autism: comprehensive meta-analysis.Br J Psychiatry. 2009;195(1): 7–14

27. Rosen NJ, Yoshida CK, Croen LA. Infection in the first 2 years of life and autism spectrum disorders.Pediatrics. 2007;119(1). Avail-able at: full/119/1/e61

28. Fatemi SH, Folsom TD, Reutiman TJ, Huang H, Oishi K, Mori S. Prenatal viral infection of mice at E16 causes changes in gene expres-sion in hippocampi of the offspring. Eur Neuropsychopharmacol. 2009;19(9): 648 – 653

29. Li Q, Cheung C, Wei R, et al. Prenatal immune challenge is an environmental risk factor for brain and behavior change relevant to schizophrenia: evidence from MRI in a mouse model.PLoS One. 2009;4(7):e6354 30. Levenson CW, Figueiroa SM. Gestational

vi-tamin D deficiency: long-term effects on the brain.Nutr Rev. 2008;66(12):726 –729 31. Kalueff AV, Tuohimaa P. Neurosteroid

hor-mone vitamin D and its utility in clinical nu-trition.Curr Opin Clin Nutr Metab Care. 2007;10(1):12–19

32. Cannell J. Vitamin D “advertisement.”Am J Obstet Gynecol. 2010;202(5):e9 – e10 33. Hultman CM, Sparen P, Cnattingius S.


DOI: 10.1542/peds.2010-0052 originally published online October 11, 2010;



Møller-Madsen and Jørn Olsen

Rikke Damkjær Maimburg, Bodil Hammer Bech, Michael Væth, Bjarne

Neonatal Jaundice, Autism, and Other Disorders of Psychological Development


Updated Information & including high resolution figures, can be found at:

References This article cites 29 articles, 4 of which you can access for free at:

Subspecialty Collections


Fetus/Newborn Infant

following collection(s):

This article, along with others on similar topics, appears in the

Permissions & Licensing in its entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or



DOI: 10.1542/peds.2010-0052 originally published online October 11, 2010;



Møller-Madsen and Jørn Olsen

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.


TABLE 1 Characteristics of 733 826 Children and Their Parents in Danish Cohort


Characteristics of 733 826 Children and Their Parents in Danish Cohort p.4
FIGURE 1HRs with 95% CIs for neonatal jaundice and selected outcomes, according to gestational age


with 95% CIs for neonatal jaundice and selected outcomes, according to gestational age p.5
TABLE 2 HRs for Neonatal Jaundice and Disorders of Psychological Development for 733 826Children Born in 1994–2004


HRs for Neonatal Jaundice and Disorders of Psychological Development for 733 826Children Born in 1994–2004 p.5
TABLE 3 HRs for Neonatal Jaundice and Pervasive Developmental Disorders for Children Bornat Term


HRs for Neonatal Jaundice and Pervasive Developmental Disorders for Children Bornat Term p.6