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Pre- and Perinatal Risk Factors in Adults withAttention-Deficit/Hyperactivity DisorderAnne Halmøy, Kari Klungsøyr, Rolv Skjærven, and Jan Haavik
Background: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and disabling lifespan disorder, but little is yet known aboutrisk factors for ADHD persisting beyond adolescence. The present study investigates the association between pregnancy and birthcomplications and ADHD in adulthood.
Methods: We used data from the Medical Birth Registry of Norway to compare pre-and perinatal risk factors among 2323 adults approvedfor medical treatment for ADHD, with the remaining population born during the same years, 1967–1987, and surviving into adulthood (n �1,170,073). Relative risks (RR) adjusted for potential confounders were calculated.
Results: Preterm (� 37 weeks of gestation) and extremely preterm birth (� 28 weeks of gestation) were associated with 1.3- and 5-foldincreased risks of ADHD, respectively. Birth weights �2500 g and �1500 g also increased the risk of ADHD (RR: 1.5, 95% confidence interval[CI]: 1.2–1.8, and RR: 2.1, 95% CI: 1.3–3.6, respectively). Five-minute Apgar scores �4 and �7 were associated with 2.8- and 1.5-fold increasedrisks of persisting ADHD, respectively. Maternal epilepsy (RR: 1.7, 95% CI: 1.1–2.7) and offspring oral cleft (RR: 2.8, 95% CI: 1.6 – 4.9) occurredmore frequently among adult ADHD patients.
Conclusions: This is the first population-based study of pre-and perinatal risk factors in adults with ADHD. We show that low birth weight,preterm birth, and low Apgar scores increase the risk of ADHD, persisting up to 40 years after birth. The increased risk of ADHD related to oral
cleft and to maternal epilepsy warrants further investigation to explore possible causal mechanisms.aha(asewr
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Key Words: Adults, attention-deficit/hyperactivity disorder (ADHD),birth weight, gestational age, prenatal, risk factors
A ttention-deficit/hyperactivity disorder (ADHD) is a prevalentand disabling neuropsychiatric disorder affecting approxi-mately 5% of children worldwide (1). Adding to a strong
enetic influence, environmental factors also seem to be involvedn its multifaceted etiology (2). Pre- and perinatal risk factors (PPRF)re theoretically attractive as causal factors for neuropsychiatricisorders, because of their potential influence on the developingrain (3). Childhood ADHD is associated with maternal smoking (4),lcohol use and psychological distress in pregnancy (5), complica-ions in pregnancy such as eclampsia, prolonged delivery andleedings (6), preterm birth (7,8) and low birth weight (LBW) (9,10),s well as parental socioeconomic status (11).
Although ADHD is one of the most frequently encountered di-gnoses in child psychiatry, ADHD in adults has been more contro-ersial and only recently recognized as a valid diagnosis (12). Lon-itudinal follow-up studies of clinical samples of children withDHD have shown that, depending on the criteria being used,5%– 65% of children with ADHD will continue to suffer from theisorder as adults (13). Recent cross-sectional population-basedtudies report a pooled worldwide prevalence estimate of ADHDmong adults of approximately 2%–3% (14,15) (i.e., approximatelyne-half of the prevalence in children). However, little is known
From the Department of Psychiatry (AH, JH), Haukeland University Hospital;Department of Biomedicine (AH); Department of Public Health and Pri-mary Health Care (KK, RS); K.G. Jebsen Centre for Research on Neuropsy-chiatric Disorders (AH, KK, JH), University of Bergen; Medical Birth Regis-try of Norway (KK, RS), The Norwegian Institute of Public Health, Bergen,Norway.
Address correspondence to Anne Halmøy, M.D., Ph.D., Department of Bio-medicine, K.G. Jebsen Centre for Research on Neuropsychiatric Disor-ders, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway;E-mail: [email protected].
sReceived May 13, 2011; revised Nov 15, 2011; accepted Nov 16, 2011.
0006-3223/$36.00doi:10.1016/j.biopsych.2011.11.013
bout factors predicting persistence of ADHD symptoms into adult-ood (16). It has been suggested that persisting ADHD might havedifferent etiology than ADHD that remits during younger age
17,18). Heritability estimates of ADHD are found to be lowermong adults than children (19), emphasizing the importance oftudying risk factors in ADHD across the lifespan. Despite the quitextensive literature on pre- and perinatal risk factors in childrenith ADHD, it is still unclear whether and how these risk factors are
elevant for ADHD persisting to adulthood.Earlier studies on PPRF and ADHD are mainly retrospective case-
ontrol studies of children with ADHD or prospective cohort studiesf infants exposed to a putative risk factor (e.g., LBW or pretermirth). Information on PPRF has in case-control studies mainly beenased on questionnaires or interviews of the mothers several yearsfter birth, with the possibility of recall bias. In the cohort studies,he outcome phenotype has often been symptoms or behaviorselated to ADHD rather than the full syndrome (20). Both types oftudies are limited by relatively small and selected samples. Re-ently, studies with larger, population-based samples and system-tic registry-based information on both diagnosis and PPRF haveppeared but so far only on children and yielding partly inconsis-ent results (7–9,11).
In an attempt to provide an unbiased assessment of a possiblessociation between PPRF and persistent ADHD, we compared thePRF profile in a national cohort of adults with clinically diagnosedDHD with that in the general population. On the basis of the
iterature on children with ADHD, our a priori hypothesis was thatndividuals born preterm or with LBW would be at increased risk ofeveloping persistent ADHD and that maternal health in preg-ancy might influence the risk of persistent ADHD.
aterials and Methods
We performed, on the basis of data from the Medical Birth Reg-stry of Norway (MBRN), a population-based nested case-controltudy, where cases were 2323 adult ADHD patients and control
ubjects were the remaining general population registered in theBIOL PSYCHIATRY 2012;71:474–481© 2012 Society of Biological Psychiatry
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MBRN, born in the same time period (1967–1987) and surviving intoadulthood (n � approximately 1.17 million).
ADHD PatientsFrom October 1, 1997 to May 1, 2005, adults (�18 years) with
ADHD in Norway were allowed to receive treatment with centralstimulants only after a systematic and mandatory diagnostic evalu-ation by one of three regional diagnostic committees (The ExpertCommittees of ADHD/Hyperkinetic Disorder). During this 8-yearperiod, approximately 5000 adults with suspected ADHD were re-ferred from their doctors (mainly psychiatrists) to the committees.Of these, 3397 (approximately 70%) were found eligible for stimu-lant treatment (i.e., the evaluation confirmed their ADHD diagnosis,their need for medical treatment, and the absence of contra-indica-tions for such treatment [mainly psychosis or ongoing substanceabuse]). The diagnostic assessment was based on thorough recordsprovided by the referring clinicians; including data on childhoodand adult symptoms of ADHD, information from informants, andassessment of other psychiatric and medical conditions. A diagno-sis of ADHD was made according to ICD-10 research criteria (21)modified to be comparable to the DSM-IV criteria (22) (i.e., allow-ance was made for the predominantly inattentive subtype to besufficient for a diagnosis of ADHD and for the presence of comorbidpsychiatric disorders, as long as the criteria for ADHD were presentbefore the appearance of the comorbid disorder). According toformal diagnostic criteria, symptoms and problems of ADHD shouldhave been present since the age of 7 and persisted from childhood.However, �25% of the included patients had received a formaldiagnosis before the age of 18 years. Parts of this adult ADHD
Table 1. Sociodemographic Characteristics of Adult ADHD Patients, the Ad
Patients (n � 2323)
n %
Male Gender 1646 70.9%Year of Birth
1967–1971 422 18.2%1972–1976 503 21.7%1977–1981 613 26.4%1982–1987 785 33.8%
Educational LevelLow (�10 years) 1424 61.8%Medium (10–12 years) 665 28.9%High (13 or more years) 216 9.4%
Maternal CharacteristicsYounger than 20 Years at Delivery 315 13.6%Parity
Para 0 1048 45.1%Para 1 755 32.5%Para 2� 520 22.4%
Educational LevelLow (�10 years) 812 35.2%Medium (10–12 years) 987 42.8%High (13 or more years) 508 22.0%
Paternal CharacteristicsEducational Level
Low (�10 years) 707 31.0%Medium (10–12 years) 1053 46.2%High (13 or more years) 519 22.8%
ADHD, attention-deficit/hyperactivity disorder; para, number of previouaOn the basis of �2 tests.bPearson �2.
patient sample have been described in earlier reports (23–25). Pa- p
ients in the present study consisted of all of these adult ADHDatients who were approved for stimulant treatment in Norwayuring 1997–2005 and who were born between 1967 and 1987 (n �323). Patients born before 1967 (n � 1074) were excluded, be-ause the MBRN does not contain data on births before this year.
BRNThe MBRN contains, on the basis of compulsory notification,
nformation on all live births and stillbirths from 16-week gestationn Norway since 1967, with more than 2.5 million registered births inanuary 2011. The registry contains information on demographicariables, data on maternal health before and during pregnancy,revious reproductive history, complications during pregnancynd delivery, and pregnancy outcomes including congenital anom-lies.
This study includes all individuals born in Norway between 1967nd 1987, who survived 18 years of age. The cohort thus consists ofhe 2323 individuals registered with treatment for ADHD as adultsnd 1,170,073 individuals who were not (remaining birth cohort).
ational Education DatabaseWe obtained information about the level of education for the
hole birth cohort and their parents from the Norwegian Nationalducation Database. This database covers all Norwegian inhabit-nts of at least 16 years of age and is continuously updated.
ecord Linkage and Variable DescriptionEvery resident in Norway has a unique national identification
umber available in all the national registries and for the ADHD
eneral Population Born in the Same Time Period, and Their Parents
Remaining Birth Cohort(n � 1,170,073) Statisticsa
n % �2b df p
599,064 51.2% 358.6 1 �.001166.0 3 �.001
324,681 27.7%289,774 24.8%251,713 21.5%303,905 26.0%
2505.9 2 �.001235,862 20.4%479,686 41.5%439,405 38.0%
100,186 8.6% 73.9 1 �.001
482,655 41.2% 14.3 1 �.001400,189 34.2% 3.0 1 .084287,229 24.5% 5.9 1 .016
38.5 2 �.001340,139 29.3%541,895 46.7%278,319 24.0%
50.9 3 �.001286,298 24.9%551,080 48.0%310,981 27.1%
hs (�16 weeks of gestation).
ult G
s birt
atients. Record linkage was established, by means of the identifi-
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cation numbers, between the MBRN, the patient sample, and theNational Education Database. We used these linked data to com-pare PPRF between the ADHD patients and the rest of the popula-tion.
The following PPRF were studied: induced delivery, caesareansection, breech delivery, categories of birth weight and gestationalage, small for gestational age (SGA) (�10th percentile of birthweight for gestation) (26), low Apgar scores (�7 and �4 at 5 min),and congenital anomalies. The following maternal variables werestudied: pregestational hypertension, diabetes, epilepsy, and pre-eclampsia. We also investigated Z scores of birth weight by gesta-tional age (26).
Gestational age was based on menstrual dates and was missingfor 6.9% of the patients and for 5.0% of the control population (p �.0001; �2 test). Due to the acknowledged uncertainty in menstrual
ates, gestational age was validated against registered birtheight. Births with birthweight �4 SD above the mean sex-specificirthweight for a given gestational week (birthweight Z scores �4)ere excluded in all analyses using gestational age (n � 2371, .2%).
Data on birth weight were missing for .2% (.04% of ADHD patients).When studying gestational age, birth weight, and SGA, only single-ton births were included. Apgar scores—a globally used index ofthe condition of the child at birth, including its state of oxygen-ation— have been registered in the MBRN since 1978, and we stud-ied Apgar scores �4 and �7 at 5 min for individuals born after 1977(1241 patients, 493,911 population control subjects). Congenitalanomalies were diagnosed at the time of delivery or during thefollowing stay at the birth clinic. We defined categories of majorbirth defects according to the European Congenital Anomaly Sur-veillance Consortium (http://www.eurocat-network.eu/) on the ba-sis of 3- and 4-digit codes of the ICD, 8th Revision. Certain congen-ital anomalies, such as heart defects, were underreported to theMBRN in the time period of the present study. Other anomalies,such as oral clefts, have been satisfactorily reported to the MBRNduring the entire Registry period (27).
Educational level was based on completed years of education asregistered in 2008 and was grouped into low (�10 years), me-dium (10 –12 years), and high level (�13 years), correspondingto the national system of primary (compulsory), secondary, andtertiary (university/college) educational levels (http://ssb.no/
Table 2. Pregnancy and Delivery Factors Related to Risk of ADHD Persisting
Patients(n � 2323)
n %
aternal Health Before/During PregnancyHypertension, chronic 5 .2%Diabetes 7 .3%Epilepsy 21 .9%Preeclampsia 72 3.1%
eliveryInduced delivery 350 15.1% 1Caesarian section 186 8.0%Breech deliveryb 78 3.4%
Data are numbers (%). Adjusting for all significant maternal health risk fADHD, attention-deficit/hyperactivity disorder; CI, confidence interval; RaAdjusted by year of birth (5-year intervals from 1967 to 1987), parity (pa
5 years or more), educational level of mother (�10, 10 –12, or 13 or moreersus vs. without a partner).
bAlso adjusted for infant gender.
emner/04/utdanning_tema/). F
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tatistical AnalysesDescriptive statistics with �2 tests and independent sample t
ests were used for the comparison of sociodemographic data andrevalence of PPRF with the PASW Statistics (version 18; SPSS, Chi-ago, Illinois). We used contingency tables to calculate crude rela-ive risks (RR) for categorical variables, and multivariate RR modelss available in STATA (STATA Statistical Software, Release 9, 2005;tataCorp, College Station, Texas) were used to adjust for con-ounders and evaluate interactions. Maternal age at delivery, parity,ime period of birth (5-year categories), maternal educational level,
aternal marital status, and infant sex were evaluated as confound-ng variables—all modeled as categorical variables as shown in theootnotes to the tables.
Because part of our material comprised nonindependent birthso the same mother, we also analyzed mothers with more than oneirth, by calculating RR with clustered robust standard errors asvailable through STATA, identifying the mother as the unit ofnalysis. Relative risks and adjusted RR were reported with 95%onfidence intervals.
thicsThe study was approved by the Regional Committee for Medical
nd Health Research Ethics (IRB #3 [FWA00009490, IRB00001872]),he Norwegian Directorate of Health and Social Services and theorwegian Data Inspectorate. Because the data were treated anon-mously, no further consent was required.
esults
ociodemographic DataTable 1 shows that the proportion of men was higher among
DHD patients than in the general population and that patients onverage were younger (i.e., a higher proportion was born in the laterears of the study period). The mean age of the ADHD patients athe time of inclusion into the study was 31.2 years, compared with2.6 years for the rest of the birth cohort (SDs 5.8 and 6.1, respec-ively, p � .001, t test, independent samples). Furthermore, patients
ore often had the lowest level of education compared with theest of the population born in the same period. Mothers of ADHDdults were younger at delivery and were more often nulliparous.
dulthood
aining BirthCohort1,170,073)
% Unadjusted RR (95% CI) Adjusted RRa (95% CI)
5 .1% 1.6 (.7–3.9) 1.5 (.6–3.7)4 .2% 1.8 (.9–3.8) 1.8 (.8–3.7)0 .5% 1.9 (1.3–3.0) 1.7 (1.1–2.7)3 2.4% 1.3 (1.0–1.6) 1.2 (1.0–1.6)
4 13.3% 1.2 (1.0–1.3) 1.2 (1.0–1.3)5 5.9% 1.4 (1.2–1.6) 1.3 (1.1–1.5)8 3.0% 1.1 (.9–1.4) 1.1 (.9–1.4)
simultaneously did not change the results significantly.ative risk.para 1, para 2, para 3�), age of mother at birth (�20, 20 –24, 25–29, 30 –34,of education), and marital status of mother (married/living with a partner
to A
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urthermore, mothers of ADHD patients were more often single
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and had lower levels of education than other mothers. The fathersof patients were also younger and had less education than fathersfrom the control population.
Pregnancy and Delivery Factors Related to the Risk of ADHDAs shown in Table 2, maternal pregestational diabetes or hyper-
tension was not associated with a significantly increased risk ofADHD persisting to adulthood, and the prevalence of these mater-nal factors did not differ significantly between patients and theremaining population. In contrast, offspring born to motherswith epilepsy did have a significantly higher risk of ADHD per-sisting to adulthood compared with those born to mothers with-out epilepsy. Also, maternal preeclampsia was associated with aslightly increased risk of adult ADHD, although this associationwas only borderline significant. Induced delivery and caesareansection occurred more often among ADHD cases than controlsubjects.
Infant Factors Related to the Risk of ADHDAdults with ADHD had a lower mean birth weight than the
remaining birth cohort (3460 vs. 3506 g, p � .001), and a birtheight of �2500 g increased the risk of ADHD with 50% comparedith birth weights of 2500 g or more (adjusted RR: 1.5, 95% confi-
Table 3. Infant Characteristics at Birth Related to Risk of ADHD Persisting to
Patients (n � 2323)Remain
(n �
n % n
estational Ageb
�28 weeks 5 .2% 428–32 weeks 14 .7% 5633–36 weeks 104 4.9% 39737–41 weeks (ref) 1668 78.3% 8767�42 weeks 340 16.0% 1644
irth Weightc
�1500 g 14 .6% 301500–2499 g 95 4.1% 32,52500–4499 g (ref) 2106 91.9% 1,074,5�4500 g 77 3.4% 36,0
SGAb,c
Overall proportions 316 14.8% 128,3Proportions of those born at
term (�week 37) 292 14.5% 122,6Proportions of those born
preterm (�week 37) 24 19.5% 57pgar Scoresd
Apgar �7 at 5 min 18 1.5% 44Apgar �4 at 5 min 5 .4% 6
Congenital AnomaliesMajor malformations, total 53 2.3% 19,8Oral cleft 12 .5% 19Cleft lip with/without palate 9 .4% 14Cleft palate only 3 .1% 5
Adjusting for all significant infant risk factors simultaneously did not chweight is expressed in the small for gestational age (SGA) analyses.
Ref, reference; other abbreviations as in Table 2.aAdjusted by year of birth (5-year intervals from 1967 to 1987), parity (pa
5 years or more), educational level of mother (�10, 10 –12, or 13 or moreersus living without a partner), and gender of infant.
bSelected for single births and z � 4 for birth weights by gestational agecSelected for single births (ADHD patients n � 2293, control subjects n �dIncludes individuals born after year 1977 only (ADHD patients, n � 124
ence interval: 1.3–1.8). Furthermore, being small for gestational n
ge (SGA), both at term and preterm, increased the risk of ADHDersisting to adulthood. Overall, the mean gestational age did notiffer between patients and the remaining population, but pretermirth (�37 weeks) and, in particular, extreme preterm birth (�28eeks) significantly increased the risk of developing ADHD (Table
). The risk of ADHD increased as gestational age decreased, ashown in Figure 1. Similarly, among individuals born at termweek 37– 41 of gestation), the risk of ADHD increased withecreasing Z scores of birth weight by gestational age (Figure 2).pgar scores lower than 4 at 5 min were also associated with a
ignificantly increased risk of ADHD persisting to adulthood (Ta-le 3). Among the five ADHD patients with Apgar score �4, oneas born in Week 27, whereas the others were delivered at 36eeks or later.
We found a slightly increased overall prevalence of registeredajor congenital anomalies among ADHD patients than in the
emaining population (Table 3). This was mainly due to a signifi-antly increased prevalence of oral clefts among ADHD patients. Noignificant differences were observed for other registered organpecific subgroups of congenital anomalies.
When analyzing mothers who had more than one birth by cal-ulating RR with clustered robust standard errors and identifyinghe mother as the unit of analysis, the change in results was not
lthood
irth Cohort0,073)
Unadjusted RR (95% CI) Adjusted RRa (95% CI)%
.04% 5.6 (2.3–13.4) 5.0 (2.1–11.8)
.5% 1.3 (.8–2.2) 1.2 (.7–2.0)3.7% 1.4 (1.1–1.7) 1.3 (1.0–1.5)
80.7% 1.0 (ref) 1.0 (ref)15.1% 1.1 (.9–1.4) 1.1 (.9–1.2)
.3% 2.4 (1.4–4.0) 2.1 (1.3–3.6)2.8% 1.5 (1.2–1.8) 1.5 (1.2–1.8)
93.8% 1.0 (ref) 1.0 (ref)3.1% 1.1 (.9–1.4) 1.0 (.8–1.3)
11.8% 1.3 (1.2–1.5) 1.3 (1.1–1.4)
11.8% 1.3 (1.1–1.4) 1.2 (1.1–1.4)
12.4% 1.7 (1.1–2.7) 1.6 (1.0–2.5)
.9% 1.6 (1.0–2.6) 1.5 (1.0–2.4)
.1% 2.9 (1.2–7.1) 2.8 (1.2–6.8)
1.7% 1.4 (1.0–1.8) 1.3 (1.0–1.7).2% 3.0 (1.7–5.4) 2.8 (1.6–4.9).1% 3.1 (1.6–5.9) 2.8 (1.4–5.3).04% 2.9 (.9–9.0) 2.9 (1.0–9.1)
the results noteworthy. The combined effect of gestational age and birth
para 1, para 2, para 3�), age of mother at birth (�20, 20 –24, 25–29, 30 –34,of education), and marital status of mother (married/living with a partner
D patients, n � 2131, control subjects n � 1,087,055).8,412).trol subjects, n � 493,911).
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478 BIOL PSYCHIATRY 2012;71:474–481 A. Halmøy et al.
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Discussion
This population-based investigation is the largest study on pre-and perinatal risk factors for ADHD and the first performed onadults clinically diagnosed with ADHD. Intrauterine growth restric-tion, preterm birth, LBW, and low Apgar scores were associatedwith an increased risk of ADHD in a national birth cohort of adults.The study thus confirms earlier findings on children with ADHD, andfurther expands the evidence that intrauterine factors play a role inthe risk of developing ADHD that persists as a long-lasting, dis-abling disorder. The associations between maternal epilepsy andADHD and ADHD and oral cleft have not been previously reported.
An association between LBW and a later formal diagnosis ofADHD has so far only been shown for children (9), although otherrecent studies support the view that LBW is associated with symp-toms and behavior related to ADHD also in early adolescence (28)and young adulthood (20,29). In a Norwegian twin study of adults(mean age 25 years), a lifetime history of Minimal Brain Dysfunction,as self-reported on a questionnaire, was found to be significantlyassociated with LBW (30). A direct comparison of the finding fromour adult sample with results from child studies is complicated bydifferences in study designs. For example, LBW was found to bethree times more common in children with ADHD in a retrospectivecase-control study of 251 ADHD children and 231 control children(31), whereas a population-based study in the same country (UnitedStates)—including a birth cohort of more than 5000 children— didnot find any association between LBW and ADHD (11).
In the present study, the average birth weight for adult ADHDpatients was only slightly lower, and average length of pregnancydid not differ between adults with ADHD and the general popula-tion. Being born extremely preterm (�28 weeks) or very small(�1500 g) was, however, strongly associated with ADHD in adult-hood with RRs of 5 and 2, respectively, compared with being born atterm or with normal birth weight. Furthermore, SGA was associatedwith increased risk of ADHD, both overall and at term. Some studies
Figure 1. Relative risk (RR) (unadjusted) of adult attention-deficit/hyperac-ivity disorder by gestational age at birth. Singleton births only. C.I., confi-ence interval.
with comparable designs (i.e., nested case-control studies using�S
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linical samples of ADHD patients and data from medical birthegistries) have been published on children with ADHD: a Danishtudy including 834 ADHD children and 20,100 control subjects (9),nd a recent Swedish study of 237 ADHD children and 31,775 con-rol subjects (7). A third recent registry study included a nationalohort of 1,180,616 children born in Sweden (8). Interestingly, ouresults with regard to preterm birth and risk of ADHD in adulthoodre very similar to the results from these studies of children withDHD. They are also in line with the finding from the Danishtudy that LBW at term is a risk factor for ADHD (9). The Swedishtudy did not find a significant association between LBW andDHD, but according to the authors, this might be due to low
tatistical power (7).Apgar was associated with the risk of ADHD in our cohort, with
he highest risk of ADHD associated with the lowest Apgar scores. Its known that low Apgar scores at birth might affect the cognitionnd behavior of a child also in cases where the child survives with-ut major brain damage (32,33). The recent Swedish medical birth
egistry study further found a strong, significant association be-ween low Apgar score and ADHD in childhood (7). Findings fromhe present study expand this knowledge by showing an associa-ion between asphyxia at birth and a cognitive-behavioral disorderike ADHD up to 40 years after birth.
The increased occurrence of induced delivery and caesareanection among ADHD patients probably reflects the observed com-lications during pregnancy or delivery rather than representing
ndependent causal factors.Together, results from these population and registry studies
ndicate that the pre- and perinatal risk pattern observed in childrenith ADHD might be valid also for ADHD persisting to adulthood.
The overall association found between major congenital anom-lies registered at birth and ADHD in adulthood was mainly due tohe association between oral clefts and ADHD, with an adjusted RRlose to 3. Although several anomalies might have been underre-orted to the MBRN in the first decades of the Registry, ascertain-
igure 2. Relative risk (RR) (unadjusted) of adult attention-deficit/hyperac-ivity disorder by z scores of birth weight-by-gestational age, confined tonfants born to term. Categories: �4 � �4 to �3.01, �3 � �3 to �2.01,
2 � �2 to �1.01, �1 � �1 to �.01, 0 � 0 to .99, 1 � 1 to 1.99, 2 � 2 to 2.99.ingleton births only. C.I., confidence interval.
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A. Halmøy et al. BIOL PSYCHIATRY 2012;71:474–481 479
ment of oral clefts has proved to be satisfactory in this period (27).ne explanation of the present finding could be overdiagnosing ofDHD among individuals with oral cleft due to similar associated
ymptoms and problems, such as learning disabilities or other cog-itive deficits (34). By contrast, a real co-occurrence of the ADHDnd oral cleft phenotypes in simultaneously affected individualsould be due to a common, genetic disturbance, such as the velo-ardio-facial (i.e., 22q11 deletion) syndrome (35), or exposure to annvironmental factor that might increase the risk for both pheno-ypes separately, such as cigarette smoke or alcohol exposure intero (5,36). Future studies are needed to elucidate this finding
urther, also because a “finding by chance” explanation cannot bexcluded.
Maternal epilepsy was associated with a nearly twofold in-reased risk of adult ADHD in this study. This association might haveeveral explanations. First, epileptic seizures during pregnancyould cause hypoxic states at critical gestational periods, whichight interfere with brain development (37). Second, the associa-
ion between maternal epilepsy and ADHD in the offspring coulde mediated by teratogenic effects of antiepileptic medication di-
ectly (38) or indirectly (i.e., by increasing the risk of adverse preg-ancy and birth outcomes) (39) or through maternal folic acid defi-iency (40). Third, epilepsy and ADHD co-occur more often togetherhan predicted by separate prevalence estimates (41), and the linketween maternal epilepsy and ADHD in the offspring could thuse through a common genetic vulnerability for the two disorders.
trengths and Limitations of the Present StudyThe large size of population-based records is a major strength of
ur study, being the largest systematic investigation on pre-anderinatal risk factors in ADHD and the first performed on adultDHD patients. Inevitably, the study also has limitations. First, al-
hough our findings suggest that intrauterine factors are associatedith psychopathology lasting into adulthood, caution should beade in assuming causal relations behind the observed associa-
ions. The present study lacked information on some possible con-ounding factors, such as the mental health and smoking habits ofarents, and the presence of comorbid disorders. Maternal smok-
ng has been widely associated with both LBW and ADHD. However,ew research has questioned the role of smoking in pregnancy asn independent causal risk factor of ADHD, by showing that it mighte a confounder both for genetic liability and socioeconomic fac-
ors (10,42– 44). In the aforementioned Danish and Swedish child-ood studies, the association between preterm birth and ADHDas practically unaltered when adjusting for maternal smoking
7,9). Also, adjusting for parental psychopathology did not alter theffects of LBW and prematurity found in the Danish child cohorttudy (9). Second, the ADHD patients in the present study wereiagnosed at a time when the awareness of ADHD in adult psychi-try was low. Furthermore, only medically treated adults were in-luded. The patient sample in this study thus probably includeselatively severely affected adults with ADHD, whereas the rest ofhe birth cohort probably includes individuals who would haveeen classified as ADHD cases, if a systematic assessment of thehole population had been performed (this is reflected by an esti-ated prevalence rate of adult ADHD of approximately .2% in our
ohort, which is far lower than reported prevalence rates of adultDHD of approximately 3– 4% in other population-based studies)
15,45). This pattern was also reported in the Swedish childhoodtudy (7). Some caution might therefore be necessary before gen-ralizing the findings to other clinical samples of adults with ADHD.inally, ADHD is a clinically heterogeneous disorder, with individual
ifferences in symptom profiles and a high degree of comorbidity iith other psychiatric disorders (45,46). The identified pre- anderinatal risk factors might thus be specific to subgroups of theisorder (e.g., the inattentive subtype), as indicated by findings inhild studies (47,48). Because the registry data did not include clin-
cal data on symptom profiles or comorbid disorders, this interest-ng question could not be pursued in the present study.
Recently, studies have indicated that the contribution of geneticisk might be different for adults and children with ADHD (19,49,50).
diagnosis of ADHD in adulthood requires the presence of symp-oms and problems since childhood, and the terms “adult ADHD”nd “persisting ADHD” should thus be equivalent. However, diag-osing ADHD in adulthood might be challenging, because currentymptom criteria are poorly adapted to adults and because of pos-ible recall bias in the retrospective assessment of childhood symp-oms. Comparisons of clinical samples of adults diagnosed withDHD in childhood versus in adulthood indicate, however, that
here might be some differences (e.g., in comorbidity profile) be-ween these groups (16,25). To answer the introductory question ofhether persistent ADHD shares the same risk factors as childhoodDHD, ideally, three groups should thus be compared: ADHD remit-
ing in childhood, ADHD persisting from childhood to adulthood,nd ADHD first diagnosed in adulthood.
Low birth weight and preterm delivery might be consideredarkers of a suboptimal fetal environment and have been associ-
ted with various unfavorable outcomes in childhood, adoles-ence, and adulthood, not restricted to ADHD (51,52). Underlyingausative factors might range from maternal stress to nutritionalactors or exposure to toxins, and the type and time of exposure
ight differentially influence the consequences on fetal develop-ent (52). Metabolically active parts of the brain, such as the stria-
um, have shown to be particularly vulnerable to hypoxic-ischemicvents and could thus be one plausible model for the associationetween preterm birth and low Apgar scores with ADHD (53). Re-ently, impaired maternal serotonin synthesis during embryonic
ife has been proposed as a possible cause of ADHD-related symp-oms and behavior in later life (54). The registry-based design of theresent study, however, did not allow exploration of pathophysio-
ogical mechanisms or the role of genetic or epigenetic factors thatight interact with (55,56) or directly influence the embryonic and
etal environment (54,57,58). Studies comparing samples of adultsith ADHD with samples of adults with other (neuro-) psychiatricisorders are needed to elucidate the specificity of pre- and perina-
al risk factors for ADHD.
onclusions and ImplicationsIn conclusion, this first population-based study on adults with
DHD suggests that unfavorable conditions during fetal life in-rease the risk of ADHD persisting up to 40 years after birth. Because
ncreasing proportions of newborns will survive pregnancy andirth complications, such as extreme preterm birth, the long-termonsequences for individuals and society should be addressed, andontinuous efforts should be sustained in preventing adverse preg-ancy outcomes. Future research should aim at disentangling theenetic and environmental contributions of pre- and perinatal risk
actors. This is important not only to improve our understanding ofhe etiology of ADHD and other neurodevelopmental disorders butlso to develop clinically appropriate prevention and interventiontrategies.
This work was supported by The Research Council of Norway, theniversity of Bergen, and the Western Norway Regional Health Author-
ty.
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We thank Michael B. Lensing and Ragnhild Nordenborg for theirassistance in gathering and systematizing data in the patient cohort.
Dr. Halmøy received honoraria for a lecture from Janssen-Cilag;and Dr. Haavik has received honoraria for lectures and consultancyfrom Janssen-Cilag and Novartis. Drs. Klungsøyr and Skjærven reportno biomedical financial interests or potential conflicts of interest.
None of the authors have received any support from any organiza-tion for the submitted work, and none have any financial relationshipswith any companies that might have an interest in the submitted workor other relationships or activities that could appear to have influencedthe submitted work.
The funding sources did not have any role in the study design orother decisions related to the study.
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