Published online August 1, 2005
PEDIATRICS Vol. 116 No. 2 August 2005, pp. 462-467 (doi:10.1542/peds.2004-2054)
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Smoking During Pregnancy and the Risk for Hyperkinetic Disorder in Offspring

Karen Markussen Linnet, MD, PhD*,{ddagger}, Kirsten Wisborg, MD, DMSc*, Carsten Obel, MD, PhD*, Niels Jørgen Secher, MD*,§, Per Hove Thomsen, MD, DMSc{ddagger}, Esben Agerbo, MSc|| and Tine Brink Henriksen, MD, PhD*

* Perinatal Epidemiological Research Unit, Department of Obstetrics and Pediatrics, Aarhus University Hospital, Aarhus, Denmark
{ddagger} Psychiatric Hospital for Children and Adolescents, Aarhus University Hospital, Skejby, Denmark
§ Department of Obstetrics and Gynaecology, Hvidovre Hospital, Copenhagen, Denmark
|| National Center for Register-Based Research, Aarhus University, Aarhus, Denmark


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Objective. Maternal smoking during pregnancy may increase the risk for behavioral disorders. The aim of this study was to investigate the association between smoking during pregnancy and hyperkinetic and attention-deficit/hyperactivity disorder in the offspring in a large population-based study.

Methods. This study was designed as a nested case-control study. Data were obtained from Danish longitudinal registers and included 170 children with hyperkinetic disorder and 3765 population-based control subjects, who were matched by age, gender, and date of birth. Potential confounders, including newborn characteristics, socioeconomic status, and family history of psychiatric illnesses, were evaluated by conditional logistic regression analyses.

Results. Women who smoked during pregnancy had a 3-fold increased risk for having offspring with hyperkinetic disorder compared with nonsmokers. Socioeconomic factors and history of mental disorder in the parents or siblings seemed to confound the result to some extent (adjusted relative risk: 1.9; 95% confidence interval: 1.3–2.8). Adjustment for parental age or exclusion of children with low birth weight (<2500 g), preterm delivery (<37 weeks completed gestation), and Apgar scores <7 at 5 minutes revealed no changes in the results. Also, excluding children with conduct disorders or comorbid disorders revealed no change in the results.

Conclusions. Our results showed an increased risk for hyperkinetic disorder in children of mothers who smoked during pregnancy. This could not be explained by newborn characteristics, parental socioeconomic status, family history of psychiatric hospitalizations or contact as outpatients, conduct disorders, or comorbidity.

Key Words: smoking • pregnancy • intrauterine • hyperkinetic disorder • attention-deficit/hyperactivity disorder

Abbreviations: ADHD, attention-deficit/hyperactivity disorder • ICD-10, International Classification of Diseases, Tenth Revision • IDA, Integrated Database for Labour Market Research • RR, relative risk • CI, confidence interval

More knowledge of the risk factors for hyperkinetic disorder and attention-deficit/hyperactivity disorder (ADHD) may help in the understanding of the underlying pathophysiology and focusing public health prevention programs. In our review on the association between lifestyle factors in pregnancy and ADHD and associated disorders in the offspring, we found that previous studies on maternal smoking may be biased by retrospective reporting of smoking habits, insufficient confounder control, and lack of information on familial psychopathology.1 Furthermore, few studies have investigated ADHD in relation to the Diagnostic and Statistical Manual of Mental Disorders diagnostic criteria.2–9

Animal studies have demonstrated long-lasting alterations in the brain associated with prenatal exposure to nicotine.10 Exposure to nicotine results in modulation of the dopaminergic system and an increased number of nicotine receptors in the brain both pre- and postnatally.11,12 This effect has been confirmed in studies of first-trimester human fetal brain cell cultures.12 The fetus is exposed to a relatively higher nicotine concentration compared with the mother.13 Nicotinic receptors are present in the fetal brain from the first trimester and play an important role in the development of the brain.12,13

As in any complex disorder, genetic and environmental factors,14 toxins, pregnancy and delivery complications,15–17 and social environment18 must be considered in studies of behavioral disorders. Our aim was to study the association between maternal smoking during pregnancy and the risk for hyperkinetic disorder in the offspring. Linkage between registers enabled evaluation of several potential confounders, including socioeconomic factors and family history of mental disorders, for which most previous studies were unable to adjust. We were also able to explore potential intermediate variables in the causal chain, such as newborn characteristics.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Data Sources
We conducted a nested case-control study based on data from the following 4 Danish national registers: the Danish Psychiatric Central Register,19 the Danish Medical Birth Registry,20 the Integrated Database for Labor Market Research (IDA),21 and the Danish Civil Registration System.22

The Danish Psychiatric Central Register has been computerized since 1969 and covers all inpatient admissions and outpatient contacts (from 1995) at Danish psychiatric departments. The register includes cumulative records and discharge data, dates, and diagnoses.19 From 1994, the diagnoses are in accordance with the International Classification of Diseases, 10th Revision (ICD-10)23; before that, they were in accordance with the International Classification of Diseases, Eighth Revision.24

The Danish Medical Birth Register has filed detailed information on all births in Denmark since 1973.20 The midwife present at the delivery provides mandatory information on the course of pregnancy and delivery, including information about the newborn on a specific coding form subsequently computerized in the Danish Medical Birth Register.25

The IDA contains longitudinal information on labor market affiliation and sociodemographic data for the total population. Continuous annual information is available, and missing data occur only when the parents are dead or have immigrated or the father is unknown.21

The Danish Civil Registration System contains a personal identification number for all individuals who reside in Denmark and their birth information and links to parents and siblings.22 The personal registration number enables linkage between the national registers.

Participants
Our study included all children who were born from 1991 through 1994 and recorded in the Danish Psychiatric Central Register until the end of December 1999 with 1 of the following hyperkinetic disorders as their main diagnosis (n = 170): disturbance of activity and attention (F90.0; n = 102); hyperkinetic conduct disorder (F90.1; n = 33); other hyperkinetic disorders (F90.8; n = 2); and hyperkinetic disorder, unspecified (F90.9; n = 33). ADHD without hyperactivity (F98.8) was not included because it covers broad diagnostic categories such as nail biting and thumb sucking.

Of the 170 children with hyperkinetic disorder, 127 (91%) were boys. The age of the children when diagnosed varied between 2 and 8 years (mean: 5.46; SD: 1.45).

The groups were categorized as mutually exclusive. When the child had been admitted to a psychiatric department or an outpatient clinic more than once and occurred in the register with different hyperkinetic disorders, the child was registered with the first diagnosis. We excluded all children with childhood autism, Asperger’s syndrome, other pervasive developmental disorders (F84.0–F84.9, 308.0), and mental retardation (F70–F79, 312–315).

With the use of a nested case-control design,26 each of the 170 cases with a hyperkinetic disorder was matched with a random subsample of 25 single-born children of the same gender, born on the same date, and alive at the particular date for the diagnosis of the case (matching date). Thus, the gender-birth-date–stratified control subjects were at risk at the same age and date. To make the selection feasible and to minimize the computational burden, we selected a random 5% longitudinal sample from the entire population within which control subjects were selected. Cases and control subjects were included only when they were born in Denmark.

Women were recorded as nonsmokers or smokers during pregnancy, and only participants with valid information on smoking habits during pregnancy were included in the final analyses. The final data set included 170 cases with a hyperkinetic disorder and 3765 comparison subjects.

History of hospitalizations and outpatient contacts of the cases, the control subjects, parents, and siblings was obtained from the Danish Psychiatric Central Register.19 Psychiatric data were obtained at the time when the cases and the comparison subjects were defined. Information on the time period since the last admission or contact to an outpatient clinic before the hyperkinetic diagnosis was also available.

Detailed socioeconomic data on the parents were obtained from the IDA,21 at the time of birth of the children. We included information on years of schooling after basic school, employment status, cohabitant status, and age-gender-year–specific annual income.

Statistics
The association between exposure to tobacco smoke in utero and the risk for hyperkinetic offspring was expressed as a relative risk (RR) with 95% confidence intervals (CIs).27 Variables that were considered to have a biologically plausible effect on the risk for childhood psychopathology and in other studies have been reported as risk factors for hyperkinetic disorder were considered potential confounders in the analyses. We therefore included information on history of psychiatric hospitalizations and contact as outpatients of the mother, the father, and the siblings of the cases and control subjects, and the variables are presented in Tables 1 and 2. 14–18


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  		TABLE 1. Univariate Relationship Between Maternal Smoking During Pregnancy in Singleton Deliveries and Hyperkinetic Disorder in the Offspring, Presented as RRs with 95% CIs From a Conditional Logistic Regression Model

 

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  		TABLE 2. Univariate Relationship Between Socioeconomic Characteristics of the Parents at the Time of Delivery of the Child and Risk for Hyperkinetic Disorder in the Offspring, Presented as RRs with 95% CIs From a Conditional Logistic Regression Model

 
First, the potential confounding factors were included 1 at the time. When they changed the estimate of the association between maternal smoking and hyperkinetic disorder >10%, they remained in the model.28 Subsequently, all potential confounding factors were included at the same time in a multiple conditional logistic regression model, as a number of dummy variables equal to the number of categories minus 1, based on the a priori assumption that they might confound the result.26

After that, analyses were restricted to children of parents without a history of mental disorders and to children with birth weight ≥2500 g and term deliveries (≥37 completed weeks of gestation) and children with Apgar scores >6 at 5 minutes. Furthermore, analyses were restricted to hyperkinetic offspring without conduct disorder and restricted to hyperkinetic offspring only with recorded comorbidity typically related to hyperkinetic disorder (ie, specific developmental disorders of speech, language, scholastic skills, and motor function [DF80.1–83.9]).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Among mothers with hyperkinetic offspring, 101 (59%) were smokers, whereas 35% of the mothers of control children smoked. Table 1 shows the univariate relationship between maternal smoking habits during pregnancy and newborn and parental characteristics and the risk for hyperkinetic disorder. Women who smoked during pregnancy had a nearly 3-fold increased risk for giving birth to offspring with hyperkinetic disorder compared with nonsmokers. Apgar scores <7 at 5 minutes postpartum, birth weight <2500 g, gestational age <37 completed weeks, and maternal age between 20 and 24 years were also associated with a statistically significant increased risk for hyperkinetic disorder.

Table 2 shows that few years of schooling after basic school, low annual income, being a single mother, parental divorce, and unemployment were associated with hyperkinetic disorder in the offspring. Mental illness of the mother (RR: 3.3; 95% CI: 2.0–5.6), the father (RR: 2.6; 95% CI: 1.5–4.5), and 1 or more siblings (RR: 6.0; 95% CI: 3.5–10.1; n = 19) was associated with an increased risk for hyperkinetic disorder in the offspring. The psychiatric disorders of family members other than the child were alcohol or substance abuse, chronic psychotic disorders, mood disorders, anxiety and emotional disorders, disorders of adult personality, and behavior and other disorders.

Maternal smoking during pregnancy was still associated with hyperkinetic disorder after adjustment for years of schooling after basic school, employment status, annual income, cohabitant status, and history of psychiatric disorders in the parents and siblings (RR: 1.9; 95% CI: 1.4–2.7; Table 3). None of the individual confounding factors alone accounted for the change in the risk estimate. Taking into account information on parental age, previous admissions and outpatient contacts of the cases and control subjects, and the time period since the last admission before the diagnosis of the cases, the result remained essentially unchanged.


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  		TABLE 3. Univariate and Adjusted Association Between Maternal Smoking During Pregnancy and Risk for Hyperkinetic Disorder in the Offspring

 
Restriction to children with a birth weight of 2500 g or more, gestational age >37 completed weeks, and additional restriction to children with Apgar scores of 7 or more at 5 minutes did not change the association. The results were essentially unchanged after restriction to children of parents without psychiatric admissions and outpatient contacts (Table 3). The association was finally tested after excluding cases with conduct disorder (F90.1; 33 cases); the results remained essentially unchanged.

Among children who had a diagnosis of hyperkinetic disorder, 57 (34%) also had other diagnoses. Specific developmental disorders of speech, language, scholastic skills, and motor function (DF80.1–83.9) were the most commonly recorded first subsidiary diagnosis (34 cases; 21%). Other comorbid disorders were disorders of social functioning (DF94.1, DF94.8), disorders related to congenital malformations and chromosome defects (DQ860, DQ992), emotional disorders (DF93.9), epilepsy (DG408), depression (DF43.2), nonorganic sleep disorders (DF51.4), other not specified mental disorders as a result of brain damage (DF06.8), family adjustment disorders (DZ03.2, DZ63.2), and others. Exclusion of the 23 children with hyperkinetic disorder and comorbid disorders other than specific developmental disorders of speech, language, scholastic skills, and motor function recorded as first subsidiary diagnosis did not change in the results.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
We found that smoking during pregnancy was associated with a >2-fold increased risk for hyperkinetic disorder in the offspring. Hyperkinetic disorder29 and ADHD30,31 are the most prevalent mental disorders in child psychiatry. The similarity between the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria for ADHD and the ICD-10 for hyperkinetic disorder is obvious as they essentially recognize the same behavioral characteristics.23,32 Hyperkinetic disorders are most similar to ADHD combined type (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), which is reflected in a relatively low prevalence of hyperkinetic disorder (1%).29,33 For ADHD, the prevalence varies between 3% and 5%17,33 and in some studies up to 10%, primarily cross-sectional studies in which the diagnostic criteria for symptom onset, duration, pervasiveness, and impairment are not fulfilled.30,31,33

Results from 3 case-control studies conducted within the framework of the same study population support our findings.2–4 In these studies, ADHD was measured in accordance with Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised.34 They found a 2- to 4-fold increased risk for ADHD associated with smoking. The results were adjusted for parental ADHD, socioeconomic status of the parents, alcohol intake, and use of illicit drugs during pregnancy and birth weight. The major limitation of these studies was the risk for recall bias as a result of retrospective collection of information on maternal smoking habits during pregnancy. Another case-control study5 and 4 cohort studies6–9 on ADHD, measured in accordance with Diagnostic and Statistical Manual of Mental Disorders, Third Edition6,9 or Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised,5,7,8 also obtained information on maternal smoking habits during pregnancy by retrospective collection of data. None of these studies found that intrauterine exposure to smoking increased the risk for ADHD in the offspring.5–9 The results from these studies are difficult to generalize, as the children were recruited from families with alcoholism,6 families with major depression,7 and a group only of boys who were referred for clinical psychiatric or psychological assessment,8 respectively. Very small sample size furthermore resulted in limited statistical power.9 Thus, the highly selected study populations and small sample size may explain the disagreement with our study.5–9

Our result was based on the total number of children with recorded hyperkinetic disorder in the population during the time period, and control subjects were a 5% randomly selected group of the total population. Therefore, problems with selection bias were minimized and external validity was optimized.

Our study has several other methodologic advantages. The longitudinal registers in Denmark provide detailed information on each individual, and data are collected systematically and uniformly without any knowledge of future research plans. Our study is based on information on maternal smoking habits collected during pregnancy. Thus, the risk for differential misclassification is virtually eliminated. Linkage between registers provides a unique opportunity to take into account potential confounders such as newborn and parental characteristics, socioeconomic status, and psychopathology of parents and siblings.

Limitations may be related to the selection of variables available in the registers and their validity. Smoking was recorded as a dichotomy, which compromises the study of a dose-response effect or a threshold value.

We had no information on postnatal smoking. Distinguishing between exposure to pre- and postnatal tobacco smoke is difficult because of a high correlation between maternal smoking during pregnancy and postnatally. However, exposure to passive tobacco smoke postnatally is much less intense and hardly capable of influencing brain development.10,35 Information on maternal alcohol or illicit drug use during pregnancy was not available. The effect of intake of small amounts of alcohol on long-term child behavior is unknown,1 and intake of large amounts of alcohol is rare in our population.36 Use of recreational drugs may also have long-term consequences for the fetus37 but is also a rare exposure compared with smoking.

The validity of the hyperkinetic disorder in the Psychiatric Case Registry is unknown. The diagnostic procedure has been based on the diagnostic criteria, and the diagnosis has been provided after a somatic and neurologic examination conducted by a specialist in child psychiatry. Subsequent evaluation of the family; observation of the child in child care or school, at home, and in a clinical setting; intelligence testing; and evaluation for comorbidity have been used to confirm the diagnosis. These guidelines correspond with the guidelines from the American Academy of Pediatrics in 2000.31 Comorbidity may be underassessed, partly as a result of the ICD-10’s diagnostic hierarchal system and a tendency to report the mandatory main diagnosis to the register.

We explored the risk that our result was explained by comorbid disorders by excluding subjects with comorbidity unrelated to hyperkinetic disorder. Information on psychiatric outpatient contacts by parents and siblings before 1995 were unavailable, and an underestimation of the confounding from mental illness in the family may be possible. Undiagnosed children with hyperkinetic disorder, however, may be present in the control group. If intrauterine exposure to tobacco smoke increases the risk for hyperkinetic disorder, then this will result in an underestimation of our results.

Our frequency of smokers during pregnancy corresponds with other studies with more detailed information on smoking.38 Pregnant women may underreport their smoking habits. This potential nondifferential misclassification would tend to underestimate the true association between smoking in pregnancy and the risk for hyperkinetic disorder.

Explanations of the Findings
Our results may reflect a true biological effect of cigarette smoking on the fetal brain or unaccounted factors associated with smoking during pregnancy. Nicotine acts as a stimulant, and young adults with ADHD may self-medicate by smoking.39–42 Pregnant women who smoke may have certain personality traits associated with both smoking and a genetically increased risk for having a child with a behavioral disorder. We attempted to adjust for this in 2 ways: by including information of maternal and paternal psychiatric hospitalizations or contacts as outpatients as a confounder in the statistical model and by restricting the analysis to include only children without 1 or both parents with psychopathology. The results were essentially unchanged. Therefore, we believe to have adjusted for part of the genetic confounding, represented by parental psychiatric symptoms related to ADHD, and therefore reduced the risk for residual confounding. However, maternal smoking during pregnancy may still be a marker for ADHD as only parental psychiatric disorders were accounted for, not personality traits. Maternal tobacco smoke during pregnancy therefore may be a proxy variable for a genetically increased risk for hyperkinetic disorder in the children.

If smokers have a certain parenting style that increases the risk for hyperkinetic disorder, independent of psychopathology and biological effects, then child-rearing manners may cause the results. However, adjustment for this potential confounder is difficult, other than adjustment for sibling psychopathology. Sibling’s psychopathology was used partly as a proxy variable for genetic vulnerability but also as a control for the potential referral bias in families who already attended a psychiatric department as a result of psychopathology in a sibling. We were able to limit the study to children without conduct disorder and thus reduce the risk that our results were explained by severe antisocial behavior.43


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We found that smoking during pregnancy increased the risk for hyperkinetic disorder in the offspring, also when adjusting for newborn characteristics, perinatal problems, socioeconomic factors and family history of psychiatric hospitalizations or contact as outpatients. The association was not explained by conduct disorders or comorbid disorders.


   ACKNOWLEDGMENTS
 
This study was supported by the Danish Health Insurance Fund (grant 2000B521), the Augustinusfonden (grant 0–1360), Ronald McDonald Charities, and Marie Dorthea and Holger Froms Children’s Foundation. The National Centre for Register-Based Research is funded by the Danish National Research Foundation.


   FOOTNOTES
 
Accepted Nov 22, 2004.

Reprint requests to (K.M.L.) Perinatal Epidemiological Research Unit, Department of Obstetrics and Pediatrics, Aarhus University Hospital, Skejby Sygehus, DK-8200 Aarhus N, Denmark. E-mail: kmlinnet{at}ki.au.dk

No conflict of interest declared.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics



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