Abstract

The study objective was to determine the relation of prenatal smoking exposure to the use of psychotropic medication up to young adulthood by using population-based longitudinal register data consisting of all singletons born in Finland from 1987 to 1989 (n = 175,869). Information on maternal smoking was assessed during antenatal care and received from the Finnish Medical Birth Register. Information on the children's psychotropic medication (1994–2007) was received from the Drug Prescription Register, and the children's psychiatric diagnoses related to outpatient (1998–2007) and inpatient (1987–2007) care were derived from the Finnish Hospital Discharge Register. A total of 15.3% (n = 26,083) of the children were exposed to prenatal smoking. The incidence of psychotropic medication use was 8.3% in unexposed children, 11.3% in children exposed to <10 cigarettes per day (adjusted odds ratio = 1.36, 95% confidence interval: 1.29, 1.43), and 13.6% in children exposed to >10 cigarettes per day (odds ratio = 1.63, 95% confidence interval: 1.53, 1.74). The exposure was significantly associated with the risk for all medication use and for both single- and multiple-drug consumption even after adjustment (e.g., mothers’ severe psychiatric illnesses). These findings show that exposure to smoking during pregnancy is linked to both mild and severe psychiatric morbidity.

Prenatal smoking exposure is associated with many harmful effects on fetal growth and development (1). In recent years, there has been concern over serious long-term behavioral consequences caused by the effects of prenatal smoking exposure. Several studies have shown an increased risk for problems in attention and other psychiatric problems after prenatal smoking exposure (2–6). Psychiatric morbidity has been based on symptoms assessed by the child, parents, or teachers (3, 4) or on the diagnoses in hospital care (5, 6). We have shown that the use of hospital services for psychiatric disorders was increased in the young adults exposed prenatally to smoking (5). However, our previous study covered only diagnoses from hospital care and, therefore, not milder psychiatric problems treated by medication from primary care.

There has been an increasing trend of psychotropic medication use also among children (7–9). Prescriptions of antidepressants in children below 18 years rose by 150% in the United States between the years 1997 and 2002 (8). The most common psychotropic medications prescribed were stimulants, anxiolytics, and antidepressants (7, 9), of which anxiolytics and antidepressants were prescribed mostly in primary health care. To our knowledge, there are no large epidemiologic studies that have investigated the relation of prenatal smoking exposure to the use of psychotropic medication into early adulthood. It is of interest whether children exposed to prenatal smoking use more psychotropic medications compared with unexposed children, as medication can be used as a surrogate of psychiatric morbidity covering everyone treated in hospitals or primary care.

Our current study aimed to investigate the association between prenatal smoking exposure and children's cumulative use of psychotropic medications during a 13-year period to cover also milder psychiatric disorders treated outside hospital care. Our hypothesis was that prenatal smoking exposure interferes with the development of the fetal brain and, thus, increases psychiatric morbidity leading to an increased risk for the use of psychotropic medications.

MATERIALS AND METHODS

Data sources

The Finnish Medical Birth Register includes all live- and stillbirths of fetuses with a gestational age of 22 weeks or more or with a birth weight of 500 g or more. The register data were collected from all delivery hospitals and, in the case of home births, from the assisting health-care personnel and sent to the register keeper, currently the National Institute for Health and Welfare (THL). The register includes information on the mother's and the child's identification numbers; maternal background, health care, and interventions during pregnancy and delivery; and the newborn's outcome at 7 days of age. Most of the register content corresponds well or satisfactorily with hospital record data according to 2 data quality studies (10, 11).

The Drug Prescription Register (1994–2007) is kept by the Social Insurance Institution of Finland (SII). It comprises date of distribution and name of the drug, covering 97% of all reimbursed prescriptions in Finland. Nearly all prescription-only drugs deemed necessary for treatment of an illness are partly reimbursable. Prescription medication purchases were reimbursed only if the costs of 1 purchase exceeded 8.41 euros (1994–2002) or 10 euros (2003–2005). In psychotropic drugs, only a few small packages of diazepam were excluded from the database because of the low cost. All reimbursed purchases have been registered since year 2006. One purchase can cover a maximum of 3 months of medication and, therefore, medication used for 1 year should include at least 4 purchases.

The Hospital Discharge Register collects information on all inpatient care episodes (all hospitalizations requiring an overnight stay) in public and private hospitals (since 1969) and outpatient visits in public hospitals (since 1998). The register contains information on the main diagnosis plus up to 2 other diagnoses of the patient according to the International Classification of Diseases (ICD), Eight Revision (1969–1986), Ninth Revision (1987–1996), and Tenth Revision (since 1997). Keskimäki and Aro (12) showed in a data quality study that 99% of hospitalizations relating to mental disorders were registered under the correct ICD chapter and that 98% of the main diagnoses had been correctly reported at the 3-digit ICD code level in year 1986.

Participants and background information

The study population consisted of all children born in the period between 1987 and 1989 in Finland (n = 186,246) who were registered in the Medical Birth Register. The Medical Birth Register has included information on maternal smoking during pregnancy since 1987. We chose to include the first year cohorts with exposure information in order to have long enough follow-up periods for psychiatric morbidity. We excluded multiple births (3,960 children, 2.1%) and children who had died during the first week of life (597 children, 0.3%) from the study. In addition, children with major congenital anomalies (5,820 children, 3.2%) were excluded. Individual diagnoses of cryptorchism (n = 954), luxation of the hip (n = 943), or subluxation of the hip (n = 845) were not considered major anomalies, and infants with these diagnoses were included in the study. After exclusions, the final study population consisted of 175,869 children, totaling 94.4% of all children born during the study years.

The information on maternal smoking was assessed during antenatal care from the mothers by a midwife (none/<10/>10 cigarettes per day). The questionnaire in the antenatal care categorized smoking as “less than 10 cigarettes” and “more than 10 cigarettes” per day, leaving it unclear in which group mothers who smoked exactly 10 cigarettes per day would be categorized. Other background factors were derived from the Finnish Medical Birth Register (the child's sex, gestational age, birth weight, and Apgar score at 5 minutes of age and maternal age and parity) and from the Hospital Discharge Register (mother's psychiatric morbidity requiring inpatient hospital care before the birth of the child) for the period between 1969 and 1989.

Information on drug prescriptions

The information on psychotropic medication was obtained from the Social Insurance Institution of Finland from 1994 through 2007 and included a cumulative use of psychotropic medication during a 13-year time period. Depending on the birth year, this time period ranged from 5–7 years of age to 18–20 years of age. Psychotropic medications were defined according to the Anatomic Therapeutic Chemical (ATC) [classification system]: all psychotropic medications (ATC groups N05, N06A, N06B, and N07B); antipsychotics (ATC group N05A); hypnotics/anxiolytics (ATC groups N05B and N05C); antidepressants (ATC group N06A); stimulants (ATC group N06B); and medication used in addictive disorders (ATC group N07B). Purchases with the ATC code N05BB01 (hydroxyzine hydrochloride) were excluded from the data, as the drug is mostly used to alleviate itching in small children. In year 1994, the ATC code N05AC02, related to antipsychotics, incorrectly also included 1 antibiotic drug and was therefore excluded from the data. Disulfiram (ATC code N07BB01) prescriptions covered a total of 98% of drugs for addiction. Our data did not, however, contain any information concerning the indication for which drugs were prescribed.

We studied the continuity of consumption according to the ATC groups N05A, N05B, and/or N05C, N06A, and N06B. The use of drug (ATC groups N05A, N06A, and N06B) was categorized into 4 continuity groups: 1) no purchases during the follow-up; 2) sporadic use (1 or more purchases in one 3-month period); 3) moderate use (1 purchase in at least 2 follow-up years or 2–3 purchases with an interval over 3 months between the first and last purchase during the most severe 1-year period); and 4) continuous use (4 or more purchases of the drug during more than 3 months during the most severe 1-year period). The continuity of drug use in hypnotics (ATC group N05B) and anxiolytics (ATC group N05C) was categorized into 3 groups according to the most severe 1-year period indicating misuse: 1) no purchases during the follow-up; 2) infrequent purchases (1–5 purchases); and 3) frequent purchases (6 or more purchases).

Single- and multiple-drug uses were defined as simultaneous use of several drug categories. The use of drugs (ATC group N05A and combined ATC groups N05B and N05C, N06A, N06B, and N07B) was categorized into 3 groups: 1) no purchases; 2) single-drug consumption (purchases of drugs from 1 drug group in any follow-up year); and 3) multiple-drug consumption (use of drugs from 2 or more different drug groups in any follow-up year).

Information on psychiatric morbidity

Information on psychiatric morbidity was obtained from the Finnish Hospital Discharge Register and included all inpatient episodes in public and private hospitals for the period from 1987 through 2007 and all outpatient visits to public hospitals from 1998 through 2007. We included all episodes and visits with a psychiatric diagnosis (ICD, Ninth Revision, codes 290–319, and ICD, Tenth Revision, codes F00–F99) whether occurring as a primary or other diagnosis for this study. We further studied the effect of smoking exposure by comparing the incidence of children with 1) use of psychotropic medication only (i.e., common psychiatric problems treated in primary health-care settings and not requiring psychiatric specialist services), 2) psychiatric diagnosis given in specialized hospital care only, and 3) both psychotropic medication use and psychiatric diagnosis in specialized hospital care. The psychiatric diagnoses were studied in more detail in our previous publication (5). This study explores how much the groups with hospital care and medication overlap.

All data were combined by using the child's and mother's unique personal identification numbers. The statistical authorities performed the data linkages, and therefore only unidentifiable data were delivered for the researchers working outside the National Institute for Health and Welfare. The combined data included complete follow-up information until December 31, 2007, or the death of the child. Our data did not include information on children migrating out of Finland. The register-keeping organizations (National Institute for Health and Welfare and Social Insurance Institution of Finland) gave their permission to use their confidential health register data in this study, as requested by national data-protection legislation. The study protocol was approved by the ethics committees of statistics authorities (National Institute for Health and Welfare and Social Insurance Institution of Finland).

Statistical analyses

All statistical analyses were performed by using commercially available software (SAS, version 9.1; SAS Institute, Inc., Cary, North Carolina). Differences in the results were evaluated by using 95% confidence intervals. Nonoverlapping confidence intervals were considered to be significant.

Logistic regression analysis was used to compare the incidence of any psychotropic medication, the psychotropic medication by drug groups, the continuity of drug use, single- and multiple-drug use, and both psychotropic medication use and psychiatric diagnoses. The analyses were adjusted by the following confounding factors: the child's sex, gestational age, birth weight, and 5-minute Apgar score, as well as maternal age, parity, and psychiatric morbidity before the birth of the child.

Having a teenage mother, prematurity, and low birth weight have been shown to be a risk for increased subsequent psychiatric problems in childhood and adolescence. Therefore, we analyzed the following low-risk populations separately: 1) excluding children born to mothers less than 20 years of age, 2) excluding children born prematurely (gestational age less than 37 weeks), and 3) excluding children with low birth weight (less than 2,500 g) using logistic regression analyses. In addition, we assessed the overlapping between those using psychiatric hospital care and using psychotropic medication with special interest in children using medication without any diagnoses from specialized hospital care.

RESULTS

Characteristics of the study groups according to exposure are shown in Table 1. A total of 84.7% (n = 144,299) of the children were unexposed, and 15.3% (n = 26,083) of the children were exposed to prenatal smoking. Of the exposed children, 34.0% (n = 8,869) were exposed to more than 10 cigarettes per day during pregnancy.

Table 1.

Information on Maternal Smoking and Child's Use of Psychotropic Medication by the Background Factors, Finland, 1987–2007

 No. Maternal Smoking (Excluding Unknown), % Child's Use of Psychotropic Medication, % Child's Psychiatric ICD-10 F00–F99 Diagnoses, % 
All children 175,869 15.3 8.9 15.1 
Maternal age, years     
    Less than 20 5,320 37.8 13.1 24.9 
    20–39 166,199 14.7 8.7 14.7 
    40 or more 4,288 10.8 9.3 14.9 
    Unknown 62 8.6 0.0 0.0 
Parity     
    0 69,457 16.9 9.1 15.4 
    1 61,008 14.3 8.6 14.5 
    2–3 37,478 14.9 9.1 15.4 
    4 or more 5,535 9.8 8.4 14.4 
    Unknown 2,391 23.7 9.9 16.3 
Mother's previous psychiatric diagnosis     
    No 171,932 14.9 8.7 14.7 
    Yes 3,937 35.1 16.6 29.5 
Sex     
    Male 89,862 15.3 6.7 13.6 
    Female 86,007 15.3 11.2 16.6 
Gestational age, weeks     
    22–27 223 22.6 16.1 31.8 
    28–31 642 19.8 14.8 24.3 
    32–36 6,406 19.2 10.1 17.3 
    37 or more 166,094 15.1 8.8 14.9 
    Unknown 2,504 23.2 9.8 16.4 
Birth weight, g     
     Less than 1,500 666 22.1 14.1 29.3 
    1,500–2,499 3,757 26.8 12.3 20.1 
    2,500–3,999 133,322 16.5 9.0 15.2 
    4,000 or more 36,024 9.5 7.9 13.5 
    Unknown 2,100 10.5 10.1 16.5 
Weight adjusted for gestational age     
    SGA 3,115 31.4 11.9 22.2 
    AGA 163,858 15.3 8.9 14.9 
    LGA 6,392 8.3 8.5 14.9 
    Unknown 2,504 23.2 10.1 16.4 
5-minute Apgar scorea     
    0–3 238 17.9 12.3 15.1 
    4–6 1,147 16.4 10.7 18.9 
    7–10 171,708 15.3 8.9 15.0 
    Unknown 2,640 20.7 10.2 17.1 
 No. Maternal Smoking (Excluding Unknown), % Child's Use of Psychotropic Medication, % Child's Psychiatric ICD-10 F00–F99 Diagnoses, % 
All children 175,869 15.3 8.9 15.1 
Maternal age, years     
    Less than 20 5,320 37.8 13.1 24.9 
    20–39 166,199 14.7 8.7 14.7 
    40 or more 4,288 10.8 9.3 14.9 
    Unknown 62 8.6 0.0 0.0 
Parity     
    0 69,457 16.9 9.1 15.4 
    1 61,008 14.3 8.6 14.5 
    2–3 37,478 14.9 9.1 15.4 
    4 or more 5,535 9.8 8.4 14.4 
    Unknown 2,391 23.7 9.9 16.3 
Mother's previous psychiatric diagnosis     
    No 171,932 14.9 8.7 14.7 
    Yes 3,937 35.1 16.6 29.5 
Sex     
    Male 89,862 15.3 6.7 13.6 
    Female 86,007 15.3 11.2 16.6 
Gestational age, weeks     
    22–27 223 22.6 16.1 31.8 
    28–31 642 19.8 14.8 24.3 
    32–36 6,406 19.2 10.1 17.3 
    37 or more 166,094 15.1 8.8 14.9 
    Unknown 2,504 23.2 9.8 16.4 
Birth weight, g     
     Less than 1,500 666 22.1 14.1 29.3 
    1,500–2,499 3,757 26.8 12.3 20.1 
    2,500–3,999 133,322 16.5 9.0 15.2 
    4,000 or more 36,024 9.5 7.9 13.5 
    Unknown 2,100 10.5 10.1 16.5 
Weight adjusted for gestational age     
    SGA 3,115 31.4 11.9 22.2 
    AGA 163,858 15.3 8.9 14.9 
    LGA 6,392 8.3 8.5 14.9 
    Unknown 2,504 23.2 10.1 16.4 
5-minute Apgar scorea     
    0–3 238 17.9 12.3 15.1 
    4–6 1,147 16.4 10.7 18.9 
    7–10 171,708 15.3 8.9 15.0 
    Unknown 2,640 20.7 10.2 17.1 

Abbreviations: AGA, average for gestational age; ICD-10, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; LGA, large for gestational age; SGA, small for gestational age.

a

If the 5-minute Apgar score was missing, the 1-minute Apgar score was used if the score was 8, 9, or 10. Information was missing for 136.

Psychotropic medication

A total of 8.9% (n = 15,644) of the children had used psychotropic medication during the 13-year follow-up period. The incidence of psychotropic medication was 8.3% in unexposed children but 11.3% and 13.6% in children exposed to less than 10 and more than 10 cigarettes per day, respectively. Psychotropic medication associated statistically significantly with prenatal smoking exposure when the incidence of medication was adjusted by background factors including severe maternal psychiatric illnesses (P < 0.001) (Table 2). When the medication was analyzed by drug groups, the association of prenatal smoking exposure was found in all psychotropic medication categories. The risk was most profoundly increased in the group of stimulants (ATC group N06B) and the drugs for addiction (ATC group N07B). A clear dose-response between the amount of smoking exposure and medication was seen in the use of antidepressants (ATC group N06A).

Table 2.

Children's Use of Psychotropic Medication by Maternal Smoking, Finland, 1987–2007

 No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval 
All psychotropics (ATC N05–N07)     
    No smoking 11,967 82.9 Referent 
    Less than 10 cigarettesb 1,952 113.4 1.36 1.29, 1.43 
    More than 10 cigarettesb 1,207 136.1 1.63 1.53, 1.74 
        Totalc 15,644 89.0   
Antipsychotics (ATC N05A)     
    No smoking 2,578 17.9 Referent 
    Less than 10 cigarettesb 420 24.4 1.25 1.12, 1.39 
    More than 10 cigarettesb 260 29.3 1.43 1.25, 1.63 
        Totalc 3,395 19.3   
Hypnotics/anxiolytics (ATC N05B and N05C)     
    No smoking 4,522 31.3 Referent 
    Less than 10 cigarettesb 705 41.0 1.25 1.15, 1.36 
    More than 10 cigarettesb 428 48.3 1.44 1.29, 1.59 
        Totalc 5,861 33.3   
Antidepressants (ATC N06A)     
    No smoking 8,636 59.9 Referent 
    Less than 10 cigarettesb 1,486 86.4 1.42 1.34, 1.51 
    More than 10 cigarettesb 913 103.0 1.67 1.55, 1.80 
        Totalc 11,406 64.9   
Stimulants (ATC N06B)     
    No smoking 289 2.0 Referent 
    Less than 10 cigarettesb 65 3.8 1.75 1.33, 2.30 
    More than 10 cigarettesb 49 5.5 2.57 1.89, 3.50 
        Totalc 415 2.4   
Drugs for addiction (ATC N07B)     
    No smoking 83 0.6 Referent 
    Less than 10 cigarettesb 24 1.4 2.17 1.36, 3.45 
    More than 10 cigarettesb 15 1.7 2.58 1.47, 4.53 
        Totalc 128 0.7   
 No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval 
All psychotropics (ATC N05–N07)     
    No smoking 11,967 82.9 Referent 
    Less than 10 cigarettesb 1,952 113.4 1.36 1.29, 1.43 
    More than 10 cigarettesb 1,207 136.1 1.63 1.53, 1.74 
        Totalc 15,644 89.0   
Antipsychotics (ATC N05A)     
    No smoking 2,578 17.9 Referent 
    Less than 10 cigarettesb 420 24.4 1.25 1.12, 1.39 
    More than 10 cigarettesb 260 29.3 1.43 1.25, 1.63 
        Totalc 3,395 19.3   
Hypnotics/anxiolytics (ATC N05B and N05C)     
    No smoking 4,522 31.3 Referent 
    Less than 10 cigarettesb 705 41.0 1.25 1.15, 1.36 
    More than 10 cigarettesb 428 48.3 1.44 1.29, 1.59 
        Totalc 5,861 33.3   
Antidepressants (ATC N06A)     
    No smoking 8,636 59.9 Referent 
    Less than 10 cigarettesb 1,486 86.4 1.42 1.34, 1.51 
    More than 10 cigarettesb 913 103.0 1.67 1.55, 1.80 
        Totalc 11,406 64.9   
Stimulants (ATC N06B)     
    No smoking 289 2.0 Referent 
    Less than 10 cigarettesb 65 3.8 1.75 1.33, 2.30 
    More than 10 cigarettesb 49 5.5 2.57 1.89, 3.50 
        Totalc 415 2.4   
Drugs for addiction (ATC N07B)     
    No smoking 83 0.6 Referent 
    Less than 10 cigarettesb 24 1.4 2.17 1.36, 3.45 
    More than 10 cigarettesb 15 1.7 2.58 1.47, 4.53 
        Totalc 128 0.7   

Abbreviation: ATC, Anatomic Therapeutic Chemical [classification system].

a

Adjusted by the child's sex, gestational age, birth weight, and 5-minute Apgar score and maternal age, parity, and psychiatric diagnosis before birth of the child.

b

The questionnaire in the antenatal care categorized smoking as “less than 10 cigarettes” and “more than 10 cigarettes” per day, leaving it unclear in which group mothers who smoked exactly 10 cigarettes per day would be categorized.

c

Children with unknown smoking exposure (n = 5,487) did not differ from other children. They are not presented here, but the total number includes children with unknown smoking.

Continuity of medication

The use of psychotropic medication in all consumption categories was associated with an increased risk in children exposed to more than 10 cigarettes per day compared with unexposed children (Tables 3 and 4). The most profound association of prenatal exposure was on the continuous use of stimulants (ATC group N06B).

Table 3.

Continuity of Psychotropic Medication Use According to Drug Groups (Antipsychotics, Antidepressants, and Stimulants), Finland, 1987–2007

 No Purchases, no. Sporadic Use
 
Moderate Use
 
Continuous Use
 
 No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval 
Antipsychotics (ATC N05A)              
    No smoking 141,721 1,008 7.0 Referent 348 2.4 Referent 1,222 8.5 Referent 
    Less than 10 cigarettesb 16,794 157 9.1 1.22 1.03, 1.45 81 4.7 1.68 1.31, 2.15 182 10.6 1.15 0.98, 1.35 
    More than 10 cigarettesb 8,609 106 12.0 1.55 1.26, 1.90 40 4.5 1.53 1.10, 2.14 114 12.9 1.32 1.08, 1.60 
        Totalc 172,474 1,325 7.5   495 2.8   1,575 9.0   
Antidepressants (ATC N06A)              
    No smoking 135,663 5,474 37.9 Referent 1,371 9.5 Referent 1,791 12.4 Referent 
    Less than 10 cigarettesb 15,728 1,006 58.4 1.52 1.42, 1.63 230 13.4 1.34 1.16, 1.54 250 14.5 1.15 1.01, 1.32 
    More than 10 cigarettesb 7,956 610 68.8 1.79 1.64, 1.95 148 16.7 1.60 1.34, 1.91 155 17.5 1.35 1.14, 1.60 
        Totalc 164,463 7,311 41.6   1,814 10.3   2,281 13.0   
Stimulants (ATC N06B)              
    No smoking 144,010 166 1.2 Referent 52 0.4 Referent 71 0.5 Referent 
    Less than 10 cigarettesb 17,149 32 1.9 1.55 1.05, 2.27 0.5 1.07 0.50, 2.26 25 1.5 2.77 1.74, 4.42 
    More than 10 cigarettesb 8,820 26 2.9 2.48 1.63, 3.79 1.0 2.29 1.12, 4.71 14 1.6 3.01 1.68, 5.41 
        Totalc 175,454 231 1.3   71 0.4   113 0.6   
 No Purchases, no. Sporadic Use
 
Moderate Use
 
Continuous Use
 
 No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval 
Antipsychotics (ATC N05A)              
    No smoking 141,721 1,008 7.0 Referent 348 2.4 Referent 1,222 8.5 Referent 
    Less than 10 cigarettesb 16,794 157 9.1 1.22 1.03, 1.45 81 4.7 1.68 1.31, 2.15 182 10.6 1.15 0.98, 1.35 
    More than 10 cigarettesb 8,609 106 12.0 1.55 1.26, 1.90 40 4.5 1.53 1.10, 2.14 114 12.9 1.32 1.08, 1.60 
        Totalc 172,474 1,325 7.5   495 2.8   1,575 9.0   
Antidepressants (ATC N06A)              
    No smoking 135,663 5,474 37.9 Referent 1,371 9.5 Referent 1,791 12.4 Referent 
    Less than 10 cigarettesb 15,728 1,006 58.4 1.52 1.42, 1.63 230 13.4 1.34 1.16, 1.54 250 14.5 1.15 1.01, 1.32 
    More than 10 cigarettesb 7,956 610 68.8 1.79 1.64, 1.95 148 16.7 1.60 1.34, 1.91 155 17.5 1.35 1.14, 1.60 
        Totalc 164,463 7,311 41.6   1,814 10.3   2,281 13.0   
Stimulants (ATC N06B)              
    No smoking 144,010 166 1.2 Referent 52 0.4 Referent 71 0.5 Referent 
    Less than 10 cigarettesb 17,149 32 1.9 1.55 1.05, 2.27 0.5 1.07 0.50, 2.26 25 1.5 2.77 1.74, 4.42 
    More than 10 cigarettesb 8,820 26 2.9 2.48 1.63, 3.79 1.0 2.29 1.12, 4.71 14 1.6 3.01 1.68, 5.41 
        Totalc 175,454 231 1.3   71 0.4   113 0.6   

Abbreviation: ATC, Anatomic Therapeutic Chemical [classification system].

a

Adjusted by the child's sex, gestational age, birth weight, and 5-minute Apgar score and maternal age, parity, and psychiatric diagnosis before birth of the child.

b

The questionnaire in the antenatal care categorized smoking as “less than 10 cigarettes” and “more than 10 cigarettes” per day, leaving it unclear in which group mothers who smoked exactly 10 cigarettes per day would be categorized.

c

Children with unknown smoking exposure (n = 5,487) did not differ from other children. They are not presented here, but the total number includes children with unknown smoking.

Table 4.

Continuity of Psychotropic Medication Use According to Drug Groups (Hypnotics and Anxiolytics), Finland, 1987–2007

 No Purchases, no. Infrequent Purchase
 
Frequent Purchase
 
 No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval 
Hypnotics (ATC N05B)          
    No smoking 141,152 2,648 18.4 Referent 499 0.5 Referent 
    Less than 10 cigarettesb 16,777 350 20.3 1.07 0.96, 1.20 87 1.5 1.31 1.04, 1.65 
    More than 10 cigarettesb 859 204 23.0 1.16 1.00, 1.34 75 1.6 2.17 1.70, 2.79 
        Totalc 171,868 3,314 18.8   687 0.6   
Anxiolytics (ATC N05C)          
    No smoking 142,491 1,497 10.4 Referent 311 2.2 Referent 
    Less than 10 cigarettesb 16,864 288 16.7 1.53 1.35, 1.74 62 3.6 1.60 1.22, 2.12 
    More than 10 cigarettesb 8,661 167 18.8 1.70 1.45, 2.01 41 4.6 2.05 1.47, 2.86 
        Totalc 173,420 2,020 11.5   429 2.4   
 No Purchases, no. Infrequent Purchase
 
Frequent Purchase
 
 No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval 
Hypnotics (ATC N05B)          
    No smoking 141,152 2,648 18.4 Referent 499 0.5 Referent 
    Less than 10 cigarettesb 16,777 350 20.3 1.07 0.96, 1.20 87 1.5 1.31 1.04, 1.65 
    More than 10 cigarettesb 859 204 23.0 1.16 1.00, 1.34 75 1.6 2.17 1.70, 2.79 
        Totalc 171,868 3,314 18.8   687 0.6   
Anxiolytics (ATC N05C)          
    No smoking 142,491 1,497 10.4 Referent 311 2.2 Referent 
    Less than 10 cigarettesb 16,864 288 16.7 1.53 1.35, 1.74 62 3.6 1.60 1.22, 2.12 
    More than 10 cigarettesb 8,661 167 18.8 1.70 1.45, 2.01 41 4.6 2.05 1.47, 2.86 
        Totalc 173,420 2,020 11.5   429 2.4   

Abbreviation: ATC, Anatomic Therapeutic Chemical [classification system].

a

Adjusted by the child's sex, gestational age, birth weight, and 5-minute Apgar score and maternal age, parity, and psychiatric diagnosis before birth of the child.

b

The questionnaire in the antenatal care categorized smoking as “less than 10 cigarettes” and “more than 10 cigarettes” per day, leaving it unclear in which group mothers who smoked exactly 10 cigarettes per day would be categorized.

c

Children with unknown smoking exposure (n = 5,487) did not differ from other children. They are not presented here, but the total number includes children with unknown smoking.

Single- and multiple-drug use

Drugs from more than 1 drug group had been prescribed for a total of 2.2% (n = 3,936) of the children in any year during the 13-year follow-up period. Multiple-drug use was found in 2.1% of unexposed children, 3.0% of children exposed to less than 10 cigarettes per day, and 3.5% in children exposed to more than 10 cigarettes per day (Table 5). The adjusted incidence of multiple-drug use associated statistically significantly with prenatal smoking exposure (P < 0.001).

Table 5.

Single- and Multiple-Drug Use of Psychotropic Medication, Finland, 1987–2007

 No Purchases,no. Single-Drug Use
 
Multiple-Drug Use
 
 No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval 
No smoking 132,332 9,014 62.5 Referent 2,953 20.5 Referent 
Less than 10 cigarettesb 15,262 1,430 83.1 1.31 1.24, 1.39 522 30.3 1.41 1.28, 1.55 
More than 10 cigarettesb 7,662 893 100.7 1.59 1.47, 1.71 314 35.4 1.59 1.41, 1.80 
    Totalc 160,225 11,708 66.6   3,936 22.4   
 No Purchases,no. Single-Drug Use
 
Multiple-Drug Use
 
 No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval 
No smoking 132,332 9,014 62.5 Referent 2,953 20.5 Referent 
Less than 10 cigarettesb 15,262 1,430 83.1 1.31 1.24, 1.39 522 30.3 1.41 1.28, 1.55 
More than 10 cigarettesb 7,662 893 100.7 1.59 1.47, 1.71 314 35.4 1.59 1.41, 1.80 
    Totalc 160,225 11,708 66.6   3,936 22.4   
a

Adjusted by the child's sex, gestational age, birth weight, and 5-minute Apgar score and maternal age, parity, and psychiatric diagnosis before birth of the child.

b

The questionnaire in the antenatal care categorized smoking as “less than 10 cigarettes” and “more than 10 cigarettes” per day, leaving it unclear in which group mothers who smoked exactly 10 cigarettes per day would be categorized.

c

Children with unknown smoking exposure (n = 5,487) did not differ from other children. They are not presented here, but the total number includes children with unknown smoking.

Psychotropic medication use and psychiatric morbidity

The effect of smoking exposure was studied separately in the children with drug use only (3.2% of the study population), psychiatric diagnosis only (9.4%), and both drug use and diagnosis (5.7%). Smoking exposure was associated with an increased risk for all 3 categories (Table 6). A dose-response for smoking exposure was also seen. A total of 29.1% and 44.1% of children treated with antidepressants and hypnotics/anxiolytics, respectively, had no psychiatric diagnoses given while in hospital care compared with 14.1% and 13.7% in children treated with antipsychotics and stimulants, respectively.

Table 6.

Psychotropic Medication Use and Psychiatric Diagnoses Among the Study Population, Finland, 1987–2007

 No Treatment, no. Drug Use Only
 
Psychiatric Diagnosis Only
 
Psychiatric Drug Use and Diagnosis
 
 No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval 
No smoking 120,043 4,470 31.0 Referent 12,289 85.0 Referent 7,497 52.0 Referent 
Less than 10 cigarettesb 12,981 617 35.8 1.36 1.29, 1.43 2,281 132.5 1.51 1.44, 1.59 1,335 77.6 1.44 1.36, 1.53 
More than 10 cigarettesb 6,348 330 37.2 1.63 1.53, 1.74 1,314 148.2 1.69 1.59, 1.80 877 98.9 1.83 1.70, 1.97 
    Totalc 143,780 5,608 31.9   16,445 94.0   10,036 57.0   
 No Treatment, no. Drug Use Only
 
Psychiatric Diagnosis Only
 
Psychiatric Drug Use and Diagnosis
 
 No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval No. Incidence (per 1,000) Adjusted Odds Ratioa 95% Confidence Interval 
No smoking 120,043 4,470 31.0 Referent 12,289 85.0 Referent 7,497 52.0 Referent 
Less than 10 cigarettesb 12,981 617 35.8 1.36 1.29, 1.43 2,281 132.5 1.51 1.44, 1.59 1,335 77.6 1.44 1.36, 1.53 
More than 10 cigarettesb 6,348 330 37.2 1.63 1.53, 1.74 1,314 148.2 1.69 1.59, 1.80 877 98.9 1.83 1.70, 1.97 
    Totalc 143,780 5,608 31.9   16,445 94.0   10,036 57.0   
a

Adjusted by the child's sex, gestational age, birth weight, and 5-minute Apgar score and maternal age, parity, and psychiatric diagnosis before birth of the child.

b

The questionnaire in the antenatal care categorized smoking as “less than 10 cigarettes” and “more than 10 cigarettes” per day, leaving it unclear in which group mothers who smoked exactly 10 cigarettes per day would be categorized.

c

Children with unknown smoking exposure (n = 5,487) did not differ from other children. They are not presented here, but the total number includes children with unknown smoking.

Low-risk population analyses

The main results remained unchanged in the low-risk populations excluding 1) teenage mothers, 2) preterm children, and 3) low-birth-weight children. These exclusions were done separately. Exposure to less than 10 cigarettes per day was associated with an increased use of any psychotropic medications (adjusted odds ratio (OR) = 1.36, 95% confidence interval (CI): 1.29, 1.43; OR = 1.36, 95% CI: 1.29, 1.44; and OR = 1.37, 95% CI: 1.30, 1.44, respectively). Exposure to more than 10 cigarettes per day was also associated with an increased use of any psychotropic medications (OR = 1.61, 95% CI: 1.51, 1.73; OR = 1.65, 95% CI: 1.54, 1.76; and OR = 1.63, 95% CI: 1.53, 1.74, respectively).

DISCUSSION

To our knowledge, this is the first report of the associations between maternal smoking during pregnancy and the cumulative use of psychotropic medications of the offspring into young adulthood. This approach of using pharmacy data, instead of hospital-based psychiatric morbidity (5), provided us a new target group (i.e., patients who used psychotropic medications but had no had psychiatric treatment in the hospital). This population treated with psychotropic medication in primary-care settings consisted mostly of patients using hypnotics/anxiolytics and antidepressants. Of those patients, 29%–44% were not included in hospital registers. In our study, exposure to smoking during pregnancy was associated with an increased medication use in all continuity categories and in both single- and multiple-drug consumption groups. This indicates that prenatal smoking exposure is linked to both mild and severe psychiatric problems.

Our study covered the cumulative use of psychotropic drugs during a 13-year period, ranging from 5–7 years to 18–20 years. Most studies of psychotropic drug use have a cross-sectional study design of 1 or more years covering children at all ages (7–9, 13). In our study, the incidence of psychotropic medication was cumulatively 8.9%. Studies using a cross-sectional approach yielded lower percentages ranging between 2.0% and 6.7% (13, 14). A cumulative approach provides a more comprehensive picture of the utilization pattern and, therefore, yields a higher percentage.

The profile of drug consumption differs between countries. In our study, antidepressants and hypnotics/anxiolytics were the most commonly used drugs (6.5% and 3.3%, respectively). There has been a shift in the drug consumption profile over time. Stimulants have risen to be the most used psychotropic medication instead of hypnotics/anxiolytics (9, 13).

Prenatal smoking exposure has been shown to increase the risk for different psychiatric problems (3, 5, 6, 15), although it has been linked mostly to attention and hyperactivity problems (5, 15, 16). Smoking exposure was associated with an increased use of all different psychotropic drug groups, but the use of stimulants was most strongly increased. In addition, the drug use was related to smoking exposure within all continuity categories. More intensive smoking exposure was also associated with increased multiple-drug use.

The possible etiologic pathways for the effect of prenatal smoking exposure on children's neurologic development have been suggested to be low birth weight and decreased in-utero brain growth (17, 18). The adverse effects of smoking on fetuses might be mediated by chronic fetal hypoxia (19) or directly by nicotine. In animal studies, prenatal nicotine exposure has been shown to have an independent damaging effect on brain development (20, 21). The effect of prenatal smoking exposure on brain development is not well determined in humans. Full-term infants exposed to smoking had smaller head circumferences compared with unexposed infants (22, 23). In addition, the frontal lobe and cerebellar volumes, important for normal cognitive development, were significantly smaller in prematurely born infants exposed to smoking compared with unexposed infants (24). Recent studies have suggested that children with specific gene polymorphisms might be more sensitive to smoking exposure and, therefore, more likely to develop later attention problems (25, 26). There might also be other gene-environmental interactions affecting the consequences of smoking exposure in an individual.

The strengths of our study included a 3-year national cohort of all singletons born without major congenital anomalies, covering a total of 94% of all children born in Finland. Our study had complete follow-up from year 1994 when the Drug Prescription Register at the Social Insurance Institution of Finland was founded until December 31, 2007, when the study cohort was 18–20 years of age. Therefore, we had cumulative data for a 13-year time period for all study subjects. This register comprises data on the date of distribution and the name of reimbursed prescription drugs. As drugs for psychiatric illness are reimbursable in Finland, we have information on virtually all psychotropic drugs. Therefore, self-medication with “over-the-counter” drugs is unlikely to interfere with the results. A further strength was a thorough adjustment of background factors, including mothers’ psychiatric illnesses requiring hospital care which covers part of the genetic predisposition for psychiatric illnesses such as severe mood disorders and psychoses.

The study does have some limitations. Self-reporting of maternal smoking during pregnancy is known to underestimate the true prevalence of smoking (27). We do not have information on mothers of this study who quit smoking before or during pregnancy. However, only 1 out of 10 smokers in Finland quit smoking during the first trimester in 1990 (28). Our data did not contain information on the dose or the indication for which drugs were prescribed. Although the drugs purchased are not necessarily used, it has been shown that there is sufficient agreement for research purposes between self-report of medication use and data on purchases for antipsychotics and antidepressants (29).

One of the limitations of our study was a lack of information on maternal socioeconomic status. Women who smoke during pregnancy are more often younger, single, and of lower socioeconomic status (23, 30). These women have a higher rate of unplanned pregnancies and, therefore, they might also use alcohol, psychiatric medications, and illicit drugs more often during pregnancy compared with women with planned pregnancies (31). We did separate analyses for low-risk populations (e.g., excluding young mothers), which showed that the associations also persisted in low-risk populations, suggesting direct effects of smoking exposure. To continue smoking in pregnancy might be due to strong nicotine addiction or personality characteristics, which might be a sign of genetic risks for psychiatric problems or which associate with poor parenting skills leading to psychiatric problems. Although the mothers’ earlier psychiatric hospital care was taken into account, we lack information on the mothers’ milder psychiatric problems not requiring hospital care and the mothers’ later psychiatric problems after the birth of the child. Therefore, this study was not adjusted for the use of psychotropic medication during pregnancy or psychiatric problems impairing parenting.

The households might also differ in substantial ways between smoking and nonsmoking pregnant women. Children might be exposed to environmental secondhand smoking during their first years of life, which has shown to have negative effects on the child's health (32, 33). Unfortunately, we did not have any information on household smoking habits after the birth of the child. Neither did we have any data on the fathers’ psychiatric profile. Because of strict confidentiality legislation, the Finnish Medical Birth Register has never been authorized to collect information on fathers. In addition, information on alcohol and illicit drug use was not available, even though smoking women and their spouses may have more substance use than nonsmokers do.

It would be important to investigate how to decrease maternal smoking during pregnancy. Wide variation in the prevalence of smoking during pregnancy between countries could yield information on preventive measures. In the future, it would be important to explore the factors in the social environment affecting smoking and child outcome more deeply. The gene-environment interactions should be studied between smoking exposure and different genomic alleles on psychiatric morbidity and use of psychotropic medication.

In conclusion, this study found a clear and significant association between prenatal smoking exposure and the use of psychotropic medication during childhood and adolescence. The results were robust over all drug groups and the amount of drugs used, and the association was found also in low-risk groups after excluding, for example, teenage mothers. In addition, a dose relation was found. This study emphasizes the importance of efforts to reduce smoking during pregnancy.

Abbreviations

    Abbreviations
  • ATC

    Anatomic Therapeutic Chemical [classification system]

  • CI

    confidence interval

  • ICD

    International Classification of Diseases

  • OR

    odds ratio

Author affiliations: Department of Pediatrics, Turku University Hospital and University of Turku, Turku, Finland (Mikael Ekblad, Liisa Lehtonen); National Institute for Health and Welfare, Helsinki, Finland (Mika Gissler); Nordic School of Public Health, Gothenburg, Sweden (Mika Gissler); Department of Psychiatry, University of Turku, Turku, Finland (Jyrki Korkeila); and Department of Psychiatry, Harjavalta Hospital, Satakunta Hospital District, Finland (Jyrki Korkeila).

This work was supported by the Turku University Hospital Research Foundation, the South-West Finnish Fund of Neonatal Research, the Finnish Foundation for Alcohol Studies, and the Society Duodecim, Turku.

Preliminary results were presented at the Pediatric Academic Societies’ Annual Meeting in Vancouver, Canada, on May 4, 2010.

The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of data; and preparation, review, or approval of the manuscript.

Conflict of interest: none declared.

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