This population-based cohort study was based on register data in a national research database, WomMed, financed by the US National Institute of Child Health and Human Development and located at the Centre for Primary Health Care Research, Lund University, Sweden. This database includes annual data from prenatal and birth records, hospital admissions and death records for each mother and child in Sweden. Information on date of delivery, birthweight and length, mode of delivery and maternal and fetal complications is transferred from hospital records, together with prenatal care data, to the Swedish Medical Birth Registry, which is the main register in the WomMed Database.
The WomMed Database also contains individual-level socio-demographic information, including age, marital status, socio-economic status indicators and country of origin, collected annually starting in 1990. For the current study, socio-demographic characteristics were identified using the Swedish Population and Housing Census of 1990, the most recent census when the participants in this study (who were then 11–17 years of age) were still likely to be residing in the same household as their mothers. This census information was used to identify maternal characteristics that would reflect the social conditions of these individuals during their upbringing, and which may be associated with subsequent mental health outcomes. Socio-economic deprivation is a well-established risk factor for premature birth. To the extent that low maternal socio-economic status may have resulted from having given birth to a child prematurely, adjustment for these characteristics would be expected to bias the results conservatively, towards the null hypothesis.
Information on psychotropic medication prescriptions was obtained using a national pharmacy register maintained by the National Board of Health and Welfare. These data were linked to the national Medical Birth Register using an anonymous, serial number version of each individual’s unique personal identification number. The national pharmacy register includes a record of each medication that is prescribed by a health-care provider and dispensed directly to a patient by any outpatient or inpatient pharmacy in Sweden. For inpatients, the register includes all medications prescribed and dispensed to a patient upon discharge from the hospital, but not medications directly administered to a patient during the hospital course prior to discharge. The unavailability of data for medications administered during a hospital course is non-differential with respect to preterm birth status and would also be expected to bias the results towards the null hypothesis.
All pharmacy data are categorized according to the Anatomical Therapeutic Chemical (ATC) Classification System developed by the WHO Collaborating Centre for Drug Statistics Methodology. We obtained information on medication prescriptions for conditions of the nervous system (code N), which were further sub-classified as antipsychotics (N05A), anxiolytics (N05B), hypnotics/sedatives (N05C), antidepressants (N06A) and psychostimulants (N06B).
A total of 699
650 women and men, born 1973 through 1979, were identified in the Swedish Medical Birth Registry. For each individual, we identified the gestational age at birth based on maternal report of last menstrual period. An anonymous, serial-number version of the personal identification number of the mother (similar to the US social security number) was used to link mothers to offspring and to determine maternal age at the time of each individual’s birth. A total of 11
695 (1.7%) individuals died prior to 2005 (when the national pharmacy register was started) and were excluded from the current analysis. Approximately half of these deaths occurred within the first year of life. Of the remaining individuals, we excluded 39
106 (5.6%) who had moved away from Sweden prior to 2005, 573 (0.1%) who had missing information on gestational age at birth and 7995 (1.2%) who had significant congenital anomalies (i.e. other than undescended testicle, preauricular appendage, congenital nevus or hip dislocation). In order to remove possible coding errors, 4342 (0.6%) individuals were excluded who had a birthweight >3 standard deviation (SD) above the mean or <6
SD below the mean for gestational age and sex, and 6 (<0.01%) were excluded who had a reported gestational age <23 weeks. A total of 635
933 individuals (90.9% of the original cohort) remained for inclusion in the analysis.
All study participants, born 1973 through 1979, were followed up for prescription of psychotropic medications from 1 July 2005 through 31 December 2006, the first 1.5 years that the national pharmacy register was kept. These individuals were between 25.5 and 34.0 years of age during the period of follow-up.
Infant’s gestational age at birth. This variable was categorized as 23–27, 28–32, 33–34, 35–36, 37–42 (full term) and ≥43 weeks. Near-term births were stratified into finer categories (33–34 and 35–36 weeks) in order to provide more detail for this range in which there may be discretion by the physician on the timing of delivery.
Infant’s date of birth. Infant’s date of birth was modelled as a continuous variable. We adjusted for this to control for differences by age and for changes in prenatal or neonatal care that may have occurred during the study period.
Infant’s gender. Maternal age at birth of child. Modelled as a continuous variable.
Maternal immigration status. ‘Born in Sweden’, ‘immigrated from Finland’ or ‘immigrated from another country’.
Maternal marital status in 1990. ‘Married/cohabiting’, ‘never married’, ‘divorced’ or ‘widowed’.
Maternal occupation in 1990. ‘Unskilled worker’, ‘skilled worker’, ‘professional’, ‘white collar’, ‘other occupations’ or ‘unknown’.
Maternal income in 1990. Calculated as the mother’s annual family income divided by the number of people in the family, or family income per capita, using a weighted system whereby small children are given lower weights than adolescents and adults. The final variable was categorized in quartiles.
Maternal education in 1990. ‘Compulsory high school or less (≤9 years)’, ‘practical high school or some theoretical high school (10–11 years)’ or ‘theoretical high school and/or college (≥12 years)’.
Paternal education in 1990. ‘Compulsory high school or less (≤9 years)’, ‘practical high school or some theoretical high school (10–11 years)’ or ‘theoretical high school and/or college (≥12 years)’.
Maternal region of residence in 1990. ‘Large city’, ‘medium city’ or ‘small city or rural area’. We adjusted for this variable because it may be associated with access to prenatal care, and to psychiatric care in young adulthood.
Maternal time lived at current residence as of 1990. Dichotomized to <5 years or ≥5 years.
Maternal prescription of psychotropic medications. We adjusted for whether the mothers of the study participants were prescribed psychotropic medications (antipsychotics, antidepressants, anxiolytics, hypnotics/sedatives and/or psychostimulants) during the follow-up period (1 July 2005 through 31 December 2006). Each of these medication groups was entered into the model separately and dichotomized to ‘no prescriptions’ or ‘one or more prescriptions’.
Maternal hospitalization for mental disorders. We adjusted for whether the mothers of the study participants were ever hospitalized for a mental disorder (ICD-9 codes 290–319, ICD-10 codes F00–F99 or the equivalent coding in earlier ICD versions) from 1 January 1964 through 31 December 2006, dichotomized to ‘never’ or ‘ever’ hospitalized for a mental disorder.
The outcome of interest was one or more prescriptions of a psychotropic medication dispensed at any outpatient or inpatient pharmacy in Sweden during the follow-up period (1 July 2005 through 31 December 2006). This outcome was evaluated separately for each of the following medication groups: antipsychotics, antidepressants, anxiolytics, hypnotics/sedatives and psychostimulants. In addition, we evaluated the outcome of one or more prescriptions in ‘any of the above’ medication groups.
We also evaluated oral contraceptive prescription as a ‘control medication’. Oral contraceptive use in young adulthood would not a priori be expected to be associated with preterm birth status. If an association were found between preterm birth and psychotropic medications in young adulthood, and not between preterm birth and oral contraceptive use in young adulthood, the association with psychotropic medications would be less likely to be due to an artifact in the data or diagnostic bias among individuals who were born preterm. Oral contraceptive prescription was dichotomized as ‘never’ or ‘ever’ during the same follow-up period as above.
Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between gestational age at birth (categorized as 23–27, 28–32, 33–34, 35–36, 37–42, ≥43 weeks) and prescription of psychotropic medication (one or more vs none) in young adulthood (ages 25.5–34.0 years), using full-term birth (37–42 weeks) as the reference category. Analyses were conducted unadjusted, and then were adjusted for infant and maternal characteristics that are potential confounders (infant date of birth, infant gender, maternal age at the birth of the child, maternal immigration status, maternal marital status, maternal occupation, maternal income, maternal education, paternal education, maternal region of residence, maternal time lived at current residence, maternal prescription of psychotropic medications during the follow-up period, and maternal hospitalization for a mental disorder from 1964 through 2006). We explored for interaction effects between gestational age at birth and each of these infant and maternal characteristics with respect to prescription of psychotropic medication in young adulthood, using a likelihood ratio test to evaluate for statistical significance. All analyses were conducted using Stata statistical software, version 9.1.20