Obstetric Risk Factors and Autism Spectrum Disorders in Finland P€aivi Polo-Kantola, MD, PhD1,2, Katja M. Lampi, MSc3, Susanna Hinkka-Yli-Salom€aki, PhLic3, Mika Gissler, MSocSc, PhD4,5, Alan S. Brown, MD, MPH6,7, and Andre Sourander, MD, PhD3,8 Objective To examine the relationship between obstetric risk factors and childhood autism, Asperger syndrome, and other pervasive developmental disorders (PDDs).
Study design Registry-based case-control study from all singleton births in Finland from 1990-2005. Cases with childhood autism, Asperger syndrome, or PDD (n = 4713) were identified from the Finnish Hospital Discharge Register. Each case was matched to 4 controls on sex, date of birth, and place of birth. Information on obstetric risk factors was from the Finnish Medical Birth Register. Conditional logistic regression models were used for statistical analyses. Results When adjusted with confounders, childhood autism was associated with maternal high blood pressure (OR 1.49, 95% CI 1.1-2.1, P = .018), Apgar scores less than 7 (1 minute, OR 1.46, 95% CI 1.1-2.0, P = .021), and neonatal treatment with monitoring (OR 1.40, 95% CI 1.02-1.9, P = .038). PDD was associated with induced labor (OR 1.25 95% CI 1.1-1.5, P = .007), planned cesarean delivery (OR 1.34, 95% CI 1.1-1.7, P = .009), 1-minute Apgar scores 7-8 ( OR 1.22, 95% CI 1.1-1.4, P = .008) and less than 7 (OR 1.34, 95% CI 1.03-1.8, P = .032), and neonatal intensive care unit treatment (OR 1.52, 95% CI 1.2-2.0, P = .003). Asperger syndrome was associated only with 1-minute Apgar scores 7-8 (OR 1.19, 95% CI 1.03-1.4, P = .018). Conclusions Low Apgar scores as well as conditions requiring neonatal special follow-up are important risk factors for childhood autism and PDD. These findings suggest that fetal distress is a potential risk factor for these disorders, but not for Asperger syndrome. (J Pediatr 2014;164:358-65).
A
utism spectrum disorders (ASDs) represent a group of neuropsychiatric syndromes, which are characterized by qualitative abnormalities in reciprocal social interactions, in language and patterns of communication, and by a restrictive, stereotyped, repetitive repertoire of interests and activities. Based on the International Classification of Diseases-10th Revision (ICD-10), specific diagnostic criteria for childhood autism include all these symptoms and onset before the age of 3 years. Major cognitive problems or intellectual disability occur commonly in childhood autism.1 The main difference between Asperger syndrome and childhood autism is the absence of marked delay in early language development and cognitive functioning; intellectual capacity is expected to be age-appropriate in Asperger syndrome.2 Thus, Asperger syndrome can be considered as a milder variant of autism, although deficits in pragmatic language and social interaction are often present. Other pervasive developmental disorders (PDDs) are the least well defined subtypes. Children with a diagnosis of PDD typically have several developmental delays in learning, communication, and socialization skills, although the phenotype displays significant variation between cases. The diagnosis of PDD is often used when a child does not meet all criteria for childhood autism or Asperger syndrome. ASD has been shown to be heritable,3-5 but evidence points to a role of From the Department of Obstetrics and Gynecology, environmental factors.6 Several adverse events in the pre-, peri-, and neonatal University of Turku, Turku, Finland; Department of Obstetrics and Gynecology, Turku University Hospital, periods have been associated with increased risk of childhood autism or the Turku, Finland; Department of Child Psychiatry, broader phenotype of ASD. In general, current research suggests that obstetric University of Turku, Turku, Finland; National Institute of Health and Welfare (THL), Helsinki, Finland; Nordic risk factors occur more in ASD compared with unaffected siblings or matched School of Public Health, Gothenburg, Sweden; Department of Psychiatry, New York State Psychiatric controls.7-9 Uterine bleeding10,11 and threatened abortion7 have been associated Institute, College of Physicians and Surgeons of with ASD, although the findings are inconsistent.12 Some studies found an Columbia University, New York, NY; Department of 1
2
3
4
5
6
7
ASD FHDR FIPS-A FMBR ICD-9 ICD-10 NICU PAR PDD SES SGA
Autism spectrum disorder Finnish Hospital Discharge Register Finnish Prenatal Study of Autism Finnish Medical Birth Register International Classification of Diseases-9th Revision International Classification of Diseases-10th Revision Neonatal intensive care unit Population attributable risk Pervasive developmental disorder Socioeconomic status Small for gestational age
Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; and 8Department of Child Psychiatry, Turku University Hospital, Turku, Finland Supported by National Institute of Environmental Health Sciences (NIEHS) (1R01ES019004), Autism Speaks, National Institute of Mental Health (NIMH) (1K02MH65422), Emil Aaltonen Foundation (Finland), Sigrid Juselius Foundation (Finland), and Foundation for Pediatric Research (Finland). A.B. received the following funding, which do not conflict with the current study: National Institutes of Health (NIH)/NIEHS (1R01ES019004-01 [PI: A.B.]) and NIH/NIMH (R01 MH073080 [PI: A.B.], 1P50MH090966-01, and 2 K02 MH065422-06). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.09.044
358
Vol. 164, No. 2 February 2014 association between ASD and maternal hypertension or preeclampsia,10,11,13,14 but this has not been verified (eg, in an Australian population-based study7). Breech presentation12,15 and cesarean delivery7,10,12 have also been associated with ASD, although in a large study by Bilder et al,12 the significance of cesarean delivery for ASD was lost after controlling for breech presentation. Further, low Apgar scores7,10,15,16 have been related to ASD, although not all studies support this.12 In studies from Denmark17 and the US,18 an association has been found between neonatal intensive care unit (NICU) treatment after birth and autism, but a study from Australia did not support the finding.7 Previous population-based studies examining obstetric risk factors have usually included only cases with childhood autism or have used a broader definition of ASD. There are very few studies that have examined obstetric risk factors specifically for Asperger syndrome or PDD. An exception is a Swedish study,19 which found an association between postnatal hypoxia and Asperger syndrome. However, another Swedish study2 based on careful diagnostic interviews and a population-based study from Australia7 showed no association between obstetric risk factors and Asperger syndrome. The Australian study, which was one of the few studies examining the relationship between obstetric risk factors and PDD, showed that PDD was associated with threatened abortion, induced labor, cephalopelvic disproportion, and cesarean delivery.7 The aim of this study was to examine associations between obstetric risk factors and the 3 main subtypes of ASD separately: childhood autism, Asperger syndrome, and PDD. Although we acknowledge that in the Diagnostic and Statistical Manual of Mental Disorders-5, all ASDs will be subsumed under 1 category, at present there remain separate diagnostic criteria for subtypes based on the ICD-10, which was used in this study. Moreover, regardless of current diagnostic categories, ASD as a group encompasses significant phenotypic heterogeneity, which is believed to stem from substantial etiologic heterogeneity. Observing differences in obstetric risk factors between ASD subtypes may suggest that these factors are specific to certain subtypes or severity of ASD. Based on previous research findings, our hypothesis was that obstetric risk factors are associated with the most severe form of ASD (ie, childhood autism as well as with PDD), the more heterogeneous phenotype of ASD. However, according to previous studies,2,7 we expected that Asperger syndrome, which is considered a milder form of ASD, would show weaker or no association with obstetric risk factors. These hypotheses are also supported by our previous findings showing that very low gestational age, low birth weight, and being small for gestational age (SGA) were associated with childhood autism and PDD, but not with Asperger syndrome.20
Methods Subject ascertainment was based on a large, ongoing epidemiologic study of autism and ASDs in Finland (the Finnish Prenatal Study of Autism [FIPS-A]). In this study, cases consisted of all
infants born in Finland between 1990 and 2005 and who were diagnosed with ASD by December 31, 2007. They were identified from the Finnish Hospital Discharge Register (FHDR) using the current International Classification of Diseases-criteria. Diagnostic codes 299x (International Classification of Diseases9th Revision [ICD-9]) and F84.x (F = mental and behavioral disorders, ICD-10) were used, and a total of 5018 ASD cases were found. The majority of the cases were diagnosed according to the ICD-10, and only 19 cases (0.4%) were diagnosed according to the ICD-9. Of all ASD cases, 94% belonged to 1 of the 3 subtypes: childhood autism (n = 1036), Asperger syndrome (n = 1466), and other PDDs/PDD-unspecified (n = 1602). In this study, both diagnoses of other PDDs (other PDD or PDD-unspecified) are referred as PDD. The association between obstetric risk factors and these 3 main subtypes of ASD was examined, excluding the less common ASD subtypes, such as Rett syndrome or childhood disintegrative disorder. Controls were selected from the remainder of the national birth cohort. They were residents of Finland at the time of case diagnosis, were born during the study years, and did not have ASD or severe/profound intellectual disability. Excluding these forms of intellectual disability was justified by considerable diagnostic overlap with childhood autism. Each case was individually matched to 4 controls on sex, date of birth, place of birth, and residence in Finland. A full description of the study design of the FIPS-A has been published previously.21 The study was authorized by the Ministry of Social Affairs and Health in Finland (STM/2593/2008) with the approval from the ethics committee of the hospital district of Southwest Finland and the National Institute for Health and Welfare, and approved by the Institutional Review Board of the New York State Psychiatric Institute. National Registry Information This study was based on data from 2 nationwide registries: the FHDR and the Finnish Medical Birth Register (FMBR). The FHDR covers all somatic and psychiatric hospitals, inpatient wards of local health centers, military wards, prison hospitals, and private hospitals. Since 1998, the FHDR has covered all outpatient care in public hospitals. All medical diagnoses from 1969 to the present were available in the FHDR. In Finland, diagnostic classification based on the ICD-10 has been used since 1996. The registration routines are standardized across Finland. In this study, the most recent registry diagnosis was used for diagnostic classification. The Finnish public health care system includes primary health care as well as district, central, and university hospitals. Primary health care physicians are gatekeepers for referral to the more specialized services where the diagnostic assessment is led by a child neurologist or child psychiatrist. The FMBR was established in 1987 and includes comprehensive data on all live births and stillbirths (from 22 gestational weeks and/or 500 g) and the neonatal period up to the age of 7 days of all births in Finland. The linkage between registries was done using a unique personal identity code assigned to all residents in Finland. The Finnish personal identity code is issued 359
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www.jpeds.com
to all Finnish citizens and permanent residents at birth or at migration. A full description of all national registries used in the FIPS-A has been published previously.21 Obstetric Risk Factors Information on all obstetric risk factors was from the FMBR. In this study, they were classified as maternal factors, birth factors, and neonatal factors. Maternal factors included high blood pressure or uterine bleeding that required hospitalization, both of which were classified as binary variables (yes/no). In Finland, during pregnancy, blood pressure higher than 140/90 is considered as high. In the present study, maternal high blood pressure included both pre-eclampsia and pregnancy induced hypertension. Birth factors included birth presentation, birth type, induction of labor (yes/no), and Apgar scores. Birth presentation was classified into 3 categories: cephalic, breech (including lower limb), or other (eg, transverse, oblique, or upper limb). Birth type was classified into 5 categories: vaginal cephalic, vaginal breech, vacuum extractor or forceps, planned cesarean delivery, or other cesarean delivery, including urgent and emergency. Apgar scores were measured at 1 minute and classified as 9-10, 7-8, or less than 7. Neonatal factors included neonatal treatment, which was classified into 3 categories: normal follow-up, monitoring in maternal postpartum department (monitoring), or intensive care of the infant at the NICU treatment. Confounding Factors Four potential maternal confounding factors that have been associated with both ASD and obstetric risk factors were included in the analyses: maternal age,7,22 maternal smoking during pregnancy,10,23 number of previous births,24,25 and maternal psychiatric history.15,26 Maternal age was classified in the following categories: less than 20, 20-24, 25-29, 30-34, 35-39, and 40 years or more. Maternal smoking was classified as a binary variable (yes/no). Number of previous births was categorized as 0, 1, 2, 3, or 4 or more. A mother was classified as having a psychiatric history (yes/no) if she had any of the following diagnoses recorded in the FHDR during her lifetime: F10-F99 (excluding F70-79) based on the ICD-10, 291-316 (excluding 293-294) based on the ICD-9, and 291-309 based on the International Classification of Diseases-Eighth Revision. These diagnoses included mental and behavioral disorders because of psychoactive substance use, schizophrenia, schizotypal and delusional disorders, mood disorders, neurotic, stress-related and somatoform disorders, behavioral syndromes associated with physiological disturbances and physical factors, disorders of adult personality and behavior, disorders of psychological development, behavioral and emotional disorders with onset usually occurring in childhood and adolescence, and unspecified mental disorder. Data on maternal age, smoking during pregnancy, number of previous births, birth weight, and gestational age were available in the FMBR, whereas data on maternal psychiatric diagnoses were obtained from the FHDR. 360
Vol. 164, No. 2 Statistical Analyses Conditional logistic regression models were used to examine the associations between the ASD outcome and obstetric risk factors. Unadjusted OR and 95% CI were first calculated for each ASD subtype. In the adjusted model, all previously presented possible confounders (maternal age, smoking during pregnancy, number of previous births, and maternal psychiatric history) were included in the analysis. Based on the results of the adjusted model, obstetric risk factors and possible confounders with statistically significant associations at the level of P < .1 were entered into the final model. There were 3 different final models, 1 for each ASD subtype. In the final multivariate analyses, a 2-sided P value of
Study design Registry-based case-control study from all singleton births in Finland from 1990-2005. Cases with childhood autism, Asperger syndrome, or PDD (n = 4713) were identified from the Finnish Hospital Discharge Register. Each case was matched to 4 controls on sex, date of birth, and place of birth. Information on obstetric risk factors was from the Finnish Medical Birth Register. Conditional logistic regression models were used for statistical analyses. Results When adjusted with confounders, childhood autism was associated with maternal high blood pressure (OR 1.49, 95% CI 1.1-2.1, P = .018), Apgar scores less than 7 (1 minute, OR 1.46, 95% CI 1.1-2.0, P = .021), and neonatal treatment with monitoring (OR 1.40, 95% CI 1.02-1.9, P = .038). PDD was associated with induced labor (OR 1.25 95% CI 1.1-1.5, P = .007), planned cesarean delivery (OR 1.34, 95% CI 1.1-1.7, P = .009), 1-minute Apgar scores 7-8 ( OR 1.22, 95% CI 1.1-1.4, P = .008) and less than 7 (OR 1.34, 95% CI 1.03-1.8, P = .032), and neonatal intensive care unit treatment (OR 1.52, 95% CI 1.2-2.0, P = .003). Asperger syndrome was associated only with 1-minute Apgar scores 7-8 (OR 1.19, 95% CI 1.03-1.4, P = .018). Conclusions Low Apgar scores as well as conditions requiring neonatal special follow-up are important risk factors for childhood autism and PDD. These findings suggest that fetal distress is a potential risk factor for these disorders, but not for Asperger syndrome. (J Pediatr 2014;164:358-65).
A
utism spectrum disorders (ASDs) represent a group of neuropsychiatric syndromes, which are characterized by qualitative abnormalities in reciprocal social interactions, in language and patterns of communication, and by a restrictive, stereotyped, repetitive repertoire of interests and activities. Based on the International Classification of Diseases-10th Revision (ICD-10), specific diagnostic criteria for childhood autism include all these symptoms and onset before the age of 3 years. Major cognitive problems or intellectual disability occur commonly in childhood autism.1 The main difference between Asperger syndrome and childhood autism is the absence of marked delay in early language development and cognitive functioning; intellectual capacity is expected to be age-appropriate in Asperger syndrome.2 Thus, Asperger syndrome can be considered as a milder variant of autism, although deficits in pragmatic language and social interaction are often present. Other pervasive developmental disorders (PDDs) are the least well defined subtypes. Children with a diagnosis of PDD typically have several developmental delays in learning, communication, and socialization skills, although the phenotype displays significant variation between cases. The diagnosis of PDD is often used when a child does not meet all criteria for childhood autism or Asperger syndrome. ASD has been shown to be heritable,3-5 but evidence points to a role of From the Department of Obstetrics and Gynecology, environmental factors.6 Several adverse events in the pre-, peri-, and neonatal University of Turku, Turku, Finland; Department of Obstetrics and Gynecology, Turku University Hospital, periods have been associated with increased risk of childhood autism or the Turku, Finland; Department of Child Psychiatry, broader phenotype of ASD. In general, current research suggests that obstetric University of Turku, Turku, Finland; National Institute of Health and Welfare (THL), Helsinki, Finland; Nordic risk factors occur more in ASD compared with unaffected siblings or matched School of Public Health, Gothenburg, Sweden; Department of Psychiatry, New York State Psychiatric controls.7-9 Uterine bleeding10,11 and threatened abortion7 have been associated Institute, College of Physicians and Surgeons of with ASD, although the findings are inconsistent.12 Some studies found an Columbia University, New York, NY; Department of 1
2
3
4
5
6
7
ASD FHDR FIPS-A FMBR ICD-9 ICD-10 NICU PAR PDD SES SGA
Autism spectrum disorder Finnish Hospital Discharge Register Finnish Prenatal Study of Autism Finnish Medical Birth Register International Classification of Diseases-9th Revision International Classification of Diseases-10th Revision Neonatal intensive care unit Population attributable risk Pervasive developmental disorder Socioeconomic status Small for gestational age
Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; and 8Department of Child Psychiatry, Turku University Hospital, Turku, Finland Supported by National Institute of Environmental Health Sciences (NIEHS) (1R01ES019004), Autism Speaks, National Institute of Mental Health (NIMH) (1K02MH65422), Emil Aaltonen Foundation (Finland), Sigrid Juselius Foundation (Finland), and Foundation for Pediatric Research (Finland). A.B. received the following funding, which do not conflict with the current study: National Institutes of Health (NIH)/NIEHS (1R01ES019004-01 [PI: A.B.]) and NIH/NIMH (R01 MH073080 [PI: A.B.], 1P50MH090966-01, and 2 K02 MH065422-06). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.09.044
358
Vol. 164, No. 2 February 2014 association between ASD and maternal hypertension or preeclampsia,10,11,13,14 but this has not been verified (eg, in an Australian population-based study7). Breech presentation12,15 and cesarean delivery7,10,12 have also been associated with ASD, although in a large study by Bilder et al,12 the significance of cesarean delivery for ASD was lost after controlling for breech presentation. Further, low Apgar scores7,10,15,16 have been related to ASD, although not all studies support this.12 In studies from Denmark17 and the US,18 an association has been found between neonatal intensive care unit (NICU) treatment after birth and autism, but a study from Australia did not support the finding.7 Previous population-based studies examining obstetric risk factors have usually included only cases with childhood autism or have used a broader definition of ASD. There are very few studies that have examined obstetric risk factors specifically for Asperger syndrome or PDD. An exception is a Swedish study,19 which found an association between postnatal hypoxia and Asperger syndrome. However, another Swedish study2 based on careful diagnostic interviews and a population-based study from Australia7 showed no association between obstetric risk factors and Asperger syndrome. The Australian study, which was one of the few studies examining the relationship between obstetric risk factors and PDD, showed that PDD was associated with threatened abortion, induced labor, cephalopelvic disproportion, and cesarean delivery.7 The aim of this study was to examine associations between obstetric risk factors and the 3 main subtypes of ASD separately: childhood autism, Asperger syndrome, and PDD. Although we acknowledge that in the Diagnostic and Statistical Manual of Mental Disorders-5, all ASDs will be subsumed under 1 category, at present there remain separate diagnostic criteria for subtypes based on the ICD-10, which was used in this study. Moreover, regardless of current diagnostic categories, ASD as a group encompasses significant phenotypic heterogeneity, which is believed to stem from substantial etiologic heterogeneity. Observing differences in obstetric risk factors between ASD subtypes may suggest that these factors are specific to certain subtypes or severity of ASD. Based on previous research findings, our hypothesis was that obstetric risk factors are associated with the most severe form of ASD (ie, childhood autism as well as with PDD), the more heterogeneous phenotype of ASD. However, according to previous studies,2,7 we expected that Asperger syndrome, which is considered a milder form of ASD, would show weaker or no association with obstetric risk factors. These hypotheses are also supported by our previous findings showing that very low gestational age, low birth weight, and being small for gestational age (SGA) were associated with childhood autism and PDD, but not with Asperger syndrome.20
Methods Subject ascertainment was based on a large, ongoing epidemiologic study of autism and ASDs in Finland (the Finnish Prenatal Study of Autism [FIPS-A]). In this study, cases consisted of all
infants born in Finland between 1990 and 2005 and who were diagnosed with ASD by December 31, 2007. They were identified from the Finnish Hospital Discharge Register (FHDR) using the current International Classification of Diseases-criteria. Diagnostic codes 299x (International Classification of Diseases9th Revision [ICD-9]) and F84.x (F = mental and behavioral disorders, ICD-10) were used, and a total of 5018 ASD cases were found. The majority of the cases were diagnosed according to the ICD-10, and only 19 cases (0.4%) were diagnosed according to the ICD-9. Of all ASD cases, 94% belonged to 1 of the 3 subtypes: childhood autism (n = 1036), Asperger syndrome (n = 1466), and other PDDs/PDD-unspecified (n = 1602). In this study, both diagnoses of other PDDs (other PDD or PDD-unspecified) are referred as PDD. The association between obstetric risk factors and these 3 main subtypes of ASD was examined, excluding the less common ASD subtypes, such as Rett syndrome or childhood disintegrative disorder. Controls were selected from the remainder of the national birth cohort. They were residents of Finland at the time of case diagnosis, were born during the study years, and did not have ASD or severe/profound intellectual disability. Excluding these forms of intellectual disability was justified by considerable diagnostic overlap with childhood autism. Each case was individually matched to 4 controls on sex, date of birth, place of birth, and residence in Finland. A full description of the study design of the FIPS-A has been published previously.21 The study was authorized by the Ministry of Social Affairs and Health in Finland (STM/2593/2008) with the approval from the ethics committee of the hospital district of Southwest Finland and the National Institute for Health and Welfare, and approved by the Institutional Review Board of the New York State Psychiatric Institute. National Registry Information This study was based on data from 2 nationwide registries: the FHDR and the Finnish Medical Birth Register (FMBR). The FHDR covers all somatic and psychiatric hospitals, inpatient wards of local health centers, military wards, prison hospitals, and private hospitals. Since 1998, the FHDR has covered all outpatient care in public hospitals. All medical diagnoses from 1969 to the present were available in the FHDR. In Finland, diagnostic classification based on the ICD-10 has been used since 1996. The registration routines are standardized across Finland. In this study, the most recent registry diagnosis was used for diagnostic classification. The Finnish public health care system includes primary health care as well as district, central, and university hospitals. Primary health care physicians are gatekeepers for referral to the more specialized services where the diagnostic assessment is led by a child neurologist or child psychiatrist. The FMBR was established in 1987 and includes comprehensive data on all live births and stillbirths (from 22 gestational weeks and/or 500 g) and the neonatal period up to the age of 7 days of all births in Finland. The linkage between registries was done using a unique personal identity code assigned to all residents in Finland. The Finnish personal identity code is issued 359
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www.jpeds.com
to all Finnish citizens and permanent residents at birth or at migration. A full description of all national registries used in the FIPS-A has been published previously.21 Obstetric Risk Factors Information on all obstetric risk factors was from the FMBR. In this study, they were classified as maternal factors, birth factors, and neonatal factors. Maternal factors included high blood pressure or uterine bleeding that required hospitalization, both of which were classified as binary variables (yes/no). In Finland, during pregnancy, blood pressure higher than 140/90 is considered as high. In the present study, maternal high blood pressure included both pre-eclampsia and pregnancy induced hypertension. Birth factors included birth presentation, birth type, induction of labor (yes/no), and Apgar scores. Birth presentation was classified into 3 categories: cephalic, breech (including lower limb), or other (eg, transverse, oblique, or upper limb). Birth type was classified into 5 categories: vaginal cephalic, vaginal breech, vacuum extractor or forceps, planned cesarean delivery, or other cesarean delivery, including urgent and emergency. Apgar scores were measured at 1 minute and classified as 9-10, 7-8, or less than 7. Neonatal factors included neonatal treatment, which was classified into 3 categories: normal follow-up, monitoring in maternal postpartum department (monitoring), or intensive care of the infant at the NICU treatment. Confounding Factors Four potential maternal confounding factors that have been associated with both ASD and obstetric risk factors were included in the analyses: maternal age,7,22 maternal smoking during pregnancy,10,23 number of previous births,24,25 and maternal psychiatric history.15,26 Maternal age was classified in the following categories: less than 20, 20-24, 25-29, 30-34, 35-39, and 40 years or more. Maternal smoking was classified as a binary variable (yes/no). Number of previous births was categorized as 0, 1, 2, 3, or 4 or more. A mother was classified as having a psychiatric history (yes/no) if she had any of the following diagnoses recorded in the FHDR during her lifetime: F10-F99 (excluding F70-79) based on the ICD-10, 291-316 (excluding 293-294) based on the ICD-9, and 291-309 based on the International Classification of Diseases-Eighth Revision. These diagnoses included mental and behavioral disorders because of psychoactive substance use, schizophrenia, schizotypal and delusional disorders, mood disorders, neurotic, stress-related and somatoform disorders, behavioral syndromes associated with physiological disturbances and physical factors, disorders of adult personality and behavior, disorders of psychological development, behavioral and emotional disorders with onset usually occurring in childhood and adolescence, and unspecified mental disorder. Data on maternal age, smoking during pregnancy, number of previous births, birth weight, and gestational age were available in the FMBR, whereas data on maternal psychiatric diagnoses were obtained from the FHDR. 360
Vol. 164, No. 2 Statistical Analyses Conditional logistic regression models were used to examine the associations between the ASD outcome and obstetric risk factors. Unadjusted OR and 95% CI were first calculated for each ASD subtype. In the adjusted model, all previously presented possible confounders (maternal age, smoking during pregnancy, number of previous births, and maternal psychiatric history) were included in the analysis. Based on the results of the adjusted model, obstetric risk factors and possible confounders with statistically significant associations at the level of P < .1 were entered into the final model. There were 3 different final models, 1 for each ASD subtype. In the final multivariate analyses, a 2-sided P value of
