Autism Spectrum Disorders in IVF Children
Autism Spectrum Disorders in IVF Children
The study is part of the Finnish Prenatal Study of Autism, which is a nested case–control study based on a national birth cohort, and aims to identify pregnancy, infancy and childhoood risk factors for ASDs. An overview of the study has been presented previously Lampi et al., 2011). The study was authorized by the Ministry of Social Affairs and Health of Finland with approvals from the National Institute for Health and Welfare (THL), the Ethics Committee of the Intermunicipal Hospital District of Southwest Finland, and the Institutional Review Board of the New York State Psychiatric Institute. No informed consent was required for this study. To assess the association between IVF and ASDs, we conducted a linkage between two national registers for 4164 autistic cases and their 16 582 matched controls born in 1991–2005. There were 111 cases and 436 controls, which were twins. There were originally five cases (0.1% of all cases) born from triplet pregnancies but they were excluded from this study because it would have been difficult to find matched controls. Of all the children born in Finland during the same period 0.09% were born from pregnancies with more than two fetuses (National Institute for Health and Welfare, 2012).
The data on IVF were collected from the Finnish Medical Birth Register (FMBR), which is a national register maintained by THL. Information was collected on maternal background, pregnancy, delivery and early outcomes of the newborn for all births in Finland. The register includes all mother's and child's personal identification numbers, which can be linked to one another. The FMBR commenced in 1987, and data on fertilization treatment has been collected since October 1990. In 1990–1995, IVF was denoted by the item 'assisted reproduction,' including IVF with or without ICSI or FET. In 1996, two items, 'in vitro fertilization' and 'other assisted reproduction' were introduced. A validation study Gissler et al., 2004), however, showed that the latter category also included mostly IVF children, and that the two categories could not be separated. Hence, in the current study the two items were combined. In 2004, the terminology was revised again, and the treatments, which include IVF, could be clearly differentiated from the others. By merging the items from all three time periods, we obtained one variable referring to IVF treatments. Different subtypes of IVF, however, could not be specified.
Children born in 1991–2005 and diagnosed with ASDs by the year 2007 were identified from the Finnish Hospital Discharge Register (FHDR), another nationwide register maintained by THL. The FHDR includes the personal identification numbers and covers the diagnoses and the days of admission and discharge in all public and private inpatient care units in Finland. The diagnoses are based on the International Classification of Diseases and Related Health Problems (ICD). All diagnostic codes indicating an ASD were collected according to the ICD-9 in 1991–1995 and ICD-10 in 1996–2007. The most recent registry diagnosis was used. The diagnostic categories included in this study were, first, the whole group of ASDs (F84) and, secondly, three of its subcategories: childhood autism (F84.0), Asperger's syndrome (F84.5) and other pervasive developmental disorder (PDD) and PDD, not otherwise specified (PDD NOS) (F84.8 and F84.9). A validation study Lampi et al., 2010) has shown that the validity of childhood autism diagnosis in the FHDR is very good: when a re-assessment using Autism Diagnostic Interview-Revised was made, 96% of the cases with registry diagnoses of childhood autism met the diagnostic criteria.
Four controls selected from the FMBR were matched to each case. For singletons the matching criteria were date of birth (± 30 days), place of birth, sex and residency in Finland. For twins the matching criteria were date of birth (±6 months but for eight controls the range ±11 months had to be used), region of birth, sex and birth order within a twin pair. No data for whether twins were mono- or dizygotic were available for analysis because this information is not included in the FMBR. The exclusion criteria for controls were ASDs or severe/profound mental retardation according to the FHDR, and eight controls were excluded for this reason. In addition, for 66 controls the personal identification number of the mother or the child was incorrect or incomplete. Altogether 74 controls were removed from the database, which led to 16 582 controls.
An additional analysis was conducted in which stratification by intellectual disability was performed. For this purpose, information on diagnoses indicating intellectual disability (F70-79 in ICD-10 and 317–319 in ICD-9) was collected from the FMBR.
Prior to adjustment, bivariate analyses had been conducted to test the significance of association between covariates and IVF among controls as well as between covariates and ASDs (Table I). Maternal age, mother's socioeconomic status (SES), gestational age and parity were all significantly associated with both the exposure and outcome. The data on these covariates were collected from the FMBR. All variables were defined categorically. When studying maternal age at birth, age 20–34 years was used as a reference. For mother's SES, upper white collar workers were used as a reference and the comparison was made with lower white collar workers, blue collar workers and others, which includes entrepreneurs and people outside the labor force, such as students, housewives and unemployed people. The measure of SES follows the national classifications on occupations and socioeconomic groups (Statistics Finland, 1987; Statistics Finland, 1989), and it was primarily based on occupational status, even though educational level was also considered for white collar workers. For gestational age, the category 38–41 weeks was used as a reference. For parity, the reference category was no previous births.
Associations between IVF and different ASDs were quantified by calculating ORs with 95% CIs using conditional logistic regression analysis. In addition to crude ORs, we calculated ORs adjusted first for maternal age at birth, mother's SES, gestational age and parity separately, and then for all variables simultaneously. The analyses were conducted separately for singletons and for the whole sample, which included both singleton and twin births. Because of the secular changes in the frequency of IVF treatment, the prevalence of ASDs and the developments in IVF techniques, we assessed whether the association between IVF and ASDs was modified by birth year. Data about the children born in 1991–1995, 1996–2000 and 2001–2005 were analyzed separately and the results of the three time periods were compared with each other. Data were also analyzed separately for children with and without intellectual disability, and separately for boys and girls. The sample size of this study was sufficient to detect a 1.5- to 2.1-fold difference in IVF between cases and controls for total ASDs, childhood autism, Asperger's syndrome and PDD when using 80% power. A two-sided test with type I error rate (alpha) of 0.05 and matched case control study design were applied for this calculation (Dupont, 1988). Statistical analysis was performed using SAS statistical software (SAS Institute Inc. SAS Version 9.3. Cary, NC, USA). The power calculations were performed with the R (2.15.1) packages epicalc (http://cran.r-project.org/web/packages/epicalc/epicalc.pdf) and epiR (http://cran.r-project.org/web/packages/epiR/epiR.pdf).
Materials and Methods
The study is part of the Finnish Prenatal Study of Autism, which is a nested case–control study based on a national birth cohort, and aims to identify pregnancy, infancy and childhoood risk factors for ASDs. An overview of the study has been presented previously Lampi et al., 2011). The study was authorized by the Ministry of Social Affairs and Health of Finland with approvals from the National Institute for Health and Welfare (THL), the Ethics Committee of the Intermunicipal Hospital District of Southwest Finland, and the Institutional Review Board of the New York State Psychiatric Institute. No informed consent was required for this study. To assess the association between IVF and ASDs, we conducted a linkage between two national registers for 4164 autistic cases and their 16 582 matched controls born in 1991–2005. There were 111 cases and 436 controls, which were twins. There were originally five cases (0.1% of all cases) born from triplet pregnancies but they were excluded from this study because it would have been difficult to find matched controls. Of all the children born in Finland during the same period 0.09% were born from pregnancies with more than two fetuses (National Institute for Health and Welfare, 2012).
Exposure
The data on IVF were collected from the Finnish Medical Birth Register (FMBR), which is a national register maintained by THL. Information was collected on maternal background, pregnancy, delivery and early outcomes of the newborn for all births in Finland. The register includes all mother's and child's personal identification numbers, which can be linked to one another. The FMBR commenced in 1987, and data on fertilization treatment has been collected since October 1990. In 1990–1995, IVF was denoted by the item 'assisted reproduction,' including IVF with or without ICSI or FET. In 1996, two items, 'in vitro fertilization' and 'other assisted reproduction' were introduced. A validation study Gissler et al., 2004), however, showed that the latter category also included mostly IVF children, and that the two categories could not be separated. Hence, in the current study the two items were combined. In 2004, the terminology was revised again, and the treatments, which include IVF, could be clearly differentiated from the others. By merging the items from all three time periods, we obtained one variable referring to IVF treatments. Different subtypes of IVF, however, could not be specified.
Outcome
Children born in 1991–2005 and diagnosed with ASDs by the year 2007 were identified from the Finnish Hospital Discharge Register (FHDR), another nationwide register maintained by THL. The FHDR includes the personal identification numbers and covers the diagnoses and the days of admission and discharge in all public and private inpatient care units in Finland. The diagnoses are based on the International Classification of Diseases and Related Health Problems (ICD). All diagnostic codes indicating an ASD were collected according to the ICD-9 in 1991–1995 and ICD-10 in 1996–2007. The most recent registry diagnosis was used. The diagnostic categories included in this study were, first, the whole group of ASDs (F84) and, secondly, three of its subcategories: childhood autism (F84.0), Asperger's syndrome (F84.5) and other pervasive developmental disorder (PDD) and PDD, not otherwise specified (PDD NOS) (F84.8 and F84.9). A validation study Lampi et al., 2010) has shown that the validity of childhood autism diagnosis in the FHDR is very good: when a re-assessment using Autism Diagnostic Interview-Revised was made, 96% of the cases with registry diagnoses of childhood autism met the diagnostic criteria.
Four controls selected from the FMBR were matched to each case. For singletons the matching criteria were date of birth (± 30 days), place of birth, sex and residency in Finland. For twins the matching criteria were date of birth (±6 months but for eight controls the range ±11 months had to be used), region of birth, sex and birth order within a twin pair. No data for whether twins were mono- or dizygotic were available for analysis because this information is not included in the FMBR. The exclusion criteria for controls were ASDs or severe/profound mental retardation according to the FHDR, and eight controls were excluded for this reason. In addition, for 66 controls the personal identification number of the mother or the child was incorrect or incomplete. Altogether 74 controls were removed from the database, which led to 16 582 controls.
An additional analysis was conducted in which stratification by intellectual disability was performed. For this purpose, information on diagnoses indicating intellectual disability (F70-79 in ICD-10 and 317–319 in ICD-9) was collected from the FMBR.
Covariates
Prior to adjustment, bivariate analyses had been conducted to test the significance of association between covariates and IVF among controls as well as between covariates and ASDs (Table I). Maternal age, mother's socioeconomic status (SES), gestational age and parity were all significantly associated with both the exposure and outcome. The data on these covariates were collected from the FMBR. All variables were defined categorically. When studying maternal age at birth, age 20–34 years was used as a reference. For mother's SES, upper white collar workers were used as a reference and the comparison was made with lower white collar workers, blue collar workers and others, which includes entrepreneurs and people outside the labor force, such as students, housewives and unemployed people. The measure of SES follows the national classifications on occupations and socioeconomic groups (Statistics Finland, 1987; Statistics Finland, 1989), and it was primarily based on occupational status, even though educational level was also considered for white collar workers. For gestational age, the category 38–41 weeks was used as a reference. For parity, the reference category was no previous births.
Statistical Analysis
Associations between IVF and different ASDs were quantified by calculating ORs with 95% CIs using conditional logistic regression analysis. In addition to crude ORs, we calculated ORs adjusted first for maternal age at birth, mother's SES, gestational age and parity separately, and then for all variables simultaneously. The analyses were conducted separately for singletons and for the whole sample, which included both singleton and twin births. Because of the secular changes in the frequency of IVF treatment, the prevalence of ASDs and the developments in IVF techniques, we assessed whether the association between IVF and ASDs was modified by birth year. Data about the children born in 1991–1995, 1996–2000 and 2001–2005 were analyzed separately and the results of the three time periods were compared with each other. Data were also analyzed separately for children with and without intellectual disability, and separately for boys and girls. The sample size of this study was sufficient to detect a 1.5- to 2.1-fold difference in IVF between cases and controls for total ASDs, childhood autism, Asperger's syndrome and PDD when using 80% power. A two-sided test with type I error rate (alpha) of 0.05 and matched case control study design were applied for this calculation (Dupont, 1988). Statistical analysis was performed using SAS statistical software (SAS Institute Inc. SAS Version 9.3. Cary, NC, USA). The power calculations were performed with the R (2.15.1) packages epicalc (http://cran.r-project.org/web/packages/epicalc/epicalc.pdf) and epiR (http://cran.r-project.org/web/packages/epiR/epiR.pdf).
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