1 INTRODUCTION

Male predominance is a consistent finding in studies of autism spectrum disorder (ASD), with male to female ratios (MFR) or male: female odds ratio (MFOR; depending on type of study) as high as 4.2–4.3, also in recent studies.1, 2 This strong male predominance has fueled various causal hypotheses of ASD, eg testosterone exposure in utero, the extreme male brain theory3 and a female protective effect in ASD.4 The idea of a female protective effect in ASD comes from the finding that the MFR/MFOR seems to increase with level of ability. In samples of individuals with predominantly low ability (intelligence quotient (IQ) below 70), the MFR has been reported as low as 1.8,5 rising to 4.2 in samples with a majority within the normal range of ability.1 The interaction between gender difference and ability has been interpreted as females possibly requiring a stronger neurodevelopmental impact to develop ASD. However, there is evidence that some of the male predominance in ASD could be a male ascertainment bias.1 Studies have shown that females to a larger degree are not being detected and diagnosed with ASD despite large difficulties.6-9 Under detection of female ASD could be eg gender differences in the clinical presentation of ASD, assessment bias and diagnostic instruments being tailor-made to the male ASD presentation. Girls have different clinical presentations10 and it has also been shown that diagnostic instruments are not as sensitive to the female phenotype, creating considerably poorer diagnostic precision in females.11 In line with this, a meta-analysis indicated that the MFR/MFOR in children may be overestimated based on current studies, as studies with lower risk of ascertainment bias had a lower MFOR than studies with a higher risk of ascertainment bias.1 The same ascertainment bias has been suggested in ADHD, where a lower MFR in adults than in children has been found,12 possibly caused by later identification and gender barriers to child and adolescent mental health services for girls with ADHD.13, 14 Regarding adult ASD, there are some emerging studies, but we still know little of the natural development of ASD through the life course15 and even less about the gender distribution in adult ASD. Brugha et al. found an even stronger relationship between the level of ability and gender differences in adult ASD. Using an OR weighted for age, gender, ID and type or residence, they found an OR of 1.35 (95% CI 0.64–2.83) for ASD in males relative to females with moderate to profound intellectual disability (ID) but an OR of 8.97 (95% CI 2.20–36.52) and 8.62 (95% CI 2.2–34.5) in adults with mild ID or borderline/normal intelligence.16, 17 Their large confidence intervals preclude firm conclusions, but the authors hypothesized that the high male OR in adults with normal intelligence could stem partly from assessment bias and difficulties in diagnosing ASD particularly in higher functioning females. In a total population study in the Faroe Island, considerably more females were found in the second assessment, with a MFR of 2.7:1 in their 15–24-year-old sample,18 which could indicate that the same child-adult gender differences may exist in ASD as found in ADHD. The large differences in the number of females identified in the second vs. the first study in the Faroe Island could be several of the causes mentioned above, eg better identification, increased awareness for female ASD, impairment developing later in females etc.18 There are thus great discrepancies between the few adult studies that have examined gender and adult ASD, from increased MFR/MFOR to lower MFR/MFOR relative to childhood studies. The cited adult studies included few individuals, and two employed active case-searching methods, producing estimates of MFR and MFOR respectively with very broad confidence intervals and carrying a high risk of ascertainment bias. There is thus a need for larger studies examining the MFR across the lifespan of ASD and how it is influenced by comorbid intellectual disability.

1.1 Aims of the study

The main aim of the present study was to estimate the MFR and the male prevalence ratio (PR) in adults compared with children with ASD in a total population and to examine the impact of comorbid ID and/or ADHD. We furthermore examined the variation of the MFR and male PR with age and ASD subtypes to evaluate possible reasons for ASD MFR variation. Being a total population study, PR was used as the adjusted measure of gender ratio estimates rather than MFOR.19

2 MATERIALS AND METHODS 2.1 Sample

The study population included all individuals born and registered in the Medical Birth Registry of Norway (MBRN), during 1967–2011, who was living in Norway at record linkage in 2015 (n = 2,486,088). Information from three nationwide population-based registries was linked to obtain information on diagnosis and medication: The MBRN, established in 1967,20 the Norwegian Prescription Database (NorPD), established in 200421 and the Norwegian Patient Registry (NPR),22 with linkable data from 2008. The NorPD registers all medical prescriptions dispensed to individuals from any Norwegian pharmacy and includes the Anatomical Therapeutic Chemical (ATC) Classification System codes. The NPR includes information about diagnoses and interventions given to patients treated in secondary health care, in hospitals and outpatient clinics. Diagnoses are registered by the International Classification of Diseases (ICD), version 10. Record linkage was performed using the national identification number unique to every Norwegian resident. Individuals born before 1967 are not part of the MBRN and could not be included. The study was approved by the Regional Committees for Medical Research Ethics in Norway (2011/2272) and reported according to guidelines suggested by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative.23

2.2 Variables 2.2.1 Outcome: ASD with and without comorbid ID and/or ADHD

Diagnoses coded by F84 with subcategories (ICD-10) were analysed jointly under the umbrella term autism spectrum disorders (ASD); defined as individuals registered in the NPR (2008–2015) with the following ICD-10 codes: F84.0–84.1+F84.5+F84.8–84.9 (Table 3). We identified individuals with ADHD if they were registered with an ADHD diagnosis (ICD-10 code F90; NPR 2008–2015) and/or having been dispensed a prescription of ADHD medication during 2004–2015 (NorPD). The ADHD medications identified were the central stimulants methylphenidate (N06B A04), racemic amphetamine (N06B A01) and dexamphetamine (N06B A02) and the non-stimulant drug atomoxetine (N06B A09). Lisdexamphetamine (N06B A12) was not included as it was only introduced on the Norwegian market in the fall of 2014. ID was defined as individuals registered in the NPR with any of the ICD-10 codes: F70-79.

Adults were individuals who were 18 years or more by the time of record linkage, ie born before 1998. In sub-analyses, we further divided adults into older (born 1967–1983) and younger (born 1984–1997) adults. The childhood population was defined as individuals aged 4–17 years (born 1998–2011) at linkage in 2015 and was further divided into younger and older children, age 4–10 years and age 11–17 years.

The remaining population included all individuals who had not been dispensed neither an ADHD medication nor had an ASD, an ADHD nor an ID diagnosis, in the NorPD and NPR, respectively. Any individuals diagnosed with ASD, ADHD or ID before 2008 and not in contact with specialist health services in 2008–2015, nor prescribed any ADHD medication in 2004–2015 were included in the remaining adult population since it was not possible to identify their diagnoses.

2.2.2 Measures and statistical analyses

We analysed the male to female ratio (MFR) for all ASD (including both ADHD and ID) and then split all ASD by ADHD status to analyse the impact of comorbid ADHD on the MFR. We then reran analyses by ID status, to analyse the impact of comorbid ID. We calculated the male prevalence ratio (PR) as the adjusted measure, which corresponds to the percentage increase in males in the clinical population versus the non-clinical population. A PR of 1.4 equals 40% more males than in the population without the studied diagnoses. As diagnostic practices have changed considerably over the studied decades, we present descriptive statistics of the overall registered prevalence of ASD, ADHD and ID and specifically for Asperger syndrome (AS) that was introduced as a diagnosis in 1994.24 We analysed the MFR in younger (born 1984–1997) and older adults (born 1967–1983) as well as for all children, children aged 4–10 years and aged 11–17 years separately. Finally, we analysed the MFR in the ASD subtypes separately.

We used the STATA command ‘binreg’ for the calculation of PR with gender as the exposure and with adjustment for birth year (5-year periods, from 1967 to 1997, with 1967–1973 as the reference). Statistical differences were based on evaluation of confidence intervals (CI), using 95% intervals as the range to evaluate significance.

3 RESULTS 3.1 Study groups

A total of 1,701,206 adult individuals born during 1967–1997 and living in Norway at linkage in 2015 were included. We identified 8,995 adults with any ASD (0.5%), 53,822 adults with any ADHD (3.2%) and 9,178 adults with any ID (0.5%). There were 5,300 adults with ASD only (0.3%), 49,908 adults with ADHD only (2.9%), 2,512 adults with ADHD+ASD (0.1%) and 1,183 adults with ASD+ID (0.1%) in our study population (no ADHD). Very few had all three disorders, ASD+ADHD+ID, n = 328 (0.2‰), see Table 1. The adult population with no ASD, ADHD nor ID consisted of 1,684,543 individuals, 823,546 (49%) women. The mean age in 2015 for adults (born before 1998) for the ASD only group was 26.2 years, for the ASD+ADHD 24.1 years and the remaining adults 33.1 years.

TABLE 1. Male/female ratio (MFR) and male prevalence ratio (PR) in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) with and without intellectual disability (ID) compared with males among individuals without ASD, ADHD and ID, Norway, all born 1967–2011 Group N (%) MFR PR (95% CI) Comorbid ID, N (%) MFR PR (95%CI) No ID, N (%) MFR PR (95%CI) ADULTS, born 1967–1997 Reference pop. M 864,856 (51.1) 1.05 Reference 3,857 (50.3) 1.01 Reference 860,997 (51.1) 1.05 Reference F 827,355 (48.9) 3,809 (49.7) 823,546 (48.9) Any ASD M 6,474 (72.0) 2.57 1.41 (1.39–1.42) 1,036 (68.6) 2.18 1.36 (1.30–1.41) 5,438 (72.7) 2.66 1.42 (1.40–1.44) F 2,521 (28.0) 475 (31.4) 2,046 (27.3) ASD (no ADHD) M 4,617 (71.2) 2.47 1.39 (1.37–1.41) 779 (65.9) 1.93 1.31 (1.25–1.37) 3,838 (72.4) 2.62 1.41 (1.39–1.44) F 1,866 (28.8) 404 (34.2) 1,462 (27.6) ASD+ADHD M 1,857 (73.9) 2.83 1.44 (1.41–1.48) 257 (78.4) 3.61 1.52 (1.43–1.62) 1,600 (73.3) 2.75 1.43 (1.39–1.47) F 655 (26.1) 71 (21.7) 584 (26.7) ALL CHILDREN, born 1998–2011 Reference pop. M 406,063 (51.0) 1.04 Reference 2,158 (57.2) 1.33 Reference 403,905 (51.0) 1.04 Reference F 390,027 (49.0) 1,618 (42.9) 388,409 (49.0) Any ASD M 6,332 (78.6) 3.67 1.54 (1.53–1.56) 913 (72.4) 2.62 1.26 (1.21–1.32) 5,419 (79.8) 3.94 1.57 (1.55–1.59) F 1,724 (21.4) 349 (27.7) 1,375 (20.2) ASD (no ADHD) M 4,229 (77.5) 3.44 1.52 (1.50–1.54) 650 (71.8) 2.55 1.25 (1.19–1.32) 3,579 (78.6) 3.67 1.54 (1.52–1.57) F 1,230 (22.5) 255 (28.2) 975 (21.4) ASD+ADHD M 2,103 (81.0) 4.26 1.59 (1.56–1.62) 263 (73.7) 2.80 1.29 (1.01–1.39) 1,840 (82.1) 4.6 1.62 (1.58–1.65) F 494 (19.0) 94 (26.3) 400 (17.9) CHILDREN, aged 4–10, born 2005–2011 Reference pop. M 209,374 (51.1) 1.05 Reference 738 (58.1) 1.39 Reference 208,636 (51.1) 1.05 Reference F 200,104 (48.9) 532 (41.9) 199,572 (48.9) Any ASD M 2,170 (81.7) 4.46 1.60 (1.57–1.63) 337 (73.1) 2.72 1.26 (1.17–1.35) 1,833 (83.5) 5.05 1.63 (1.60–1.66) F 487 (18.3) 124 (26.9) 363 (16.5) ASD (no ADHD) M 1,669 (80.9) 4.23 1.58 (1.55–1.62) 272 (72.2) 2.59 1.24 (1.15–1.34) 1,397 (82.8) 4.82 1.62 (1.59–1.66) F 395 (19.1) 105 (27.9) 290 (17.2) ASD+ADHD M 501 (84.5) 5.45 1.65 (1.60–1.71) 65 (77.4) 3.42 1.33 (1.17–1.51) 436 (85.7) 5.97 1.68 (1.62–1.74) F 92 (15.5) 19 (22.6) 73 (14.3) CHILDREN, aged 11–17, born 1998–2004 Reference pop M 196,689 (50.9) 1.04 Reference 1,420 (56,7) 1.31 Reference 195,269 (50.8) 1.03 Reference F 189,923 (49.1) 1,086 (43.3) 188,837 (49.2) Any ASD M 4,162 (77.1) 3.36 1.52 (1.49–1.54) 576 (71.9) 2.56 1.27 (1.20–1.34) 3,586 (78.0) 3.54 1.53 (1.51–1.56) F 1,237 (22.9) 225 (28.1) 1,012 (22.0) ASD (no ADHD) M 2,560 (75.4) 3.07 1.48 (1.45–1.51) 378 (71.6) 2.52 1.26 (1.18–1.34) 2,182 (76.1) 3.19 1.50 (1.47–1.53) F 835 (24.6) 150 (28.4) 685 (23.9) ASD+ADHD M 1,602 (79.9) 3.99 1.57 (1.54–1.61) 198 (72.5) 2.64 1.28 (1.18–1.39) 1,404 (81.1) 4.29 1.60 (1.56–1.63) F 402 (20.1) 75 (27.5) 327 (18.9) Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; CI, confidence intervalF, female; ID, intellectual disability; M, male; MFR, male/female ratio; PR, prevalence ratio.

We identified 804,146 children (391,751 (48.7%) females), born 1998–2011. We identified 8,056 (1.0%) children with any ASD, 26,967 with any ADHD (3.4%) and 5,038 with any ID (0.6%). The number of children with ASD only was 5,459 (0.7%), ADHD only 24,370 (3.0%) and 2,597 had ADHD+ASD (0.3%). Only 357 (0.4‰) had all three disorders (ASD+ADHD+ID) (0.04%). The remaining children with no ASD, ADHD nor ID consisted of 792,314 individuals (388, 409 (49.6%) females).

3.2 Gender ratios in adults – impact of ADHD and ID

Table 1 and Figure 1 show the MFR and the male prevalence ratio in ASD with and without comorbid ADHD and ID as compared with males in the population without ASD, ADHD and ID (Table 1 and Figure 1). The overall MFR for adult ASD was 2.57 and the PR 1.41 (95% confidence interval (CI) 1.39–1.42). The overall MFR for ASD only (excluding ADHD and ID) was 2.62 with a PR of 1.41 (1.39–1.44). The group with comorbid ADHD but no ID had an MFR of 2.75 with a PR of 1.43 (1.39–1.47). The lowest MFR of 1.93, PR 1.31 (1.25–1.37) was seen in the group with ID and ASD (no ADHD) whereas the highest MFR among adults was found in the group with ASD+ADHD+ID: 3.61, PR 1.52 (1.43–1.62).

Male prevalence ratio for children and adults with autism spectrum disorder (ASD), ASD with ADHD and ASD with intellectual disability (ID) compared with the corresponding reference population without these diagnoses

3.3 Older versus younger adults and prevalence trends

The registered prevalence of ASD, ADHD and ID all increased from older (born 1967–1983) to younger (born 1984–1997) adults (Table 2). Figure 2 shows the population prevalence of ASD with and without comorbid ADHD and/or ID in males and females by birth year cohorts (Figure 2). ASD was the diagnosis with the largest change, increasing from 0.2% in adults born 1967–1983 to 0.9% in adults born 1984–1997. The rise was mainly accounted for by increasing prevalence of Asperger syndrome (AS) that was registered almost nine times as often in individuals born in the last 5-year period (1994–1997) compared with the reference birth years (1967–1973) (Figure 3). Older adults with ASD had a lower MFR than younger adults: 2.36, PR 1.38 (1.34–1.42) vs. 2.63, PR 1.41 (1.39–1.43), although with overlapping confidence intervals.

TABLE 2. Prevalence of Norwegian Patient Registry diagnoses of ASD, ADHD and ID in older (born 1967–1983) versus younger adults (born 1984–1997), Norway, diagnoses from 2008–2015

ASD (incl ADHD/ID)

N (%)

ADHD (incl ASD/ID)

N (%)

ID (incl ADHD/ASD)

N (%)

All older adults 1,991 (0.2) 17,270 (1.9) 3,356 (0.4) Men 1,399 (0.3) 9,433 (2.0) 1,701 (0.4) Women 592 (0.1) 7,837 (1.7) 1,655 (0.4) All younger adults 7,004 (0.9) 36,552 (4.7) 5,822 (0.7) Men 5,075 (1.3) 22,662 (5.7) 3,193 (0.8) Women 1,929 (0.5) 13,890 (3.7) 2,629 (0.7) Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, Autism spectrum disorder; ID, intellectual disability.

Population prevalence of ASD with and without comorbid ADHD and/or ID in males and females by birth year cohorts

Population prevalence of Asperger syndrome (AS) in adult males and females by birth year cohorts

3.4 Comparison with children

The MFR in the childhood population (4–17 years old) with any ASD of 3.67, PR 1.54 (1.53–1.56) was higher than in adults (Table 1). Similarly, younger children (4–10 years old) had a higher MFR than older (11–17 years old) children, 4.46, PR 1.60 (1.57–1.63) and 3.36, PR 1.52 (1.49–1.54), respectively. In the age group 4–10 years old, the effect of concurrent ID was notable, with an MFR of 2.72, PR 1.26 (1.17–1.35) in ASD with ID compared with 5.05, PR 1.63 (1.60–1.66) for ASD without ID. However, in both age groups (and in the total population of children), the MFRs and the PRs were higher in cases without concurrent ID.

3.5 Variance in gender ratio according to ASD subtypes

The MFRs for different ASD subtypes (adults and children combined) are shown in Table 3. The highest MFR of 4.49, PR 1.60 (1.57–1.63) was seen for childhood autism without ID and the lowest MFR of 2.25, PR 1.22 (1.15–1.29) was found for pervasive developmental disorder-not otherwise specified (PDD-NOS) with ID (Table 3). The MFR for Asperger syndrome (AS) without ID was 2.98, PR 1.46 (1.45–1.55) (very few individuals overall were diagnosed with AS with ID (Table 3)).

TABLE 3. Male/female ratio (MFR) and male prevalence ratio (PR) for ASD subtypes as compared with males in the population without ASD, ADHD and ID, Norway, all individuals born 1967–2011 All ASD, N (%) MFR PR (95% CI) Comorbid ID, N (%) MFR PR (95% CI) No ID, N (%) MFR PR (95% CI) F84.0 (Childhood autism, 27.0% of all ASD) Men 3,578 (77.6) 3.46 1.51 (1.49–1.54) 1,290 (71.2) 2.47 1.29 (1.25–1.34) 2,288 (81.80) 4.49 1.60 (1.57–1.63) Women 1,031 (22.4)a 522 (28.8) 509 (18.20) F84.1 (Atypical autism, 13.5% of all ASD) Men 1,665 (72.2) 2.60 1.41 (1.37–1.44) 680 (70.6) 2.40 1.26 (1.20–1.31) 985 (73.3) 2.75 1.43 (1.39–1.48) Women 641 (27.8) 283 (29.4) 358 (26.7) F84.5 (Asperger syndrome, 53.3% of all ASD) Men 6,797 (74.8) 2.96 1.46 (1.44–1.48) 178 (69.5) 2.28 1.28 (1.18–1.39) 6,619 (74.9) 2.98 1.46 (1.45–1.48) Women 2,296 (25.3) 78 (30.5) 2,218 (25.1) F84.8 (Pervasive developmental disorder, otherwise specified, 2.2% of all ASD) Men 289 (73.7) 2.80 1.44 (1.35–1.52) 60 (70.6) 2.39 1.22 (1.06–1.40) 229 (74.6) 2.94 1.45 (1.36–1.55) Women 103 (26.3) 25 (29.4) 78 (25.4) F84.9 (Pervasive developmental disorder, not otherwise specified, 15.2% of all ASD) Men 2,588 (74.5) 2.92 1.45 (1.42–1.48) 418 (69.2) 2.25 1.22 (1.15–1.29) 2,170 (75.6) 3.10 1.48 (1.44–1.51) Women 887 (25.5) 186 (30.8)