16. Safety: autistic spectrum disorders.

Study ID and design	Population	Outcome definition	Exposure MMR/MMRV vaccine	Findings	Crude data	Estimate (95% CI)
cb‐Madsen 2002 Retrospective cohort	Danish children born between January 1991 and December 1998 (n = 537,303)	(a) Autistic disorders ICD‐10 codes F84.0 or similar DSM‐IV code 299; (b) Other autistic spectrum disorders ICD‐10 codes F84.1 through F84.9 and DSM‐IV codes 299.1‐ through 299.80. From medical records in Danish Psychiatric Central Register	MMR vaccine: Moraten (measles), Jeryl Lynn (mumps), Wistar RA 27/3 (rubella) Vaccination data reported in the National Board of Health. Vaccinated n = 440,655 Unvaccinated n = 96,648	This study provides 3 strong arguments against a causal relation between MMR vaccination and autism. The risk of autism was similar in vaccinated and unvaccinated children, in both age‐adjusted and fully adjusted analyses. There was no temporal clustering of cases of autism at any time after immunisation. Neither autistic disorder nor other autistic‐spectrum disorders were associated with MMR vaccination. Furthermore, the results were derived from a nationwide cohort study with nearly complete follow‐up data.	(a) Autistic disorders cases unvaccinated n = 53 PT unvaccinated PT(years) = 482,360 versus cases vaccinated n = 263 PT vaccinated PT(years) = 1,647,504 (b) Other autistic spectrum disorters cases unvaccinated n = 77 PT unvaccinated PT(years) = 482,360 versus cases vaccinated n = 345 PT vaccinated PT(years) = 1,647,504	rr (95% CI)(*) (a) 0.92 (0.68 to 1.24) (b) 0.83 (0.65 to 1.07) (*) adjusted rr. Log‐linear Poisson regression
cb‐Hviid 2019 Retrospective cohort study	n = 657,461 children born in Denmark from 1999 through 31 December 2010, with follow‐up from 1 year of age and through 31 August 2013.	Autism spectrum disorders ICD‐10: F84.0 autistic disorder, F84.1 atypical autism, F84.5 Asperger syndrome, F84.8 (other pervasive developmental disorder), F84.9 (unspecified pervasive developmental disorder). Autism risk score: In a preliminary analysis based on autism risk factors (maternal age, paternal age, smoking during pregnancy, method of delivery, preterm birth, 5‐minute Apgar score, low birthweight, and head circumference) a Risk Score was estimated for each child in the cohort. (b1) very low risk (b2) low risk (b3) moderate risk (b4) high risk Siblings status (at age 1 years): (c1) no siblings with autism (c2) siblings with autism (c3) no siblings	MMR vaccine Schwarz (measles, 2000 to 2007) or Enders' Edmonston (measles, 2008 to 2013), Jeryl Lynn (mumps), and Wistar RA 27/3 (rubella) Vaccinated n = 625,842 Unvaccinated n = 31,619	The study found: no support for the hypothesis of increased risk for autism after MMR vaccination in a nationwide unselected population of Danish children; no support for the hypothesis of MMR vaccination triggering autism in susceptible subgroups characterised by environmental and familial risk factors; no support for a clustering of autism cases in specific time periods after MMR vaccination.	Cases vaccinated/vaccinated versus Cases unvaccinated/ unvaccinated All children (a) 5992/625,842 versus 525/31,619 Autism risk score (*) (b1) 1296 versus 91 cases (b2) 1637 versus 133 cases (b3) 2106 versus 206 cases (b4) 953 versus 95 cases Siblings status (*) (c1) 2297 versus 227 (c2) 32 versus 5 (c3) 3594 versus 283 (*) denominator not reported	HR (95% CI)(*) All children (a) 0.93 (0.85 to 1.02) Autism risk score (b1) 0.93 (0.74 to 1.16 (b2) 0.86 (0.71 to 1.04) (b3) 0.91 (0.78 to 1.06) (b4) 1.06 (0.85 to 1.32) Siblings status (c1) 0.98 (0.84 to 1.13) (c2) 2.96 (0.58 to 12.43) (c3) 0.89 (0.78 to 1.01) (*) adjusted by birth year, sex, other vaccines received, siblings history of autism, and autism risk score). Cox regression
cb‐Jain 2015 Retrospective cohort	Children continuously enrolled in the health plan from birth to at least 5 years of age during 2001 to 2012 who also had an older sibling continuously enrolled for at least 6 months between 1997 and 2012. n = 95,727 children in the cohort, (a) n = 93,798 older siblings without ASD (b) n = 1929 older sibling with ASD.	Autism spectrum disorders Status in index children and older siblings was determined using a claims‐based algorithm that required 2 or more claims on separate dates of service with an ICD‐9‐CM diagnosis code in any position for autistic disorder, other specified pervasive developmental disorder including: Asperger syndrome, or unspecified PDD (299.0x, 299.8x, and 299.9x). Both index child and older sibling ASD status were determined using their entire enrolment time that fell within the study period. Index children had to have at least 1 older sibling with 2 claims with ASD diagnoses or all older siblings with no ASD diagnoses. Children with an older sibling with only 1 claim with an ASD diagnosis were excluded. Index children with only 1 claim with an ASD diagnosis were also excluded.	MMR vaccine receipt was defined as having a Current Procedural Terminology (CPT) or ICD‐9‐CM procedure code indicating receipt of each component (measles, mumps, and rubella) after 1 year of age.	The study found: MMR vaccine was not associated with increased risk of ASD, regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even amongst children already at higher risk for ASD.	Cases vaccinated/vaccinated versus Cases unvaccinated/ unvaccinated age 2 years ‐ 1 dose (a) 53/77,822 versus 13/15,249 (b) 7/1394 versus 6/520 age 3 years ‐ 1 dose (a) 239/79,666 versus 45/12,853 (b) 38/1458 versus 17/438 age 4 years ‐ 1 dose (a) 395/79,691 versus 65/11,957 (b) 64/1491 versus 25/387 age 5 years ‐ 1 dose (a) 339/40,495 versus 56/7735 (b) 51/864 versus 23/269 age 5 years ‐ 2 doses (a) 244/45,568 versus 56/7735 (b) 30/796 versus 23/269	HR (95% CI)(*) age 2 years ‐ 1 dose (a) 0.91 (0.68 to 1.20) (b) 0.76 (0.48 to 1.22) age 3 years ‐ 1 dose (a) 0.97 (0.77 to 1.21) (b) 0.81 (0.53 to 1.25) age 4 years ‐ 1 dose (a) 1.03 (0.81 to 1.31) (b) 0.86 (0.56 to 1.34) age 5 years ‐ 1 dose (a) 1.10 (0.79 to 1.53) (b) 0.92 (0.56 to 1.50) age 5 years ‐ 2 doses (a) 1.09 (0.76 to 1.54) (b) 0.56 (0.30 to 1.04) (*) Hazard rate ratio from Cox proportional hazards model adjusting for birth year, sex, region, race/ethnicity, maternal or paternal highest education level, household income, mother’s age at birth of index infant, father’s age at birth of index infant, continuous enrolment with mental health carve‐out benefit, Childhood Chronic Conditions score, seizure, allergies, and preterm birth. Cox regression
cb‐Uchiyama 2007 Retrospective cohort	Children born between 1976 and 1999 with clinical diagnosis of ASD analysed n = 858 (whole sample n = 904; n = 46 cases were excluded due to insufficient information on ASD regression)	Regression in autism spectrum disorders ASD regression defined as “a documented deterioration in any aspect of development or reported loss of skills, however transient” Note: over time 2 different diagnostic processes have been adopted at YPCD: until February 2000, the diagnostic process consisted of the assessment of ASD initially conducted by a child psychiatrist using the DSM‐IV (American Psychiatric Association, 1994), after which a clinical psychologist conducted an intelligence test. After admission a psychiatrist followed the patients once or twice a month. All doctors had been trained in using a common concept of diagnosis. From February 2000 onwards, a child psychiatrist with a clinical psychologist conducted the full assessment in 1 day. Diagnosis of ASD was made by 3 experienced child psychiatrists based on clinical observations, intellectual and developmental tests, and interviews with parents and patients.	MMR vaccine AIK‐C (measles), Urabe AM9 (mumps) To‐336 (rubella) strains. Data concerning MMR vaccination were moreover obtained from records of the Maternal and Child Health Handbook and were referred to the MMR generation group only. Participants were classified according to the chance of having received MMR vaccine (MMR was administered in Japan from April 1989 to April 1993 in children 12 to 36 months of age): pre‐MMR generation (before): born between January 1976 and December 1984, all ASD cases n = 100; MMR generation (MMR‐era): born between January 1985 and December 1991, all ASD cases n = 275; post–MMR generation (after): aged 1 to 3 years old after 1993 when MMR programme was terminated, all ASD cases n = 483 (regression n = 16); across all generations n = 769.	The study found: within the MMR era, the rate of regression in those who received MMR was not higher than those who did not. Moreover, there was no indication that the rate of regression in ASD was higher during the era when MMR was used, compared to the ‘‘before’’ period and ‘‘after’’ period, and the ‘‘before" and "after’’ periods combined.	N cases vaccinated/ N vaccinated versus N cases unvaccinated/ N unvaccinated MMR‐generation (a) 15/54 versus 45/132 All generations (*) (b) 15/54 versus 272/715 (*) 98 cases out of 275 (MMR‐generation) were excluded due to unclear vaccination status, analysed n = 186. ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ MMR‐era versusbefore (c) 98/275 versus 34/100 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ MMR‐era versusafter (d) 98/275 versus 193/483 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ MMR‐era versus(before + after) (e) 98/275 versus 227/583	OR (95% CI) (a) 0.744 (0.349 to 1.571) (b) 0.626 (0.323 to 1.200) (c) 1.075 (0.646 to 1.791) (d) 0.832 (0.605 to 1.144) (e) 0.868 (0.638 to 1.182)
bb‐Smeeth 2004 Case‐control	Children with a first diagnosis of a PDD during the study period registered with a GPRD practice. Cases: n = 1294 Controls: n = 4469	Pervasive developmental disorder “Those with autistic disorders and similar presentations were classified as having 'autism' and those with other description (such as Asperger’s syndrome) were classified as having 'other PDD'. Patients who had more than one PDD diagnostic code recorded at different times (for example, autism and then Asperger’s syndrome) were classified as having the most specific diagnosis (in this example Asperger’s syndrome)” From diagnosis contained in UK General Practice Research Database (GPRD electronic records).	MMR vaccine: No single clinical code was immediately implemented for MMR, then MMR was identified by codes of measles, mumps, and rubella administered on the same day. Information on MMR exposure: cases: was abstracted from the GPRD records from their date of birth up until their date of diagnosis with a PDD; controls: was abstracted from their date of birth up to their index date, defined as the date when they were the same age (to the nearest month) as their matched case at the time the case was first diagnosed with a PDD.	The study found: MMR vaccination was not associated with an increased risk of subsequently being diagnosed with a PDD.	MMR vaccination Before index date (a) at any age (b1) before third birthday (b2) after third birthday (c1) before age 18 months (c2) after age 18 months (d) autism only (e) other PDD only	OR (95% CI)(*) (a) 0.86 (0.68 to 1.09) (b1) 0.90 (0.70 to 1.15) (b2) 0.77 (0.55 to 1.08) (c1) 0.90 (0.70 to 1.15) (c2) 0.80 (0.61 to 1.05) (d) 0.88 (0.67 to 1.15) (e) 0.75 (0.46 to 1.23) (*)adjusted conditional logistic regression
bb‐De Stefano 2004 Case‐control	Children with autism aged 3 to 10 years in 1996. All sample Cases: n = 624 Controls: n = 1824 Birth certificate subsample Cases: n = 355 Controls: n = 1020	Autism cases were identified through screening and abstraction of source files at schools, hospitals, clinics, and specialty providers. Clinical psychologists with expertise in the diagnosis of autism reviewed the abstracted records according to a standardised coding scheme to determine the presence of behavioural characteristics consistent with the DSM‐IV criteria for ASDs.	MMR vaccine type: not stated MMR vaccination was abstracted from “standardized state immunization forms”. 3 specific years cutoff: (a) 18 months of age, as an indicator of “on‐time” vaccination according to the recommended vaccination schedule for MMR vaccine; (b) 24 months of age, the age by which atypical development has become apparent in most children with autism; (c) 36 months of age, the age by which autistic characteristics must have developed to meet DSM‐IV criteria for autism.	The study found: no significant associations for vaccinated before 18 months or before 24 months of age, including children with some indication of regression or plateau in development, the group of most concern. Vaccination before 36 months of age was more common amongst case children than control children, although only a small proportion of children in either group received their first MMR vaccination after 36 months of age. Rather than representing causal relationships, associations with the 36‐month cutoff would be more likely than associations with earlier age cutoffs to have been influenced by factors related to the evaluation, management, and treatment of the child, e.g. case children might have been more likely than control children to have been vaccinated as a requirement for enrolment in early intervention or preschool special education programs. This possibility is supported by the finding that the difference between case and control children in the proportion vaccinated before 36 months of age was strongest in the 3‐ to 5‐year‐old age group. A majority of case children who were vaccinated after 36 months of age, however, had indications of developmental problems before 36 months of age.	All cases (a1) < 18 months (b1) < 24 months (c1) < 36 months Birth certificate (a2) < 18 months (b2) < 24 months (c2) < 36 months	OR (95% CI) All cases(*) (a1) 1.12 (0.91 to 1.38) (b1) 1.21 (0.93 to 1.57) (c1) 1.49 (1.04 to 2.14) Birth certificate (**) (a2) 0.93 (0.66 to 1.30) (b2) 0.99 (0.63 to 1.55) (c2) 1.23 (0.64 to 2.36) (*)partially adjusted estimates: conditional logistic regression model stratified by the matching variables (age, gender, school). (**)adjusted estimates: conditional logistic regression model stratified by the matching variables (age, gender, school) and adjusted for birthweight, multiple gestation, maternal age, and maternal education.
bb‐Mrozek‐Budzyn 2010 Case‐control	Children aged 2 to 15 years diagnosed with childhood or atypical autism. Cases: n = 96 Controls: n = 192 children matched for birth year, gender, and practice	Childhood or atypical autism classified according to ICD‐10 criteria as F84.0 or F84.1, respectively. Every diagnosis of autism was made by child psychiatrist. Dates of these diagnoses were recorded in general practitioner files. Cases with uncertain diagnosis of autism, secondary to disease state or trauma, were excluded. Parents were interviewed. Questions for all children included information about prenatal and postnatal development, mental and physical development, chronic diseases, malformations and injuries, history of bowel disturbances, birth order, family size, and parents’ socioeconomic status. Parents of children with autism were additionally asked about the date of onset of symptom, the period when parents first suspected their child’s symptoms might be related to autism, and their knowledge and beliefs regarding the cause of autism.	Vaccine type: MMR: not described MV: measles vaccine monovalent: not described Information about vaccination history was extracted from physician records.	The study found: MMR vaccination was not significantly associated with an increased risk of autism in children. In a separate analysis, a similar result was achieved for the single‐antigen measles vaccine. An unexpected finding was that odds ratios associated with MMR were lower than with the single measles vaccine. The decreased risk of autism amongst vaccinated children may be due to some other confounding factors in their health status. For example, healthcare workers or parents may have noticed signs of developmental delay or disease before the actual autism diagnosis and for this reason have avoided vaccination.	Any vaccine versusunvaccinated (a1) vaccinated before symptom onset (a2) vaccinated before diagnosis MMR vaccine versusunvaccinated (b1) vaccinated before symptom onset (b2) vaccinated before diagnosis MV vaccine versusunvaccinated (c1) vaccinated before symptom onset (c2) vaccinated before diagnosis	OR (95% CI)(*) any vaccine versusunvaccinated (a1) 0.65 (0.26 to 1.63) (a2) 0.28 (0.01 to 0.76) MMR versusunvaccinated (b1) 0.42 (0.15 to 1.16) (b2) 0.17 (0.06 to 0.52) MV versusunvaccinated (c1) 0.86 (0.33 to 2.23) (c2) 0.36 (0.13 to 1.00) (*)Adjusted for mother’s age (15 to 35, 36 to 44 years), medication during pregnancy, gestation time (36 to 37, 38 to 43 weeks), perinatal injury, 5‐minute Apgar scale score (3 to 8, 9 to 10).
bb‐Uno 2012 Case‐control	The study analysed case data from patients of YPDC; the cases consisted of patients who: (1) were diagnosed with ASD, and (2) had been born between 1 April 1984 and 30 April 1992, the possible time period for MMR vaccination. Children aged 6 to 36 months cases: n = 189 control: n = 224	Diagnosis of ASD: based on the classifications of pervasive developmental disorders in the DSM‐IV and standardised criteria using the Diagnostic Interview for Social and Communication Disorder (DISCO).	MMR vaccine: not described	The study found: there was no convincing evidence that MMR vaccination and increasing the number of vaccine injections were associated with an increased risk of ASD in a genetically homogeneous population. Consequently, these findings indicate that there is no basis for avoiding vaccination out of concern for ASD.	Cases vaccinated/N cases versus Control vaccinated/N controls 47/189 versus 54/224	OR (95% CI)(*) 1.04 (0.65 to 1.68) (*) matched odds ratio
gb‐Fombonne 2006 Case‐only ecological method	Children aged 5 to 11 years (birth cohorts 1987 to 1998 attending a boarding school in Montreal (n = 27,749, out of whom 180 with PDD)	Pervasive developmental disorders Children with a diagnosis of PDD were identified by school personnel and given a study code to preserve the anonymity of the data. Children’s diagnoses were not verified by direct assessments, but it is worth noting that a majority of these children (N = 155; 86.1%) were diagnosed at the Montreal Children’s Hospital. School personnel further identified the diagnostic subtype using DSM‐IV diagnostic criteria, age, grade, and school the child was attending. When available, place of birth was recorded as well.	MMR (no description) Identified by vaccination records	MMR and autism: During the 11‐year interval, rates of PDD significantly increased, whereas MMR vaccine uptake showed a slight opposite trend. The opposite directions of both trends make it even less likely that a true association was not detected in the study data. The study shows a lack of association between MMR uptake and PDD rates applied to the period (1987 to 1995) where a single MMR dose was administered at 12 months of age. Rates of PDD were rapidly increasing well before the introduction of the 2‐dose schedule and, during that first phase, the increase of PDD rate bore no relationship with MMR vaccine uptake. The authors tested whether the introduction of a second MMR dose after 1995 accelerated the increase in PDD rates in the following 3 years. No statistically significant difference could be found between the rate of increase in PDD prevalence between the 1‐dosing and the 2‐dosing periods. In fact, the end point prevalence estimate for 1998 was consistent with the value predicted on the basis of the 1987 to 1995 rate of increase. Consequently, 2‐dosing schedule with MMR before age 2 is not associated with an increased risk of PDD.	No association. Significant increase in rates of PDDs from 1987 to 1998 (OR 1.10, 95% CI 1.05 to 1.16; P < 0.001) despite decrease in MMR uptake through birth cohorts from 1988 to 1998 (Chi² for trend = 80.7; df = 1; P < 0.001).	No data available for meta‐analysis
gb‐Honda 2005 Case‐only ecological method	Children born from 1988 to 1996 (n = 31,426)	Autism spectrum disorders ASD cases defined as all cases of PDD according to ICD guidelines, but an early detection clinical system called DISCOVERY that included items drawn up by the Public Health Bureau of Yokohama called YACHT (Young Autism and other developmental disorders CHeckup Tool) was active in Kohoku Ward. Definite regression Episodes in which caregiver records confirm loss of skills such as aspects of communication skills, including utterances, social behaviours, play activities, adaptive skills, or motor skills that had appeared and become established in the child’s daily life. Probable regression If there was insufficient evidence to confirm that previous skills had become firmly acquired, or that they had not fully disappeared.	MMR vaccine: no description Exposed period: 1988 to 1992 MMR vaccination rates declined from 69.8% in the 1988 birth cohort to 42.9%, 33.6%, 24.0%, and a mere 1.8% in birth cohorts 1989 to 1992. Reference period: 1993 to 1996 In birth cohorts 1993 to 1996, when not a single child was immunised.	MMR vaccination is unlikely to be a main cause of ASD, that it cannot explain the rise over time in the incidence of ASD, and that withdrawal of MMR in countries where it is still being used cannot be expected to lead to a reduction in the incidence of ASD.	Risk period (cases/population) versus Reference period (cases/population) (a) Childhood autism 58/17,704 versus 100/13,722 (b) Other ASD 50/17,704 versus 70/13,722 (c) Definite regression 29/17,704 versus 31/13,722 (d) Definite + probable regression 35/17,704 versus 37/13,722 (e) All ASD 108/17,704 versus 170/13,722	rr (95% CI) (a) 0.45 (0.33 to 0.62) (b) 0.55 (0.39 to 0.80) (c) 0.73 (0.44 to 1.20) (d) 0.73 (0.46 to 1.16) (e) 0.49 (0.39 to 0.63)
db‐Makela 2002 Person‐time cohort	Children 1 to 7 years old (n = 535,544)	Autism Autistic disorder: "Severe qualitative impairment in reciprocal social interaction, in verbal and non verbal communication and in imaginative activity and markedly restricted repertoire of activities and interests" (Steffenburg 1989) Data regarding first hospital visits during the study period identified by ICD‐8/9 codes respectively effective from 1969 to 1986 and from1987 through 1995 (299 ‐ Psychoses ex origine infantia; 2990 ‐ Autismus infantilis; 2998 ‐ Developmental disorder; 2999 ‐ Developmental disorder).	MMR II ‐ vaccine (Merck & Co, West Point, PA) Measles: Enders‐Edmonston Mumps: Jeryl Lynn Rubella: Wistar RA 27/3 Vaccination data were assessed through vaccination register. For autism the risk period is open‐ended.	The study found: no distinguishable clustering was detected in the intervals from vaccination to the hospitalisation. The number of hospital admissions remained relatively steady during the first 3 years and then gradually decreased, as was expected because of the increasing age of the vaccinees (Fig 3). 43 children were vaccinated after the first hospitalisation, and 31 were hospitalised but remained unvaccinated between November 1982 and June 1986. Of the children hospitalised for autism, none made hospital visits because of inflammatory bowel diseases in 1982 to 1995.	ASD cases n = 309	No data available for meta‐analysis
db‐Taylor 1999 Self‐controlled case series	Children born since 1979 from 8 health districts (North Thames, UK)	Autistic disorder “By use of criteria of the International Classification of Diseases, tenth revision (ICD10), the diagnosis of autism was checked against information in the available records on the child’s present condition and his or her condition between the ages of 18 months and 3 years.” ICD‐10 confirmed and non‐confirmed cases from computerised special needs/disability registers at child development centres and from records in special schools. Information on children with such disorders who were younger than 16 years of age was extracted from clinical records by 1 of 3 experienced paediatric registrars.	MMR vaccination identified by Regional Interactive Child Health Computing System (RICHS) Risk period: (a) Autism diagnosis (a1) < 12 months (a2) < 24 months after vaccination (b) Parental concern (b1) < 6 months (b2) < 12 months after vaccination (c) Regression (c1) < 2 months (c2) < 4 months (c3) < 6 months after vaccination Where vaccination and the event of interest occurred in the same month, the authors assumed that vaccination preceded the event.	The case‐series analyses showed no evidence of temporal clustering between MMR or other measles‐containing vaccines and diagnosis of autism. Regression occurred in nearly a third of the cases of core autism; regression was not clustered in the months after vaccination. For age at first parental concern, no significant temporal clustering was seen for cases of core autism or atypical autism, with the exception of a single interval within 6 months of MMR vaccine associated with a peak in reported age at first parental concern at 18 months. This peak is likely to reflect the difficulty experienced by parents in defining the precise age at onset of symptoms in their child, particularly those with atypical autism, and consequent approximation with preference for 18 months. Our results do not support the hypothesis that MMR vaccination is causally related to autism, either its initiation or to the onset of regression.	MMR vaccine (a) Autism diagnosis (n = 357) (b) Parental concern (n = 326) (c) Regression (n = 105)	rr (95% CI)(*) (a1) 0.94 (0.60 to 1.47) (a2) 1.09 (0.79 to 1.52) (b1) 1.48 (1.04 to 2.12) (b2) 0.90 (0.63 to 1.29) (c1) 0.92 (0.38 to 2.21) (c2) 1.00 (0.52 to 1.95) (c3) 0.85 (0.45 to 1.60) (*) relative incidence, Poisson regression
gb‐Fombonne 2001 Case‐only ecological method	Pre‐MMR: Maudsley Family Study (MFS) sample: n = 98 probands who had an ICD‐10 diagnosis of autism PDD. Children born between 1954 and 1979. Post‐MMR: Maudsley Hospital Clinical (MHC) sample: n = 68 children born between 1987 and 1996 and had a confirmed diagnosis of PDD. Post‐MMR: Stafford sample: n = 96 children born between 1992 and 1995 selected as part of an epidemiologic survey of PDD conducted in Staffordshire (Midlands, UK) total population n = 15,500.	Autistic enterocolitis (a) Age (in months) at first parental concern: in the 3 samples, item 2 of the ADI (earlier version of the ADI‐R) was used to assess the first onset of autistic symptoms, or the age of the child at which parents first became concerned about their child’s development. The precise wording of the question is, “How old was your child when you first wondered if there might be something not quite right with his/her development?” (b) Regression: the assessment of regression in the ADI‐R is covered with items 37 to 41 (for language) and items 95 to 103 (for other domains). The regression is assessed for language skills as follows: “Were you ever concerned that your child might have lost language skills during the first years of his/her life? Was there ever a time when he/she stopped speaking for some months after having learned to talk?” Assessment of bowel disorders and symptoms: these data were available only from the epidemiologic sample (Stafford sample). All children were reviewed regularly and are still followed up by the paediatrician, who has records of any additional hospital admissions/medical investigations for bowel disorders in these children. The occurrence of gastrointestinal symptoms was assessed by 2 sources: the parents and the paediatrician. ADI‐R: Autism Diagnostic Interview ‐ Revised was administered with the parents by trained staff. Interrater reliability on the ADI‐R interviews was assessed.	MMR vaccine type not described MFS sample (pre‐MMR): unvaccinated MHC sample (post‐MMR): likely vaccinated Stafford sample (post ‐MMR): likely vaccinated The MMR immunisation programme was introduced in 1988 in the UK (with first MMR given between 12 and 15 months of age) with coverage rates above 90%. MMR coverage rates in 2‐year‐olds fell from 92% in 1995 to 88% in 2000.	No evidence was found to support a distinct syndrome of MMR‐induced autism or of “autistic enterocolitis”. No changes in the mean age of parental recognition of first autistic symptoms were found when 2 samples of children, 1 clinical and 1 epidemiologic, all exposed to MMR immunisation, were compared with a pre‐MMR sample. No increase in the rate of regressive autism in recent years. Rates of regression in the development of children with autism were found to be similar in a pre‐ and post‐MMR sample.	‐‐‐‐MFS sample (n = 98) (a) mean = 19.5 (SD = 13.6) (b) n = 18 ‐‐‐‐MHC sample (n = 68) (a) mean = 19.2 (SD = 8.8) (b) n = 0 ‐‐‐‐Stafford sample (n = 96) (a) mean = 19.3 (SD = 8.7) (b) n = 15 No statistically relevant differences across the 2 samples for the rate of probable or definite regression.	No data available for meta‐analysis

ADI‐R: Autism Diagnostic Interview ‐ Revised
ASD: autism spectrum disorders
CI: confidence interval
DSM: Diagnostic and Statistical Manual of Mental Disorders
GPRD: General Practice Research Database
HMO: health maintenance organisation
HR: hazards ratio
ICD: International Classification of Diseases
ICD‐9‐CM: International Classification of Diseases, Ninth Revision, Clinical Modification
incidence: cases/PT
KPSC: Kaiser PermanteSsouth California
MMR: measles, mumps, rubella vaccine
MMRV: measles, mumps, rubella, and varicella vaccine
OR: odds ratio
PDD: pervasive developmental disorders
PT: person‐time
rr: rate ratio (relative incidence, incidence rate ratio)
RR: risk ratio (relative risk)
SD: standard deviation
YPDC: Yokohama Psycho‐Developmental Clinic

Definitions:

Childhood autism: children with symptoms before the age of 3 years that meet the necessary criteria under each section of the diagnostic triad for autism: communication difficulties, problems with social interaction, and behaviour problems such as stereotyped repetitions.

Atypical autism cases: with many of the features of childhood autism but not quite meeting the required criteria for that diagnosis, or with atypical features such as onset of symptoms after age 3 years (also known as pervasive developmental disorder not otherwise specified).

Developmental regression: a documented deterioration in any aspect of development or reported loss of skills, however transient (International Classification of Diseases, 10th revision (ICD‐10) and Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM‐IV)).