Materials and Methods

This was a population-based cohort study, approved by the California Protection of Human Subjects Committee; the Office of Statewide Health Planning and Development (OSHPD); and the University of California, Davis Human Subjects Committee.

We utilized a database constructed by our group in 2007 to evaluate perinatal risk factors for developmental disabilities. An 11-year birth cohort (Jan. 1, 1991, through Dec. 31, 2001) was identified within a database provided by the California OSHPD, which had previously merged birth records from the Linked Vital Statistics Birth and Infant Death File published by the California Department of Health Services with maternal and infant hospital discharge records from the entire state. The analysis was limited to infants who survived to 1 year of age, without exclusion of children with comorbid congenital or neurodevelopmental abnormalities. This database provided perinatal data that was collected prospectively (at the time of hospital discharge, and filing of birth certificate data), such as maternal demographics and comorbidities, prenatal care, delivery type, and infant BW and GA at delivery. We then identified children with autism within the California Department of Disabilities database who were born in California from Jan. 1, 1991, through Dec. 31, 2001, and linked their information to the maternal and infant birth records within the OSHPD/Department of Health Services files using linkage analysis. The overall rate of successful linkage was 85%, with a range of 81% (in 1991) to 90% (in 2001).

In the current analysis, the predictive variable was defined as BW appropriateness for GA. All births in the cohort were separated by year of birth and sex, and were then assigned to a GA group based on completed weeks of gestation at the time of birth. Regarding determination of GA, the basis for dating criteria was not a variable included within the California OSHPD administrative birth files. For each year, we calculated the threshold values for male and female BW appropriateness by GA within the annual birth cohort (at the 5th, 10th, 90th, and 95th BW percentiles). Each birth according to sex and year was identified as SGA (either <5th or 5-10th percentile), appropriate for GA (>10th to <90th percentile), or LGA (either 90-95th or >95th percentile). Annualized BW percentile thresholds for each GA were tabulated and averaged for descriptive purposes ( Table 1 ). Trend tests demonstrated no significant time trend in percentile thresholds over the 1991 through 2001 time period.

The outcome of the current analysis was a diagnosis of autism. Within California, 75-80% of children with autism are followed up by the California Department of Developmental Services (DDS), which provides services for people with autism, epilepsy, cerebral palsy, and mental retardation, without regard for income. The Client Development Evaluation Report (CDER) database held by DDS was utilized to identify cases of autism by: (1) an autistic level of “one” (full syndrome autism) on any CDER report; or (2) an International Classification of Diseases, Ninth Revision ( ICD -9) code of 299.0 (autistic disorder), 299.8, or 299.9. As specific autism ICD -9 codes were not routinely included in the CDER during the time period queried, we do not have precise information regarding the number of cases of each autism spectrum disorder included without our cohort. We suspect that the majority of cases were autistic disorder, which is the only autism spectrum disorder eligible for services through DDS, in the absence of significant disability. While autism is typically diagnosed by age 3 years, the analysis included cases identified by DDS through Nov. 30, 2006, at which time the youngest member of our cohort was 4 years and 11 months old, leaving time for most of the children with a delayed diagnosis to be included in the analysis.

To estimate the strength of association between BW percentile and autism, OR was calculated with 95% CI. A multivariate logistic regression analysis was designed to account for perinatal risk factors previously associated with both BW percentiles extremes (SGA or LGA) and autism. We screened covariates for association with BW percentile (either SGA or LGA) using previously published studies, and confirmed an association with autism through the univariate analysis, using a 95% CI entirely >1.0 or <1.0 as a threshold for inclusion. We included chronic hypertension ( ICD-9, Clinical Modification [ ICD-9-CM ] 642.0-642.2, 642.7), preeclampsia ( ICD-9-CM 642.5), maternal diabetes ( ICD-9-CM 250, 648.0, 648.8), maternal age, twin gestation ( ICD-9-CM 651.0), birth order (derived from maternal parity), race, and interpregnancy interval (derived from a search for previous deliveries in mothers with a parity >0).

To determine whether GA at birth influenced the association between autism risk and BW appropriateness, the analysis was stratified by GA: very preterm 23-27 weeks 6 days and 28-31 weeks 6 days; midpreterm 32-33 weeks 6 days; late preterm 34-36 weeks 6 days; early term 37-38 weeks 6 days; term 39-41 weeks 6 days; and postdates >42 weeks. Effect modification was ascertained for GA strata using a Cochran-Mantel-Haenszel test for difference of OR without a continuity correction.

Results

Within the cohort of 5,979,605 children born in California from 1991 through 2001, 21,717 children with autism were identified. The remainder of the birth cohort served as the control group (n = 5,957,888). Male sex, advanced maternal and paternal ages, Asian race, chronic hypertension, preeclampsia, any form of diabetes, high birth order (≥3), short interpregnancy interval, and twin gestations were significantly associated with autism ( Table 2 ).

TABLE 2

Demographic data of the 1991-2001 California birth cohort according to autism status

	No autism		Autism		Analysis
Variable	Deliveries, n	%	Deliveries, n	%	OR	95% CI
Total	5,957,888		21,717
Sex of child
Male	3,040,131	51	18011	83	4.66	4.50–4.84
Female	2,917,757	49	3706	17	1.00	Reference
Age of mother
≤20	960,822	16	1753	8	0.77	0.68–0.86
21-25	1,499,201	25	4263	20	1.00	Reference
26-30	1,633,158	27	6081	28	1.28	1.21–1.36
30-35	1,242,483	21	5927	27	1.67	1.57–1.77
35-40	530,653	9	3107	14	2.02	1.89–2.16
≥41	90,664	2	583	3	2.15	1.91–2.43
Age of father
≤20	408,807	7	668	3	0.73	0.61–0.87
21-25	1,149,714	19	2838	13	1.00	Reference
26-30	1,480,484	25	4958	23	1.30	1.21–1.39
30-35	1,339,188	22	5741	26	1.63	1.52–1.74
35-40	757,722	13	3953	18	1.98	1.84–2.12
≥41	408,036	7	2449	11	2.29	2.12–2.48
Maternal race/ethnicity
Non-hispanic white	2,082,149	35	8789	40	1.00	Reference
African American	421,764	7	1764	8	1.02	0.95–1.10
Hispanic	2,759,541	46	7809	36	0.69	0.66–0.73
Asian	593,146	10	3049	14	1.33	1.25–1.41
Other race	75,398	1	206	1	0.69	0.57–0.84
Chronic hypertension
No	5,919,730	99	21516	99	1.00	Reference
Yes	38,158	1	201	1	1.45	1.26–1.67
Preeclampsia
No	5,700,487	96	20468	94	1.00	Reference
Yes	257,401	4	1249	6	1.42	1.29–1.57
Diabetes (any)
No	5,747,210	96	20624	95	1.00	Reference
Yes	210,678	4	1093	5	1.42	1.34–1.52
Parity
Unknown	8,336	<1	23	28	0.14	0.01–1.50
Nulliparous	2,314,526	39	9194	42	1.00	Reference
1	1,851,911	31	7810	36	0.29	0.04–2.04
2	1,003,761	17	2937	14	0.20	0.03–1.41
3	440,443	7	1087	5	0.15	0.02–1.08
4	181,708	3	370	2	0.13	0.02–0.93
≥5	157,203	3	296	1	0.13	0.02–0.91
Birth order
Unknown	772,322	13	3185	41	1.16	1.11–1.20
1	5,162,747	87	18,414	36	1.00	Reference
2	22,466	<1	114	5	1.4	1.18–1.71
≥3	353	<1	4	11	3.18	1.19–8.52
Multiple gestation
No	5,882,776	99	21234	98	1.00	Reference
Yes	75,112	1	483	2	1.81	1.65–1.98
Months since last live birth
Unknown	2,721,666	46	10992	51	1.5	1.39–1.61
0-1.5 y	367,914	6	1673	8	1.70	1.60–1.81
1.5-2.5 y	796,301	13	3310	15	1.53	1.45–1.62
2.5-4 y	850,760	14	2328	11	1.00	Reference
4-6 y	604,500	10	1383	6	0.82	0.76–0.88
≥6 y	616,747	10	2031	9	1.19	1.12–1.26
Birthweight percentile
Unknown	436,800	7	1516	7	0.97	0.92–1.02
<5%	260,587	4	1090	5	1.17	1.10–1.24
5-10%	280,316	5	1070	5	1.07	1.00–1.13
>10 to <90%	4,414,624	74	15828	73	1.00	Reference
90-95%	290,242	5	1083	5	1.04	0.98–1.11
>95%	275,319	5	1130	5	1.15	1.08–1.22

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