Abstract
Maternal infection and fever during pregnancy have been implicated in the etiology of autism spectrum disorder (ASD); however, studies have not been able to separate the effects of fever itself from the impact of a specific infectious organism on the developing brain. We utilized data from the Study to Explore Early Development (SEED), a case-control study among 2- to 5-year-old children born between 2003 and 2006 in the United States, to explore a possible association between maternal infection and fever during pregnancy and risk of ASD and other developmental disorders (DDs). Three groups of children were included: children with ASD (N = 606) and children with DDs (N = 856), ascertained from clinical and educational sources, and children from the general population (N = 796), randomly sampled from state birth records. Information about infection and fever during pregnancy was obtained from a telephone interview with the mother shortly after study enrollment and maternal prenatal and labor/delivery medical records. ASD and DD status was determined by an in-person standardized developmental assessment of the child at 3–5 years of age. After adjustment for covariates, maternal infection anytime during pregnancy was not associated with ASD or DDs. However, second trimester infection accompanied by fever elevated risk for ASD approximately twofold (aOR = 2.19, 95% confidence interval 1.14–4.23). These findings of an association between maternal infection with fever in the second trimester and increased risk of ASD in the offspring suggest that the inflammatory response to the infectious agent may be etiologically relevant.
Keywords: prenatal, autism, neurodevelopment, immune function, developmental disorder, infection
Lay Summary:
Using data from a large multisite study in the United States—the Study to Explore Early Development—we found that women who had an infection during the second trimester of pregnancy accompanied by a fever are more likely to have children with ASD. These findings suggest the possibility that only more severe infections accompanied by a robust inflammatory response increase the risk of ASD.
Introduction
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social interaction and communication and restricted and repetitive patterns of behavior [American Psychiatric Association, 2013].
Maternal infection was one of the earliest suggested non-genetic risk factors for ASD. Following the rubella epidemic of 1964, children with congenital rubella syndrome were found to have an increased rate of ASD [Chess, 1971; Deykin & MacMahon, 1979]. Since then, additional studies have reported elevated rates of ASD among children gestationally exposed to viral infection. Studies examining maternal influenza infections during pregnancy provide inconsistent results [Atladottir, Henriksen, Schendel, & Parner, 2012; Brucato et al., 2017; Fang, Wang, Huang, Yeh, & Chen, 2015; Mahic et al., 2017; Zerbo et al., 2012; Zerbo et al., 2016; Zerbo et al., 2013]. Among women who were hospitalized for infection, increased risk of ASD was reported for any infection in each trimester [Lee et al., 2015], viral infection in the first trimester and bacterial infections in the second trimester [Atladottir et al., 2010], or bacterial infection in the third trimester [Zerbo et al., 2015]. Bacterial and genitourinary (GU) infections during the third trimester were also associated with ASD risk [Fang et al., 2015].
Fever also has been implicated in ASD etiology in a few studies, such as prolonged fevers during pregnancy [Atladottir et al., 2012], untreated fevers in the first and second trimester [Zerbo et al., 2013], and fever in the second trimester [Hornig et al., 2017] or third trimester [Brucato et al., 2017]. However, these studies could not separate the effects of fever itself from those of a specific infectious organism on the developing brain [Croen et al., 2018].
The inconsistencies summarized above are likely the result of methodologic differences across investigations, including study design, ascertainment source for maternal infection and child outcome, type and severity of infection examined, timing of exposure, and covariates included in analyses. Given that up to 60% of women report infection during pregnancy [Collier, Rasmussen, Feldkamp, & Honein, 2009], and the need for further clarification of infection’s relationship with ASD, we attempted to address several limitations of prior work on this topic by conducting a comprehensive analysis using detailed diagnostic and covariate data from a large case-control study. Specifically, we investigated how different types of infection by their timing during pregnancy, treatment, and presentation with fever relate to ASD and other developmental disorders (DD) in the child.
Methods
Study Population
The study population was drawn from the Study to Explore Early Development (SEED), a multisite case-control study of ASD and other developmental disabilities conducted in six sites across the United States: California, Colorado, Georgia, Maryland, North Carolina, and Pennsylvania [Schendel et al., 2012]. Children born between 2003 and 2006 who lived in a site catchment area both at birth and at study enrollment (2007–2011) were eligible to participate. Eligible children were also required to live with an English- (six sites) or Spanish-speaking (two sites) caregiver from at least 6 months of age. Three groups of children were enrolled at ages 2–5 years: children with ASD (cases), children with any one of a range of other neurodevelopmental disorders (DD controls—details summarized in Schendel et al., 2012), and children from the general population (POP controls). Children with ASD and DD were ascertained from multiple clinical and educational sources providing services for children with DD. POP controls were randomly sampled from state birth records in each site. The institutional review boards for each site approved the study and we obtained written informed consent for all enrolled participants.
Outcome Definition and Assessment
Final study group classification (ASD, DD, or POP) was determined by an in-person standardized developmental assessment [Wiggins et al., 2015]. During the study enrollment telephone call, the primary caregiver completed for the child the Social Communication Questionnaire (SCQ) [Rutter, Bailey, & Lord, 2003], a brief screener for ASD. Children who scored ≥11 on the SCQ, and children with a prior ASD diagnosis, were subsequently evaluated with the full assessment battery, which included the Autism Diagnostic Observation Schedule (ADOS) [Gotham, Risi, Pickles, & Lord, 2007; Lord et al., 2000; Lord, Rutter, DiLavore, & Risi, 1999], the Autism Diagnostic Interview Revised (ADI-R) [Lord, Rutter, & Le Couteur, 1994; Rutter, Le Couteur, & Lord, 2003], the Mullen Scales of Early Learning (MSEL) [Mullen, 1995], and the Vineland Adaptive Behavior Scales-Second Edition (VABS-II) [Sparrow, Cichetti, & Balla, 2005]. Children who scored <11 on the SCQ and who had no prior ASD diagnosis were evaluated with the MSEL followed by the VABS-II if the MSEL standard score was <78. If the assessor then suspected ASD, the full assessment battery was administered.
Children with a final classification of ASD (N = 707) were those who met the study ASD case classification criteria on both the ADOS and ADI-R [Wiggins et al., 2015]. We further classified ASD cases according to presence or absence of intellectual disability (ID), defined as a composite standard score ≤70 on the MSEL. Children with a final classification of DD (N = 1270) were those who were ascertained from clinical or education sources with an indication of a neurodevelopmental disorder and who either scored <11 on the SCQ or who scored ≥11 but did not meet study ASD criteria after the full developmental assessment. Children with a final classification of POP (N = 1223) were those ascertained from random sampling of birth certificate files who either scored <11 on the SCQ or scored ≥11 but did not meet study ASD criteria. Only one child per family was included.
Ascertainment of Maternal Infection and Fever
Information on maternal infection and fever during pregnancy was obtained from the SEED caregiver interview (CGI) and the prenatal and labor/delivery medical record. The CGI, conducted over the telephone shortly after study enrollment when the study child was between 2 and 5 years old [Schendel et al., 2012], asked about infections in the period from 3 months before conception through the delivery of the study child. For each specific infection reported, the mother was asked to specify the timing during pregnancy, the types of medications taken, and whether any fever was present. Medical records were abstracted blinded to participant status and provided information on the timing of infections, any medications taken for infections, and the timing and severity of any fever related or unrelated to infection during the pregnancy through 24 hr postpartum.
The primary exposure of interest was maternal infection during the pregnancy with the study child, as reported on either the CGI and/or the maternal medical record. Infection was further classified by the researchers according to microorganism (virus, bacteria, fungus, parasite, unknown) and organ system affected (cardiovascular, eye, skin, gastrointestinal [GI], lower respiratory, other respiratory, GU, and unknown). To evaluate the independent effects of infection and fever, we also examined associations with maternal infections accompanied by fever, and infections for which fever was absent.
Covariates
We examined several factors previously found to be associated with ASD [Lyall et al., 2017] or maternal infection during pregnancy as potential confounders [Jiang et al., 2016]. Maternal age and child sex were ascertained during study enrollment. Maternal education, race-ethnicity, hypertension during pregnancy, and household income were collected during the caregiver interview. Maternal history of psychiatric diseases was ascertained from both the CGI and a self-administered maternal medical history form.
Statistical Analysis
Children whose mothers completed the CGI and provided a prenatal medical record comprised the analytic sample. Initial analyses compared the distributions of each potential confounder by outcome group and separately by exposure status using chi-square tests to assess statistical significance.
For each exposure definition, we ran separate unadjusted and adjusted logistic regression models to estimate the association with ASD (vs. POP controls, vs. DD) and DD (vs. POP controls) by trimester of exposure (T0 = 3 months preconception; T1 = first trimester; T2 = second trimester; T3 = third trimester; and pregnancy [any trimester]). Adjusted logistic regression models included the following covariates: maternal self-reported race/ethnicity, maternal education, household income during pregnancy, maternal age at birth, maternal psychiatric condition history, maternal hypertension, child’s sex, and study site. To evaluate the association with maternal infection or fever independent of potential effects of medication used to treat the condition, we also ran models that additionally adjusted for treatment with any medication. Because all analyses were conducted as part of a single hypothesis of whether ASD is associated with maternal infection, we did not control for multiple comparisons.
Results
The proportion of males was significantly higher in the ASD group compared to the DD and POP groups (Table 1). Mothers of children with ASD or DD were significantly more likely to be non-White, and to have a lower educational attainment at time of the index child’s birth and lower household income during pregnancy compared with mothers of POP controls. ASD case mothers were also more likely to have a lifetime history of psychiatric conditions and hypertension during pregnancy than POP mothers. The majority of ASD cases had ID (59.2%).
Table 1.
Characteristics of the Study Population, Study to Explore Early Development (SEED), 2003–2006 Births
| ASD (N = 606) | DD (N = 856) | POP (N = 796) | ASD vs. POP | DD vs. POP | ASD vs. DD | |
|---|---|---|---|---|---|---|
| Variable name | N (%) | N (%) | N (%) | P-value | P-value | P-value |
| Child sex (Male) | 496 (81.85) | 569 (66.47) | 417 (52.39) | <0.0001 | <0.0001 | <0.0001 |
| Intellectual disability | 359 (59.24) | 180 (21.03) | 16 (2.01) | <0.0001 | <0.0001 | <0.0001 |
| Maternal age at birth (years) | 0.0499 | 0.0131 | 0.3524 | |||
| <20 | 17 (2.81) | 30 (3.50) | 26 (3.27) | |||
| 21–25 | 75 (12.38) | 113 (13.20) | 65 (8.17) | |||
| 26–30 | 176 (29.04) | 212 (24.77) | 211 (26.51) | |||
| 31–35 | 206 (33.99) | 290 (33.88) | 305 (38.32) | |||
| ≥36 | 132 (21.78) | 211 (24.65) | 189 (23.74) | |||
| Maternal race/ethnicity | <0.0001 | <0.0001 | 0.0429 | |||
| White | 397 (65.51) | 581 (67.87) | 621 (78.02) | |||
| Black | 109 (17.99) | 146 (17.06) | 82 (10.30) | |||
| Asian | 45 (7.43) | 32 (3.74) | 31 (3.89) | |||
| Hispanic | 25 (4.13) | 46 (5.37) | 23 (2.89) | |||
| Other | 26 (4.29) | 45 (5.26) | 34 (4.27) | |||
| Unknown | 4 (0.66) | 6 (0.70) | 5 (0.63) | |||
| Maternal education | <0.0001 | <0.0001 | 0.1078 | |||
| High school or less | 92 (15.18) | 155 (18.11) | 66 (8.29) | |||
| College or some college | 378 (62.38) | 491 (57.36) | 485 (60.93) | |||
| Graduate school | 133 (21.95) | 209 (24.42) | 244 (30.65) | |||
| Unknown | 3 (0.50) | 1 (0.12) | 1 (0.13) | |||
| Family income during pregnancy | <0.0001 | <0.0001 | 0.3011 | |||
| <30 K | 148 (24.42) | 185 (21.61) | 101 (12.69) | |||
| 30–70 K | 183 (30.20) | 256 (29.91) | 233 (29.27) | |||
| 70–110 K | 156 (25.74) | 227 (26.52) | 264 (33.17) | |||
| >110 K | 102 (16.83) | 147 (17.17) | 180 (22.61) | |||
| Unknown | 17 (2.81) | 41 (4.79) | 18 (2.26) | |||
| Maternal psychiatric condition history | <0.0001 | 0.0005 | 0.5475 | |||
| Yes | 256 (42.24) | 344 (40.19) | 247 (31.03) | |||
| No | 331 (54.62) | 490 (57.24) | 526 (66.08) | |||
| Unknown | 19 (3.14) | 22 (2.57) | 23 (2.89) | |||
| Hypertension during pregnancy | 0.0006 | <0.0001 | <0.0001 | |||
| Yes | 115 (18.98) | 132 (15.42) | 93 (11.68) | |||
| No | 472 (77.89) | 558 (65.19) | 680 (85.43) | |||
| Unknown | 19 (3.14) | 166 (19.39) | 23 (2.89) | |||
| Site | 0.7983 | 0.049 | 0.0035 | |||
| 2 | 75 (12.38) | 108 (12.62) | 100 (12.56) | |||
| 3 | 134 (22.11) | 165 (19.28) | 179 (22.49) | |||
| 4 | 111 (18.32) | 180 (21.03) | 142 (17.84) | |||
| 5 | 102 (16.83) | 102 (11.92) | 115 (14.45) | |||
| 6 | 101 (16.67) | 200 (23.36) | 151 (18.97) | |||
| 7 | 83 (13.70) | 101 (11.80) | 109 (13.69) |
Abbreviations: ASD, autism spectrum disorder; DD, developmental disorder; POP, population controls.
Approximately 60% of mothers in each study group experienced an infection during pregnancy (Table 2). GU infections were the most frequently reported maternal infections in all three study groups, and were significantly more common among the mothers of children with ASD compared with the mothers of POP controls (31.5% vs. 26.4%, P = 0.04). Respiratory tract infections occurred in approximately 25% of mothers of ASD, DD, and POP children. Cardiovascular, skin, eye, ear, and GI infections each occurred in 3% or less of mothers of children in all outcome groups. According to microorganism, bacterial infections occurred in roughly a third of the population, and significantly more often in mothers of children with ASD than mothers of POP controls (36.3% vs. 31.3%, P = 0.05). The most commonly reported bacterial infections in all study groups were Group B Streptococcus (16.8% ASD, 10.5% DD, and 13.3% POP) and urinary tract infections (17% ASD, 13.8% DD, and 11.8% POP). Viral infections occurred in ~13% of the study population, with influenza (5.6% ASD, 5.6% DD, 5.4% POP) and human papillomavirus (2% ASD, 2.6% DD, 2.1% POP) being the most frequently reported in each study group. Fungal infections (11%–13%), all of which were yeast infections, and parasitic infections (~1%–2%) were the least common infections reported during pregnancy; there were no differences in prevalence across study groups (Table 2). Among women with any infection during pregnancy, there was laboratory confirmation of infection (positive cultures) for mothers of 155 (42.2%) ASD, 197 (31.1%) DD, and 197 (41.9%) POP children. The frequency of all laboratory-identified microorganisms is listed in Supporting Information Table S1. Only conditions with at least 10 affected women in each study group in each time period were analyzed further.
Table 2.
Maternal Infection During Pregnancya, by Organ System and Organism, Study to Explore Early Development, 2003–2006 Births
| ASD (N = 606) | DD (N = 856) | POP (N = 796) | ASD vs. POP | DD vs. POP | ASD vs. DD | |
|---|---|---|---|---|---|---|
| Maternal infection | N (%) | N (%) | N (%) | P-value | P-value | P-value |
| Any infection | 367 (60.56) | 504 (58.88) | 470 (59.05) | 0.58 | 0.96 | 0.52 |
| Organ system | ||||||
| Cardiovascular | 1 (0.17) | 0 (0.00) | 1 (0.13) | 1.00 | 0.41 | |
| Eye | 5 (0.83) | 4 (0.47) | 6 (0.75) | 1.00 | 0.54 | 0.50 |
| Gastrointestinal | 17 (2.81) | 32 (3.74) | 24 (3.02) | 0.87 | 0.50 | 0.33 |
| Genitourinary | 191 (31.52) | 244 (28.50) | 210 (26.38) | 0.04 | 0.35 | 0.21 |
| Lower respiratory | 6 (0.99) | 11 (1.29) | 6 (0.75) | 0.77 | 0.34 | 0.60 |
| Other respiratoryb | 144 (23.76) | 217 (25.35) | 201 (25.25) | 0.53 | 1.00 | 0.49 |
| Skin | 11 (1.82) | 15 (1.57) | 6 (0.75) | 0.09 | 0.08 | 0.93 |
| Other organ | 25 (4.13) | 38 (4.44) | 29 (3.64) | 0.68 | 0.87 | 0.77 |
| Unknown organ | 189 (31.19) | 206 (20.07) | 198 (24.87) | 0.01 | 0.73 | 0.002 |
| Organism | ||||||
| Bacteria | 220 (36.30) | 264 (30.84) | 249 (31.28) | 0.05 | 0.87 | 0.02 |
| Virus | 82 (13.53) | 114 (13.32) | 104 (13.07) | 0.81 | 0.88 | 0.91 |
| Fungus | 82 (13.53) | 101 (11.80) | 90 (11.31) | 0.22 | 0.76 | 0.32 |
| Parasite | 9 (1.49) | 20 (2.34) | 11 (1.38) | 1.00 | 0.20 | 0.25 |
| Unknown | 188 (31.22) | 269 (31.43) | 244 (30.65) | 0.91 | 0.75 | 0.77 |
Abbreviations: ASD, autism spectrum disorder; DD, developmental disorder; POP, population controls.
Infection data obtained from both CGI and medical records.
Other respiratory includes all respiratory infections not medically identified as lower respiratory. These include upper respiratory, throat, or other infections of the respiratory system.
The bold indicates that the P-value is <0.05.
Crude and adjusted odds ratios (ORs) and 95% confidence interval (CI) for ASD and DD in association with timing of maternal infection during pregnancy are shown by organ system and by microorganism (Table 3). There was no association between any infection anytime during pregnancy (T1–T3) and risk of ASD in crude and adjusted analyses (Table 3), and odds were similar for ASD with ID (aOR = 0.89, 95% CI 0.67–1.2) and ASD without ID (aOR = 1.31, 95% CI 0.67–2.56; Supporting Information Table S2). However, maternal infection in the 3 months prior to conception (T0) was significantly associated with higher risk of ASD after adjustment for covariates (Model 1), including adjustment for treatment with medication (Model 2; Table 3). This risk was only observed for ASD with ID (aOR = 2.06, 95% CI 1.31–3.24; Supporting Information Table S2). Any maternal infection in T3 was significantly associated with reduced risk for DD after adjustment for covariates (Model 1), but this association was no longer statistically significant after additional adjustment for treatment (Table 3). In all adjusted analyses, no significant associations with ASD or DD were observed for infections with specific organ systems or specific microorganisms (Table 3).
Table 3.
Maternal Infectionc by Organ System, Organism, and Timing During Pregnancy and Risk of Autism Spectrum Disorder and Developmental Disorder, Study to Explore Early Development, 2003–2006 Births
| Infection by trimester | ASD (N = 606) N (%) |
DD (N = 856) N (%) |
POP (N = 796) N (%) |
ASD vs. POP | DD vs. POP | ||||
|---|---|---|---|---|---|---|---|---|---|
| Crude OR (95% Cl) | ORadjl (95% Cl) | ORadj2 (95% Cl) | Crude OR (95% Cl) | ORadjl (95% Cl) | ORadj2 (95% Cl) | ||||
| Any infection | |||||||||
| T0 | 76 (12.5) | 73 (8.5) | 62 (7.8) | 1.70 (1.2–2.4) | 1.58 (1.05–2.37) | 1.73 (1.03–2.93) | 1.10 (0.08–1.57) | 0.98 (0.65–1.46) | 0.91 (0.53–1.57) |
| T1 | 174 (28.71) | 227 (26.52) | 203 (25.50) | 1.18 (0.93–1.49) | 1.19 (0.90–1.56) | 1.09 (0.79–1.50) | 1.05 (0.85–1.31) | 0.99 (0.77–1.28) | 0.93 (0.69–1.25) |
| T2 | 187 (30.86) | 260 (30.37) | 221 (27.76) | 1.16 (0.92–1.46) | 1.02 (0.78–1.33) | 0.87 (0.65–1.17) | 1.14 (0.92–1.40) | 0.88 (0.69–1.13) | 0.81 (0.62–1.06) |
| T3 | 252 (41.58) | 308 (35.98) | 311 (39.07) | 1.11 (0.90–1.38) | 1.04 (0.81–1.33) | 1.11 (0.84–1.45) | 0.88 (0.72–1.07) | 0.74 (0.59–0.93) | 0.83 (0.65–1.06) |
| Pregnancy | 367 (60.6) | 504 (58.9) | 470 (59.0) | 1.07 (0.86–1.3) | 1.02 (0.79–1.31) | 0.94 (0.68–1.31) | 0.99 (0.81–1.2) | 0.84 (0.67–1.05) | 0.80 (0.59–1.08) |
| Organ system | |||||||||
| Respiratorya | |||||||||
| T0 | 17 (2.81) | 12 (1.40) | 14 (1.76) | 1.61 (0.79–3.30) | 1.35 (0.59–3.10) | 1.73 (0.46–6.49) | 0.79 (0.37–1.73) | 1.00 (0.43–2.30) | 0.79 (0.20–3.10) |
| T1 | 48 (7.92) | 70 (8.18) | 59 (7.41) | 1.07 (0.72–1.60) | 1.32 (0.84–2.08) | 1.24 (0.77–1.99) | 1.11 (0.78–1.60) | 1.13 (0.74–1.70) | 1.10 (0.72–1.68) |
| T2 | 64 (10.56) | 106 (12.38) | 87 (10.93) | 0.96 (0.68–1.35) | 1.05 (0.70–1.56) | 0.97 (0.64–1.45) | 1.15 (0.85–1.56) | 1.01 (0.71–1.45) | 0.98 (0.68–1.41) |
| T3 | 69 (11.39) | 99 (11.57) | 103 (12.94) | 0.86 (0.62–1.20) | 0.81 (0.56–1.19) | 0.84 (0.57–1.25) | 0.88 (0.66–1.18) | 0.76 (0.53–1.08) | 0.78 (0.55–1.12) |
| Pregnancy | 145 (23.93) | 219 (25.58) | 205 (25.75) | 0.91 (0.71–1.16) | 0.97 (0.73–1.30) | 0.79 (0.51–1.23) | 0.99 (0.79–1.24) | 0.88 (0.68–1.15) | 0.86 (0.58–1.26) |
| Genitourinary | |||||||||
| T0 | 38 (6.27) | 39 (4.56) | 28 (3.52) | 1.84 (1.11–3.03) | 1.67 (0.94–2.98) | 1.52 (0.76–3.04) | 1.31 (0.80–2.15) | 1.20 (0.67–2.13) | 0.93 (0.46–1.86) |
| T1 | 87 (14.36) | 99 (11.57) | 98 (12.31) | 1.19 (0.88–1.63) | 1.16 (0.81–1.66) | 1.01 (0.66–1.55) | 0.93 (0.69–1.25) | 0.80 (0.57–1.14) | 0.66 (0.44–1.00) |
| T2 | 87 (14.36) | 123 (14.37) | 87 (10.93) | 1.37 (0.99–1.88) | 1.02 (0.70–1.47) | 0.80 (0.53–1.20) | 1.37 (1.02–1.83) | 0.99 (0.70–1.39) | 0.91 (0.62–1.32) |
| T3 | 107 (17.66) | 128 (14.95) | 120 (15.08) | 1.21 (0.91–1.61) | 1.09 (0.79–1.51) | 1.17 (0.82–1.67) | 0.99 (0.76–1.30) | 0.80 (0.58–1.10) | 0.86 (0.61–1.21) |
| Pregnancy | 191 (31.52) | 244 (28.50) | 212 (26.63) | 1.27 (1.00–1.60) | 1.12 (0.86–1.48) | 1.08 (0.74–1.57) | 1.10 (0.88–1.36) | 0.86 (0.67–1.12) | 0.83 (0.57–1.19) |
| Other/unknownb | |||||||||
| T0 | 27 (4.46) | 32 (3.74) | 25 (3.14) | 1.44 (0.83–2.50) | 1.51 (0.81–2.83) | 1.48 (0.64–3.41) | 1.20 (0.70–2.04) | 0.78 (0.41–1.50) | 0.59 (0.20–1.71) |
| T1 | 83 (13.70) | 105 (12.27) | 85 (10.68) | 1.33 (0.96–1.83) | 1.23 (0.85–1.79) | 1.21 (0.78–1.86) | 1.17 (0.86–1.58) | 1.07 (0.76–1.52) | 1.01 (0.67–1.51) |
| T2 | 74 (12.21) | 94 (10.98) | 82 (10.30) | 1.21 (0.87–1.69) | 0.99 (0.68–1.45) | 0.86 (0.56–1.32) | 1.07 (0.79–1.47) | 0.79 (0.54–1.14) | 0.78 (0.53–1.16) |
| T3 | 148 (24.42) | 155 (18.11) | 156 (19.60) | 1.33 (1.03–1.71) | 1.28 (0.95–1.71) | 1.33 (0.95–1.87) | 0.91 (0.71–1.16) | 0.84 (0.64–1.11) | 0.89 (0.64–1.22) |
| Pregnancy | 213 (35.15) | 263 (30.72) | 237 (29.77) | 1.28 (1.02–1.60) | 1.18 (0.91–1.53) | 1.25 (0.87–1.79) | 1.05 (0.85–1.29) | 0.95 (0.75–1.21) | 1.02 (0.73–1.42) |
| Organism | |||||||||
| Bacteria | |||||||||
| T0 | 31 (5.12) | 31 (3.62) | 19 (2.39) | 2.20 (1.23–3.94) | 1.77 (0.90–3.50) | 1.61 (0.66–3.90) | 1.54 (0.86–2.74) | 1.06 (0.52–2.15) | 0.75 (0.23–2.51) |
| T1 | 74 (12.21) | 79 (9.23) | 80 (10.05) | 1.24 (0.89–1.74) | 1.22 (0.82–1.79) | 1.07 (0.65–1.77) | 0.91 (0.66–1.26) | 0.81 (0.55–1.19) | 0.74 (0.45–1.21) |
| T2 | 79 (13.04) | 87 (10.16) | 68 (8.54) | 1.60 (1.14–2.26) | 1.15 (0.78–1.71) | 0.80 (0.50–1.28) | 1.21 (0.87–1.69) | 0.82 (0.55–1.22) | 0.72 (0.46–1.13) |
| T3 | 152 (25.08) | 167 (19.51) | 171 (21.48) | 1.22 (0.95–1.57) | 1.14 (0.86–1.52) | 1.07 (0.77–1.49) | 0.89 (0.70–1.13) | 0.78 (0.59–1.03) | 0.87 (0.64–1.19) |
| Pregnancy | 221 (36.47) | 264 (30.84) | 249 (31.28) | 1.26 (1.01–1.58) | 1.14 (0.88–1.48) | 0.96 (0.67–1.36) | 0.98 (0.80–1.21) | 0.85 (0.67–1.08) | 0.90 (0.65–1.24) |
| Virus | |||||||||
| T0 | 21 (3.47) | 20 (2.34) | 21 (2.64) | 1.32 (0.72–2.45) | 1.44 (0.72–2.88) | 1.65 (0.78–3.47) | 0.88 (0.47–1.64) | 1.01 (0.51–2.01) | 1.04 (0.51–2.13) |
| T1 | 40 (6.60) | 44 (5.14) | 38 (4.77) | 1.41 (0.89–2.23) | 1.48 (0.88–2.47) | 1.48 (0.83–2.64) | 1.08 (0.69–1.69) | 0.89 (0.54–1.49) | 0.81 (0.46–1.42) |
| T2 | 38 (6.27) | 57 (6.66) | 55 (6.91) | 0.90 (0.59–1.38) | 0.86 (0.53–1.39) | 0.81 (0.48–1.37) | 0.96 (0.65–1.41) | 0.90 (0.59–1.39) | 0.78 (0.49–1.25) |
| T3 | 44 (7.26) | 59 (6.89) | 56 (7.04) | 1.03 (0.69–1.56) | 0.98 (0.62–1.55) | 0.91 (0.54–1.53) | 0.98 (0.67–1.43) | 0.91 (0.59–1.39) | 0.90 (0.56–1.44) |
| Pregnancy | 82 (13.53) | 114 (13.32) | 104 (13.07) | 1.04 (0.76–1.42) | 0.99 (0.69–1.40) | 0.83 (0.54–1.30) | 1.02 (0.77–1.36) | 0.87 (0.63–1.21) | 0.75 (0.49–1.14) |
| Fungus | |||||||||
| T0 | 14 (2.31) | 19 (2.22) | 14 (1.76) | 1.32 (0.62–2.79) | 1.65 (0.70–3.86) | 3.22 (0.45–22.99) | 1.27 (0.63–2.55) | 0.90 (0.39–2.06) | |
| T1 | 38 (6.27) | 51 (5.96) | 37 (4.65) | 1.37 (0.86–2.19) | 1.11 (0.66–1.88) | 0.92 (0.43–1.93) | 1.30 (0.84–2.01) | 1.16 (0.71–1.90) | 0.89 (0.43–1.82) |
| T2 | 39 (6.44) | 44 (5.14) | 37 (4.65) | 1.41 (0.89–2.24) | 1.17 (0.69–1.97) | 1.55 (0.75–3.23) | 1.11 (0.71–1.74) | 0.77 (0.45–1.30) | 0.82 (0.40–1.66) |
| T3 | 36 (5.94) | 39 (4.56) | 37 (4.65) | 1.30 (0.81–2.08) | 1.08 (0.63–1.84) | 1.51 (0.70–3.27) | 0.98 (0.62–1.55) | 0.81 (0.48–1.36) | 1.05 (0.53–2.09) |
| Pregnancy | 82 (13.53) | 101 (11.80) | 90 (11.31) | 1.23 (0.89–1.69) | 1.05 (0.72–1.51) | 1.64 (0.83–3.25) | 1.05 (0.78–1.42) | 0.87 (0.62–1.23) | 1.09 (0.55–2.17) |
| Unknown | |||||||||
| T0 | 18 (2.97) | 14 (1.64) | 15 (1.88) | 1.59 (0.80–3.19) | 1.38 (0.62–3.10) | 1.51 (0.52–4.38) | 0.87 (0.42–1.81) | 0.99 (0.44–2.23) | 1.07 (0.35–3.20) |
| Tl | 79 (13.04) | 96 (11.21) | 87 (10.93) | 1.22 (0.88–1.69) | 1.38 (0.95–2.01) | 1.38 (0.92–2.07) | 1.03 (0.76–1.40) | 1.05 (0.74–1.49) | 1.05 (0.72–1.54) |
| T2 | 77 (12.71) | 127 (14.84) | 97 (12.19) | 1.05 (0.76–1.44) | 0.98 (0.68–1.42) | 0.85 (0.57–1.25) | 1.26 (0.95–1.67) | 1.02 (0.73–1.43) | 0.98 (0.70–1.39) |
| T3 | 103 (17.00) | 124 (14.49) | 128 (16.08) | 1.07 (0.80–1.42) | 1.10 (0.79–1.53) | 1.22 (0.87–1.73) | 0.88 (0.68–1.16) | 0.78 (0.57–1.07) | 0.82 (0.59–1.14) |
| Pregnancy | 186 (30.69) | 269 (31.43) | 243 (30.53) | 1.01 (0.80–1.27) | 1.02 (0.79–1.34) | 0.90 (0.61–1.32) | 1.04 (0.85–1.28) | 0.93 (0.73–1.18 | 0.82 (0.58–1.16) |
Abbreviations: ASD, autism spectrum disorder; DD, developmental disorder; POP, population controls; OR, odds ratio; ORadj, adjusted odds ratio; T0, 3 months before conception; T1, trimester one; T2, trimester two; T3, trimester three.
Note. ORadj1 = adjusted for child sex, maternal age, maternal race, maternal education, income during pregnancy, maternal psychiatric disease history, hypertension, site. ORadj2 = adjusted by all variables in model 1 plus any medication for infection.
Respiratory = lower respiratory, other respiratory.
Other/Unknown = cardiovascular, skin, eye, GI, other, unknown.
Infection data obtained from both CGI and medical records.
The bold entries indicate that the confidence interval does not include 1.0, indicating statistical significance.
Among women who had an infection during pregnancy, fever was present for 23% of ASD cases, and 21% of both DD and POP controls. Infection accompanied by fever in T2 was associated with a doubling in odds of ASD versus POP in crude and adjusted analyses (Table 4). Infection with fever in T2 was also associated with higher odds of ASD compared to DD but the point estimate was smaller and not significant (Supplementary Table 3). Over 85% of infections with fever in T2 were respiratory infections (14% bacterial, 45% viral, 50% unknown organism). Additional adjustment for treatment with any medication (88% ASD, 52% POP), including antibiotics and antipyretics, did not alter the point estimate, but the association was no longer statistically significant (Table 4). Only two mothers (both of ASD cases) who did not report an infection reported a fever in T2. When fever from infection was combined with fever unrelated to infection, we observed a twofold increased risk for ASD associated with fever in T2, after adjusting for all covariates and treatment with any medication (aOR = 2.11, 95% CI 1.04–4.25) or treatment with acetaminophen (15% ASD, 14% POP, aOR = 2.23, 95% CI 1.15–4.35; Table 5). Risk was significantly elevated only for the ASD without ID subgroup (aOR = 3.17, 95% CI 1.51–6.67; Supporting Information Table S2). Infection without fever in T0 was associated with a marginally significant 70% increase in risk of ASD, after adjustment for all covariates including treatment with any medication (Table 4), and was driven by the ASD with ID subgroup (aOR = 1.92, 95% CI 1.26–2.92). The majority (52%) of these T0 infections without fever were GU (39% bacterial, 29% viral, 24% fungal, and 21% unknown organism). Infection without fever in T3 was associated with lower odds of DD (aOR = 0.71, 95% CI 0.55–0.90; Table 4).
Table 4.
Maternal Infectiona With and Without Fever by Timing During Pregnancy and Risk of Autism Spectrum Disorder, Study to Explore Early Development, 2003–2006 Births
| Infection by trimester | ASD N (%) |
DD N (%) |
POP N (%) |
ASD vs. POP | DD vs. POP | ||||
|---|---|---|---|---|---|---|---|---|---|
| Crude OR (95% Cl) | ORadjl (95% Cl) | ORadj2 (95% Cl) | Crude OR (95% Cl) | ORadjl (95% Cl) | ORadj2 (95% Cl) | ||||
| Any infection with fever | |||||||||
| T0 | 11 (2.03) | 4 (0.51) | 7 (0.94) | 2.18 (0.84–5.65) | 2.11 (0.68–6.58) | - | 0.54 (0.16–1.84) | 0.26 (0.05–1.48) | - |
| T1 | 20 (4.42) | 16 (2.48) | 25 (4.05) | 1.10 (0.60–2.00) | 0.91 (0.46–1.79) | 0.87 (0.32–2.40) | 0.60 (0.32–1.14) | 0.55 (0.27–1.15) | 0.61 (0.25–1.49) |
| T2 | 31 (6.89) | 38 (5.99) | 21 (3.52) | 2.03 (1.15–3.58) | 2.19 (1.14–4.23) | 2.05 (0.95–4.45) | 1.75 (1.01–3.01) | 1.65 (0.87–3.11) | 1.46 (0.74–2.87) |
| T3 | 30 (7.81) | 48 (8.05) | 44 (8.32) | 0.93 (0.58–1.52) | 0.80 (0.45–1.40) | 1.04 (0.56–1.93) | 0.97 (0.63–1.48) | 0.88 (0.54–1.44) | 1.05 (0.60–1.81) |
| Pregnancy | 73 (23.40) | 92 (20.72) | 86 (20.87) | 1.16 (0.81–1.65) | 1.08 (0.71–1.62) | 0.95 (0.45–1.98) | 0.99 (0.71–1.38) | 0.86 (0.59–1.26) | 0.63 (0.32–1.27) |
| Any infection without fever | |||||||||
| T0 | 65 (10.92) | 69 (8.10) | 55 (6.97) | 1.64 (1.12–2.33) | 1.51 (0.98–2.31) | 1.72 (1.01–2.94) | 1.18 (0.81–1.70) | 1.05 (0.69–1.59) | 0.96 (0.55–1.66) |
| T1 | 154 (26.28) | 211 (25.12) | 178 (23.09) | 1.19 (0.93–1.52) | 1.23 (0.92–1.64) | 1.16 (0.84–1.62) | 1.12 (0.89–1.40) | 1.06 (0.81–1.39) | 0.94 (0.69–1.28) |
| T2 | 156 (27.13) | 222 (27.14) | 200 (25.81) | 1.07 (0.84–1.37) | 0.92 (0.69–1.22) | 0.83 (0.61–1.12) | 1.07 (0.86–1.34) | 0.82 (0.63–1.06) | 0.77 (0.58–1.01) |
| T3 | 222 (38.45) | 260 (32.18) | 267 (35.51) | 1.14 (0.91–1.43) | 1.07 (0.83–1.38) | 1.13 (0.85–1.49) | 0.86 (0.70–1.06) | 0.71 (0.55–0.90) | 0.80 (0.62–1.04) |
| Pregnancy | 294 (55.16) | 412 (53.93) | 384 (54.08) | 1.04 (0.83–1.31) | 1.01 (0.78–1.31) | 0.96 (0.68–1.36) | 0.99 (0.81–1.22) | 0.82 (0.65–1.04) | 0.83 (0.60–1.13) |
Abbreviations: ASD, autism spectrum disorder; DD, developmental disorder; POP, population controls; OR, odds ratio; ORadj, adjusted odds ratio; T0, 3 months before conception; T1, trimester one; T2, trimester two; T3, trimester three.
Note. ORadj1 = adjusted by child sex, maternal age, maternal race, maternal education, income during pregnancy, maternal psychiatric disease history, hypertension, site. ORadj2 = adjusted by all variables in model 1 plus any medication for infection.
Infection data obtained from both CGI and medical records.
The bold entries indicate that the confidence interval does not include 1.0, indicating statistical significance.
Table 5.
Maternal Fever (Infection and Noninfection Related)a by Timing During Pregnancy and Risk of Autism Spectrum Disorder, Study to Explore Early Development, 2003–2006 Births
| ASD (N = 606) N (%) |
DD (N = 856) N (%) |
POP (N = 796) N (%) |
ASD vs. POP | ||||
|---|---|---|---|---|---|---|---|
| Fever by trimester | Crude OR | ORadj1 | ORadj2 | ORadj3 | |||
| Any fever | |||||||
| T0 | 11 (1.82) | 4 (0.47) | 7 (0.88) | 2.08 (0.80–5.41) | 2.00 (0.64–6.23) | 2.68 (0.62–11.60) | 2.27 (0.71–7.24) |
| T1 | 22 (3.63) | 16 (1.87) | 26 (3.27) | 1.12 (0.63–1.99) | 1.01 (0.53–1.91) | 0.84 (0.40–1.75) | 0.84 (0.41–1.72) |
| T2 | 33 (5.45) | 40 (4.67) | 21 (2.64) | 2.13 (1.22–3.17) | 2.31 (1.21–4.39) | 2.11 (1.04–4.25) | 2.23 (1.15–4.35) |
| T3 | 64 (10.56) | 99 (11.57) | 86 (10.80) | 0.97 (0.69–1.37) | 0.88 (0.60–1.30) | 0.89 (0.60–1.31) | 0.84 (0.56–1.25) |
| Pregnancy | 105 (17.33) | 138 (16.12) | 124 (15.58) | 1.14 (0.85–1.51) | 1.06 (0.77–1.47) | 1.05 (0.75–1.47) | 0.99 (0.71–1.38) |
Abbreviations: ASD, autism spectrum disorder; DD, developmental disorder; POP, population controls; OR, odds ratio; ORadj, adjusted odds ratio; T0, 3 months before conception; T1, trimester one; T2, trimester two; T3, trimester three.
Note. ORadj1 = adjusted by child sex, maternal age, maternal race, maternal education, income during pregnancy, maternal psychiatric disease history, hypertension, site. ORadj2 = adjusted by all variables in model 1 plus any medication for infection. ORadj3 = adjusted by all variables in model 1 plus acetaminophen use.
Infection data obtained from both CGI and medical records.
The bold entries indicate that the confidence interval does not include 1.0, indicating statistical significance.
Discussion
In this large and diverse U.S. study population, maternal infection during pregnancy occurred in approximately 60% of women. ASD was associated with maternal infection accompanied by fever during the second trimester and maternal infection without fever during the 3 months before conception, after controlling for several covariates including treatment with medication. By contrast, DD was not adversely associated with maternal infection with or without fever preconceptionally or in any trimester of pregnancy.
The prevalence of infection reported in the SEED study is comparable to that reported in another US study that defined infection based on diagnoses prospectively documented in electronic medical records [Zerbo et al., 2013]. That study also found no association between maternal infection overall and ASD. Unlike previous studies showing associations with maternal viral infection [Atladottir et al., 2012; Atladottir et al., 2010; Chess, 1971; Deykin & MacMahon, 1979; Libbey, Sweeten, McMahon, & Fujinami, 2005; Lintas, Altieri, Lombardi, Sacco, & Persico, 2010], bacterial infections [Atladottir et al., 2010; Fang et al., 2015; Zerbo et al., 2015], or GU tract infections [Fang et al., 2015], we did not identify any particular type of infection associated with ASD.
Our finding of an increased odds of ASD associated with maternal infection accompanied by fever in the second trimester is consistent with the results of three large cohort studies [Atladottir et al., 2012; Brucato et al., 2017; Hornig et al., 2017] and one case-control study [Zerbo et al., 2012]. Maternal fever in the second trimester was associated with elevated risk of ASD in a large Norwegian pregnancy cohort [Hornig et al., 2017], with prevalence of maternally reported fever (~16%) similar to that in our study. Second trimester fever of any length and fever lasting ≥7 days in the first and second trimester were also associated with increased risk of ASD in a large Danish cohort [Atladottir et al., 2012]. An increased risk for ASD was associated with maternal fever at any time during pregnancy and during the third trimester in a prospective birth cohort in Boston [Brucato et al., 2017]. Finally, second trimester fever doubled risk of ASD in CHARGE, a case-control study in California [Zerbo et al., 2012]. Unlike the CHARGE study, where use of any antipyretic treatment attenuated ASD risk, adjustment for acetaminophen use in our study and the Hornig study did not alter findings. Neither study was able to examine the impact of treatment with ibuprofen, an antipyretic with anti-inflammatory properties, since no ASD case mothers reported this exposure during pregnancy. Larger studies with information on fever and specific fever-related medications would help elucidate whether use of an anti-inflammatory to reduce fever results in lower risk of ASD compared to use of other antipyretics that do not have anti-inflammatory properties (i.e., acetaminophen).
Our finding that risk of ASD was elevated only in the presence of fever during pregnancy suggests that more severe infections accompanied by a robust inflammatory response may be etiologically relevant. Previous studies reporting increased ASD risk in association with severe, hospitalized infections [Atladottir et al., 2010; Lee et al., 2015; Zerbo et al., 2015] during pregnancy support this hypothesis. Furthermore, evidence from animal models demonstrate associations between maternal immune activation during pregnancy in the absence of infection, and behavioral and brain abnormalities in the offspring [Bauman et al., 2014; Shi, Fatemi, Sidwell, & Patterson, 2003; Shi et al., 2009], suggesting that the immune response rather than the infectious agent itself may have a direct impact on neurodevelopment. For example, rodent studies have shown that cytokines released during infection such as interleukin (IL)-6 or IL-17, can directly alter neurodevelopment [Choi et al., 2016; Shi et al., 2003]. In nonhuman primates, immune activation during pregnancy led to offspring with altered behaviors and immune responses [Rose et al., 2017]. Human studies also provide evidence that disrupted levels of immune molecules in the prenatal or neonatal periods is associated with ASD [Brown et al., 2014; Goines et al., 2011; Grether et al., 2016; Jones et al., 2016; Zerbo et al., 2016; Zerbo et al., 2014]. It is also possible that the increase in maternal body temperature alone could adversely impact fetal brain development [Duong et al., 2011].
The association specific to second trimester fever was observed for ASD but not DD, and only among the subgroup of children with ASD without ID. We also observed that infections without fever were associated with lowered risk of DD in T3. The biological bases for these findings are not clear but this specificity of fever in the second trimester to an increased risk of ASD without ID was also observed in the Norwegian study [Hornig et al., 2017].
Strengths
In this large study population drawn from several geographic areas across the United States, child development status (ASD or DD) was validated by a comprehensive in-person developmental assessment using gold-standard diagnostic instruments. Our case-control design, including a DD group, allowed us to look at the specificity of our findings to ASD and its specific phenotypes. The comprehensive data collection battery, aggregating data from self-report and medical records, allowed us to conduct analyses by time period during pregnancy for types of infections and also examine treatment and fever effects. The prevalence of maternal infection and fever during pregnancy in our study was similar to reports in previous studies with prospective data collection [Hornig et al., 2017] indicating that ascertainment of exposure was likely accurate. Finally, we carefully controlled for several potential confounders.
Limitations
The prevalence of specific types of infections was low, precluding analyses of specific infections that were associated with ASD risk in previous studies. We did not have data on number, duration, and intensity of fevers, nor the severity of infection. Maternal self-reporting of infection and fever may have introduced some exposure misclassification; however, final exposure status included information recorded in maternal medical records, diminishing the possibility of biased results due to faulty recall. Given the small counts for some analyses, our findings could be due to chance or residual confounding by unmeasured confounders. We also lacked data to explore phenotypic subtypes by behavioral or psychiatric comorbidities such as ADHD. Finally, several families of potentially eligible children did not respond to the SEED invitation letter, and the sociodemographic profile of the enrolled study population was somewhat different than expected, with a higher proportion of non-White, lower educational attainment, and lower income mothers among the ASD and DD cases than POP controls [DiGuiseppi et al., 2016]. We hypothesize that the developmental assessment offered to participants in the SEED study was more of an incentive for mothers of potential ASD and DD cases than POP controls, especially those who had lower education and income, and thus less access to clinical evaluations for autism or DDs. Despite differential response between cases and controls on select sociodemographic characteristics, findings from the SEED study appear robust for other nondemographic factors [Schieve, Harris, Maenner, Alexander, & Dowling, 2018]. Furthermore, our analyses were adjusted for maternal age, education, and race-ethnicity, the only variables associated with nonresponse.
Conclusion
Our findings suggest that maternal infection with fever in the second trimester may be associated with increased risk of ASD in offspring. Future studies with adequate sample size, detailed information on type and timing of maternal exposure to infection and fever, and specific developmental outcomes in the child are needed to further understand the specificity of the associations and elucidate potential biologic mechanisms underlying them.
Supplementary Material
Supplementary Table 1. Laboratory confirmed infections by infection status, Study to Explore Early Development (SEED), 2003–2006 births.
Supplementary Table 2. Risk of ASD associated with maternal infection and fever during pregnancy, stratified by ASD subtypes, Study to Explore Early Development, 2003–2006 births.
Supplementary Table 3. Risk of ASD associated with maternal infection and fever during pregnancy compared to DD, Study to Explore Early Development, 2003–2006 births.
Acknowledgments
This study was supported by six cooperative agreements from the Centers for Disease Control and Prevention: Cooperative Agreement Number U10DD000180, Colorado Department of Public Health; Cooperative Agreement Number U10DD000181, Kaiser Foundation Research Institute (CA); Cooperative Agreement Number U10DD000182, University of Pennsylvania; Cooperative Agreement Number U10DD000183, Johns Hopkins University; Cooperative Agreement Number U10DD000184, University of North Carolina at Chapel Hill; and Cooperative Agreement Number U10DD000498, Michigan State University. We thank the SEED Data Coordinating Center team at the Clinical and Translational Sciences Institute of Michigan State University for their support throughout this study.
Footnotes
Conflict of Interests
The authors report no competing interests.
Supporting Information
Additional supporting information may be found online in the Supporting Information section at the end of the article.
References
- American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: American Psychiatric Association. [Google Scholar]
- Atladottir HO, Henriksen TB, Schendel DE, & Parner ET (2012). Autism after infection, febrile episodes, and antibiotic use during pregnancy: An exploratory study. Pediatrics, 130(6), e1447–e1454. 10.1542/peds.2012-1107 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Atladottir HO, Thorsen P, Ostergaard L, Schendel DE, Lemcke S, Abdallah M, & Parner ET (2010). Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. Journal of Autism and Developmental Disorders, 40(12), 1423–1430. 10.1007/s10803-010-1006-y [DOI] [PubMed] [Google Scholar]
- Bauman MD, Iosif AM, Smith SE, Bregere C, Amaral DG, & Patterson PH (2014). Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biological Psychiatry, 75(4), 332–341. 10.1016/j.biopsych.2013.06.025 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brown AS, Sourander A, Hinkka-Yli-Salomaki S, McKeague IW, Sundvall J, & Surcel HM (2014). Elevated maternal C-reactive protein and autism in a national birth cohort. Molecular Psychiatry, 19(2), 259–264. 10.1038/mp.2012.197 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brucato M, Ladd-Acosta C, Li M, Caruso D, Hong X, Kaczaniuk J, … Fallin MD (2017). Prenatal exposure to fever is associated with autism spectrum disorder in the boston birth cohort. Autism Research, 10, 1878–1890. 10.1002/aur.1841 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chess S (1971). Autism in children with congenital rubella. Journal of Autism and Childhood Schizophrenia, 1(1), 33–47. [DOI] [PubMed] [Google Scholar]
- Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, … Huh JR (2016). The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science, 351(6276), 933–939. 10.1126/science.aad0314 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Collier SA, Rasmussen SA, Feldkamp ML, & Honein MA (2009). Prevalence of self-reported infection during pregnancy among control mothers in the National Birth Defects Prevention Study. Birth Defects Research. Part A, Clinical and Molecular Teratology, 85(3), 193–201. 10.1002/bdra.20540 [DOI] [PubMed] [Google Scholar]
- Croen LA, Qian Y, Ashwood P, Daniels JL, Fallin D, Schendel D, … Zerbo O (2018). Family history of immune conditions and autism spectrum and developmental disorders: Findings from the study to explore early development. Autism Research, 12, 123–135. 10.1002/aur.1979 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deykin EY, & MacMahon B (1979). Viral exposure and autism. American Journal of Epidemiology, 109(6), 628–638. [DOI] [PubMed] [Google Scholar]
- DiGuiseppi C, Daniels J, Fallin D, Rosenberg S, Schieve LA, Thomas KC, … Young L (2016). Demographic profile of families and children in the Study to Explore Early Development (SEED): Case-control study of autism spectrum disorder. Disability and Health Journal, 9(3), 544–551. 10.1016/j.dhjo.2016.01.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Duong HT, Shahrukh HS, Ramadhani T, Canfield MA, Scheuerle A, Kim WD, & Study NBDP (2011). Maternal use of hot tub and major structural birth defects. Birth Defects Research. Part A, Clinical and Molecular Teratology, 91(9), 836–841. 10.1002/bdra.20831 [DOI] [PubMed] [Google Scholar]
- Fang SY, Wang S, Huang N, Yeh HH, & Chen CY (2015). Prenatal infection and autism spectrum disorders in childhood: A population-based case-control study in Taiwan. Paediatric and Perinatal Epidemiology, 29(4), 307–316. 10.1111/ppe.12194 [DOI] [PubMed] [Google Scholar]
- Goines PE, Croen LA, Braunschweig D, Yoshida CK, Grether J, Hansen R, … Van de Water J (2011). Increased midgestational IFN-gamma, IL-4 and IL-5 in women bearing a child with autism: A case-control study. Molecular Autism, 2, 13 10.1186/2040-2392-2-13 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gotham K, Risi S, Pickles A, & Lord C (2007). The Autism Diagnostic Observation Schedule: Revised algorithms for improved diagnostic validity. Journal of Autism and Developmental Disorders, 37(4), 613–627. 10.1007/s10803-006-0280-1 [DOI] [PubMed] [Google Scholar]
- Grether JK, Ashwood P, Van de Water J, Yolken RH, Anderson MC, Torres AR, … Croen LA (2016). Prenatal and newborn immunoglobulin levels from mother-child pairs and risk of autism spectrum disorders. Frontiers in Neuroscience, 10, 218 10.3389/fnins.2016.00218 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hornig M, Bresnahan M, Che X, Schultz A, Ukaigwe J, Eddy M, … Lipkin W (2017). Prenatal fever and autism risk. Molecular Psychiatry, 23, 759–766. 10.1038/mp.2017.119 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jiang HY, Xu LL, Shao L, Xia RM, Yu ZH, Ling ZX, … Ruan B (2016). Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis. Brain, Behavior, and Immunity, 58, 165–172. 10.1016/j.bbi.2016.06.005 [DOI] [PubMed] [Google Scholar]
- Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O, … Van de Water J (2016). Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Molecular Psychiatry, 22(2), 273–279. 10.1038/mp.2016.77 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee BK, Magnusson C, Gardner RM, Blomstrom A, Newschaffer CJ, Burstyn I, … Dalman C (2015). Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders. Brain, Behavior, and Immunity, 44, 100–105. 10.1016/j.bbi.2014.09.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Libbey JE, Sweeten TL, McMahon WM, & Fujinami RS (2005). Autistic disorder and viral infections. Journal of Neurovirology, 11(1), 1–10. 10.1080/13550280590900553 [DOI] [PubMed] [Google Scholar]
- Lintas C, Altieri L, Lombardi F, Sacco R, & Persico AM (2010). Association of autism with polyomavirus infection in postmortem brains. Journal of Neurovirology, 16(2), 141–149. 10.3109/13550281003685839 [DOI] [PubMed] [Google Scholar]
- Lord C, Risi S, Lambrecht L, Cook EH Jr., Leventhal BL, DiLavore PC, … Rutter M (2000). The autism diagnostic observation schedule-generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30(3), 205–223. [PubMed] [Google Scholar]
- Lord C, Rutter M, DiLavore PC, & Risi S (1999). Autism diagnositic observation schedule. Los Angeles, CA: Western Psychological Services. [Google Scholar]
- Lord C, Rutter M, & Le Couteur A (1994). Autism diagnostic interview-revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders, 24(5), 659–685. [DOI] [PubMed] [Google Scholar]
- Lyall K, Croen L, Daniels J, Fallin MD, Ladd-Acosta C, Lee BK, … Newschaffer C (2017). The changing epidemiology of autism spectrum disorders. Annual Review of Public Health, 38, 81–102. 10.1146/annurev-publhealth-031816-044318 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mahic M, Che X, Susser E, Levin B, Reichborn-Kjennerud T, Magnus P, … Lipkin WI (2017). Epidemiological and Sero-logical Investigation into the Role of Gestational Maternal Influenza Virus Infection and Autism Spectrum Disorders. mSphere, 2(3). 10.1128/mSphere.00159-17 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mullen EM (1995). Mullen scales of early learning. Circle Pines, MN: American Guidance Service, Inc. [Google Scholar]
- Rose DR, Careaga M, Van de Water J, McAllister K, Bauman MD, & Ashwood P (2017). Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain, Behavior, and Immunity, 63, 60–70. 10.1016/j.bbi.2016.11.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rutter M, Bailey A, & Lord C (2003). SCQ: Social communication questionnaire. Los Angeles, CA: Western Psychological Services. [Google Scholar]
- Rutter M, Le Couteur A, & Lord C (2003). ADI-R: The autism diagnotic interview-revised. Los Angeles, CA: Western Psychological Services. [Google Scholar]
- Schendel DE, Diguiseppi C, Croen LA, Fallin MD, Reed PL, Schieve LA, … Yeargin-Allsopp M (2012). The Study to Explore Early Development (SEED): A multisite epidemiologic study of autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) network. Journal of Autism and Developmental Disorders, 42(10), 2121–2140. 10.1007/s10803-012-1461-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schieve LA, Harris S, Maenner M, Alexander A, & Dowling N (2018). Assessment of demographic and perinatal predictors of non-response and impact of non-response on measures of association in a population-based case control study: Findings from the Georgia Study to Explore Early Development. Emerging Themes in Epidemiology, 15(12), 15 10.1186/s12982-018-0081-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shi L, Fatemi SH, Sidwell RW, & Patterson PH (2003). Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. The Journal of Neuroscience, 23(1), 297–302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shi L, Smith SE, Malkova N, Tse D, Su Y, & Patterson PH (2009). Activation of the maternal immune system alters cerebellar development in the offspring. Brain, Behavior, and Immunity, 23(1), 116–123. 10.1016/j.bbi.2008.07.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sparrow S, Cichetti D, & Balla D (2005). Vineland adaptive behavior scales (2nd ed.). Circle Pines, MN: American Guidance Service. [Google Scholar]
- Wiggins LD, Reynolds A, Rice CE, Moody EJ, Bernal P, Blaskey L, … Levy SE (2015). Using standardized diagnostic instruments to classify children with autism in the study to explore early development. Journal of Autism and Developmental Disorders, 45(5), 1271–1280. 10.1007/s10803-014-2287-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zerbo O, Iosif AM, Walker C, Ozonoff S, Hansen RL, & Hertz-Picciotto I (2012). Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (Childhood Autism Risks from Genetics and Environment) study. Journal of Autism and Developmental Disorders, 43(1), 25–33. 10.1007/s10803-012-1540-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zerbo O, Leong A, Barcellos L, Bernal P, Fireman B, & Croen LA (2015). Immune mediated conditions in autism spectrum disorders. Brain, Behavior, and Immunity, 46, 232–236. 10.1016/j.bbi.2015.02.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zerbo O, Qian Y, Yoshida C, Fireman BH, Klein NP, & Croen LA (2016). Association between influenza infection and vaccination during pregnancy and risk of autism spectrum disorder. JAMA Pediatrics, 171(1), e163609 10.1001/jamapediatrics.2016.3609 [DOI] [PubMed] [Google Scholar]
- Zerbo O, Qian Y, Yoshida C, Grether JK, Van de Water J, & Croen LA (2013). Maternal infection during pregnancy and autism spectrum disorders. Journal of Autism and Developmental Disorders, 45(12), 4015–4025. 10.1007/s10803-013-2016-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zerbo O, Yoshida C, Grether JK, Van de Water J, Ashwood P, Delorenze GN, … Croen LA (2014). Neonatal cytokines and chemokines and risk of autism spectrum disorder: The Early Markers for Autism (EMA) study: A case-control study. Journal of Neuroinflammation, 11, 113 10.1186/1742-2094-11-113 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1. Laboratory confirmed infections by infection status, Study to Explore Early Development (SEED), 2003–2006 births.
Supplementary Table 2. Risk of ASD associated with maternal infection and fever during pregnancy, stratified by ASD subtypes, Study to Explore Early Development, 2003–2006 births.
Supplementary Table 3. Risk of ASD associated with maternal infection and fever during pregnancy compared to DD, Study to Explore Early Development, 2003–2006 births.