J Autism Dev Disord DOI 10.1007/s10803-014-2247-y
ORIGINAL PAPER
Risk of Autism Associated With General Anesthesia During Cesarean Delivery: A Population-Based Birth-Cohort Analysis Li-Nien Chien • Hsiu-Chen Lin • Yu-Hsuan Joni Shao Shu-Ti Chiou • Hung-Yi Chiou
•
Ó Springer Science+Business Media New York 2014
Abstract The rates of Cesarean delivery (C-section) have risen to [30 % in numerous countries. Increased risk of autism has been shown in neonates delivered by C-section. This study examined the incidence of autism in neonates delivered vaginally, by C-section with regional anesthesia (RA), and by C-section with general anesthesia (GA) to evaluate the risk of autism associated with C-section and obstetric anesthesia. During a mean follow-up of 4.3 years, the incidence of autism was higher in neonates delivered by C-section with GA than in neonates delivered vaginally, with an adjusted risk of 1.52 (95 % confidence interval 1.18–1.94). However, the adjusted risk of autism in neonates delivered by C-section with RA and in neonates delivered vaginally was nonsignificantly different.
Introduction
Electronic supplementary material The online version of this article (doi:10.1007/s10803-014-2247-y) contains supplementary material, which is available to authorized users.
Cesarean deliveries (C-sections) have become increasingly common in numerous countries. The rate of C-section was 32.8 % of all births in the United States in 2010 (Hamilton et al. 2013) and 23.8 % of single births in the United Kingdom in 2008 (Bragg et al. 2010). During the past 10 years, the rates of C-section have risen to [30 % in numerous Asian, European, and Latin American countries (Declercq et al. 2011; Han et al. 2011; Harper and Odibo 2010; OECD 2011). Studies have reported that C-sections can harm fetuses and neonates, and do not necessarily benefit mothers. Therefore, The American College of Obstetricians and Gynecologists (2009) established strict guidelines for nonmedically indicated C-sections prior to 39 weeks’ gestation. However, the demand for planned elective C-sections has increased (Kottmel et al. 2012). A C-section is a major surgery associated with increased risk of intensive care (Murphy et al. 2001), breathing problems (Almqvist et al. 2012; Merenstein et al. 2011), low Apgar score (Burt et al. 1988), fetal injury (Lieberman et al. 1997), and asthma (Roduit et al. 2009). However,
L.-N. Chien School of Health Care Administration, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
S.-T. Chiou Health Promotion Administration, Ministry of Health and Welfare, Taipei, Taiwan
H.-C. Lin Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
S.-T. Chiou Institution of Public Health, School of Medicine, National YangMing University, Taipei, Taiwan
H.-C. Lin Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan
H.-Y. Chiou (&) School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wu-Hsing Street, Taipei City 110, Taiwan e-mail: [email protected]
Keywords Autism Cesarean delivery Obstetric anesthesia Population-based birth cohort Li-Nien Chien and Hsiu-Chen Lin contributed equally to this work.
Y.-H. J. Shao Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan
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C-section might be necessary because of medical conditions such as labor arrest disorders, multiple gestation, suspected macrosomia, preeclampsia, and other obstetric conditions (Barber et al. 2011). Whether autism is associated with C-section is unclear. The results from several studies have suggested increased risk of autism in neonates delivered by C-section (Bilder et al. 2009; Eaton et al. 2001; Glasson et al. 2004; Hultman et al. 2002; Maimburg and Væth 2006). Data from other studies have suggested that obstetric anesthesia administered to immature brains can cause histopathological changes that adversely affect development and behavior (DiMaggio et al. 2009; Wilder et al. 2009). Glasson et al. (2004) reported that the mothers of patients with autism were likely to have received anesthesia during labor, and that epidural caudal anesthesia was significantly associated with autism. Flick et al. (2011) reported that multiple exposures to anesthesia prior to the age of 2 years can adversely affect neurodevelopment in children, resulting in learning disabilities. Regional anesthesia (RA) and general anesthesia (GA) are both acceptable modes of anesthesia during C-section delivery; however, GA is less frequently provided than RA because of potential maternal and neonatal risks (Afolabi and Lesi 2012). Whether the C-section itself or obstetric anesthesia during the C-section is the risk factor associated with autism has yet to be established. Understanding the association between autism and C-section with anesthesia is crucial for the early detection and prevention of autism. However, few studies have investigated the association between obstetric anesthesia and autism (Glasson et al. 2004; Hattori et al. 1991). Therefore, this study aimed to determine whether the risk of developing autism in early childhood is associated with vaginal delivery, C-section delivery with RA, or C-section delivery with GA, based on data from a population-based birth cohort.
Methods Data Source The National Birth Reporting Database (NBRD), the National Health Insurance Research Database (NHIRD), and the Birth Certification Registry (BCR) were used as sources of population-based data in Taiwan. The NBRD is maintained by the Health Promotion Administration, and contains data on maternal risk during pregnancy and delivery, neonatal sex, gestational age, birth weight, and the mode of delivery reported by the attending obstetrician or pediatrician. Hospitals and clinics are obligated to report birth information to local health departments within 10 days of delivery. The NHIRD is maintained by the National Health Insurance Administration, and contains information on
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nearly all of the clinical diagnoses and treatments received by beneficiaries of the National Health Insurance (NHI) program. Since 1995, all Taiwanese citizens have been required by law to enroll with the NHI. The NHI coverage rate was 99 % in 2012 (National Health Insurance Administration 2013). Payments for vaginal deliveries and C-sections are covered by the NHI. The BCR is maintained by the Ministry of the Interior, and includes data on neonatal parity, residency, parental age, education, nationality, and aboriginal status, as well as encrypted identifiers for the parents and newborns, which allow the BCR, NBRD, and NHIRD databases to be linked. Because birth registration is mandatory, the data are considered accurate and complete. Ethics Statement Confidentiality was assured by abiding by the data regulations of the Collaboration Center of Health Information Application (CCHIA), Ministry of Health and Welfare, Executive Yuan, Taiwan. The CCHIA encrypts individual identifiers to protect privacy before releasing information to investigators for research purposes. This study was approved by the Taipei Medical University Joint Institutional Review Board (Approval no. 201305001). Participants More than 800,000 single births recorded in the NBRD between January 1, 2004 and December 31, 2007 were reviewed. Newborns of unknown sex, gestational age\20 or [42 weeks, and birth weight \500 g were excluded (n = 26,539). Newborns for whom the birth records could not be linked to the NHIRD or BCR because of erroneous encrypted identifiers, unknown parents, or the delivery not being covered by the NHI were also excluded (n = 93,165). Newborns with at least one parent aged\15 years, a mother aged [45 years, or a father aged [80 years were excluded, which accounted for \1 % of all patients reviewed (n = 400). In addition, newborns with missing data on the study variables were excluded (n = 87 621). When a mother gave birth more than once during the study period, only the first birth was included in the study sample. The associations between autism and the type of anesthesia used during C-section were investigated. Because the NHI does not cover RA for vaginal delivery, such as epidural anesthesia, data on whether obstetric anesthesia was administrated for vaginal delivery were unavailable. Therefore, patients who received epidural or spinal anesthesia were included in the C-section with RA group, and patients who received GA were included in the C-section with GA group. To evaluate the risk of autism specifically associated with obstetric anesthesia, the patients who received nonobstetric anesthesia during the observational period were excluded.
J Autism Dev Disord
Fig. 1 A flow diagram of participant selection
Thus, only three modes of delivery were considered when analyzing the incidence of autism: vaginal delivery (n = 362,297), C-section with RA (n = 161,992), and C-section with GA (n = 12,384) (Fig. 1). Study Variables Outcomes The primary outcome of interest was autism, a disorder that typically appears before the age of 3 years (Filipek et al.
2000). Children with autism, as defined by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code of 299.0 were selected, because it is the most common autism-related diagnosis in early childhood. In Taiwan, autism is usually diagnosed by a pediatrician or psychiatrist, and the diagnosis is confirmed based on the results of multiple tests, such as a multiphasic psychological test, a personality assessment, and an intelligence assessment. More than one diagnostic code was considered to ensure the validity of autism diagnoses. A recent study used an algorithm that
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included two or more types of claim for autism-spectrum disorders to generate a positive predictive value of 87.4 %, which indicates a high level of reliability for identifying cases of autism-spectrum disorders in claims data (Burke et al. 2014). Covariates Neonatal characteristics, parental demographics, and maternal risk factors were controlled for as potential confounders. The neonatal characteristics considered were sex, birth weight, gestational age, parity, 5-min Apgar score, level of urbanization of residence, previous or existing jaundice, cerebral edema, respiratory distress, and birth defects. The level of urbanization was estimated based on population density, the percentage of residents with a college-level education or higher, the percentage of residents aged [65 years, the percentage of agriculture workers among the residents, and the number of physicians per 100,000 residents. The parental demographics included age, education, nationality, aboriginal status, marital status, and insurance eligibility status. Data on insurance eligibility status were obtained from the enrollment records of the NHI, and were predominantly based on wage premiums. The maternal risks and complications during pregnancy and labor included systemic lupus erythematosus, hyperthyroidism, hypertension, diabetes, epilepsy, asthma, allergic rhinitis, gestational hypertension, gestational diabetes, preeclampsia, placenta previa, premature rupture of membranes, induction, breech presentation, presence of meconium, uterine bleeding, prolonged labor, and fetal distress. Appendix 1 of ESM lists detailed information on these variables and the ICD-9-CM diagnostic codes. Subgroup Analysis Two analyses were performed to evaluate the robustness of the initial findings. In the first analysis, the ICD-9-CM diagnosis code for autism was considered. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), the diagnosis of autistic-spectrum disorders includes autistic disorder, pervasive developmental disorder not otherwise specified, Asperger syndrome, Rett syndrome, and childhood disintegrative disorder (Filipek et al. 2000). However, distinguishing the diagnoses within the pervasive developmental disorders can be problematic and unreliable, even if the diagnostic criteria have been carefully adhered to. Therefore, the ICD-9-CM diagnosis code of 299.xx was used to broaden the range of diagnostic coding, and the data were reexamined. Appendixes 2 and 3 of ESM list the results.
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The use of GA or RA is influenced by various factors, such as the urgency of a procedure, maternal status, the presence of specific contraindications, and clinician and patient preferences. Neuraxial anesthesia for RA is generally preferred to GA for C-sections because it minimizes the risk of failed intubation, ventilation, and aspiration. However, obstetric indications, such as placenta previa, can be considered absolute indications for GA (McGlennan and Mustafa 2009). To ensure effective comparisons between C-sections with GA or RA, a propensity score (PS) matching technique was used to adjust for underlying risks. The PS cohort contained a group of C-section births and a control group of C-section births with similar baseline characteristics, on whom a method of obstetric anesthesia other than GA or RA had been used. This method has been used in numerous observational studies to reduce selection bias (Austin 2008, 2011; Rosenbaum and Rubin 1984; Stukel et al. 2007). The greedy match algorithm macro developed by the Mayo Clinic (http://ndc.mayo.edu/mayo/research/) for SAS software (SAS Institute, Cary, NC, USA), was used to match two C-section deliveries with RA to one C-section delivery with GA (Kosanke and Bergstralh 2004). The matched PS cohort consisted of 12,370 patients with C-section with GA, matched to 24,580 patients with C-section with RA, based on a probability of PS with a standard deviation of 0.1. The probability of being administered GA or RA was calculated for each birth by using a logistic regression model that addressed the covariates influencing the choice of obstetric anesthesia. Appendix 4 of ESM lists the baseline characteristics of the PS-matched cohort. Statistical Analysis Patients were followed-up from the date of birth to the date of the earliest clinic visit for autism, death (obtained from the death registry), withdrawal from the NHI (obtained from the enrollment file), or the end of the observational period (December 31, 2009). The duration of follow-up ranged from 2 to 6 years. Incidence rates of autism per 1,000 person-years with 95 % confidence intervals (CIs) were estimated. Cox proportional-hazards regression models were used to estimate the adjusted hazard ratios (HRs) for the mode of delivery and risk of autism. The models did not violate the assumption of proportional hazard. The cumulative hazard curves for the modes of delivery were constructed after adjusting for all of the risk factors. All statistical analyses were performed using SAS/ STAT, Version 9.3 and STATA 12 (StataCorp LP, College Station, TX, USA) software packages, and p \ 0.05 was considered statistically significant.
J Autism Dev Disord Table 1 Basic characteristics of births born via different modes of delivery Sample size
Vaginal deliveries 362,297
C-section deliveries with RA 161,992
C-section deliveries with GA 12,384
Male (%)
51.6 %
52.9 %
52.8 %
Gestational age (weeks), Mean(SD)
38.7 (1.4)
38.2 (1.5)
38.0 (2.0)
Birth weight (g), Mean(SD)
3,112.6 (393.7)
3,153.7 (454.8)
3,061.4 (519.6)
Apgar score \7 at 5 min
0.20 %
0.26 %
2.19 %
1 2
80.8 % 16.2 %
78.9 % 17.8 %
80.2 % 16.7 %
[=3
3.0 %
3.3 %
3.1 %
Level 1 (Most urbanized)
49.3 %
54.0 %
55.4 %
Level 2
39.7 %
36.3 %
35.1 %
Level 3
6.1 %
5.2 %
5.2 %
Level 4
4.9 %
4.5 %
4.4 %
Neonatal characteristics
Parity
Urbanization of residency
Risk factors Jaundice
4.6 %
4.0 %
3.5 %
Cerebral edema
\0.1 %
0.1 %
\0.1 %
Respiratory distress
0.3 %
0.4 %
0.8 %
Any birth defect
0.5 %
0.3 %
0.5 %
Age (year), Mean (SD)
28.5 (4.6)
30.2 (4.8)
30.1 (4.8)
Education (year), Mean (SD) Citizenship, not Taiwan
13.4 (2.8) 13.1 %
13.4 (2.7) 8.2 %
13.3 (2.7) 8.3 %
Maternal characteristics
Aboriginal status (yes)
2.2 %
2.4 %
1.8 %
Married
85.8 %
90.8 %
90.4 %
Level 1 (Highest)
19.0 %
20.2 %
17.3 %
Level 2
31.0 %
29.8 %
28.8 %
Level 3
17.0 %
16.1 %
17.6 %
Level 4
13.5 %
14.9 %
15.8 %
Level 5
7.8 %
7.3 %
7.8 %
Level 6
11.7 %
11.6 %
12.7 %
Age (year), Mean (SD)
32.4 (5.5)
33.3 (5.5)
33.3 (5.6)
Education (year), Mean (SD)
13.2 (3.0)
13.3 (2.8)
13.2 (2.7)
Citizenship, not Taiwan
0.6 %
0.8 %
0.8 %
Aboriginal status (yes)
2.1 %
2.2 %
1.7 %
Socioeconomics status
Paternal characteristics
Maternal risk/complication during pregnancy or labor SLE 0.2 %
0.2 %
0.4 %
Hyperthyroidism
0.1 %
0.2 %
0.1 %
Hypertension
0.4 %
0.2 %
0.2 %
Diabetes
1.8 %
2.7 %
2.8 %
Epilepsy
0.2 %
0.3 %
0.3 %
Asthma
\0.1 %
0.1 %
\0.1 %
Allergic rhinitis
0.1 %
0.1 %
0.2 %
Gestational hypertension
0.1 %
1.3 %
1.8 %
Gestational diabetes
0.6 %
0.8 %
0.7 %
Preeclampsia
\0.1 %
0.1 %
\0.1 %
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J Autism Dev Disord Table 1 continued Sample size
Vaginal deliveries 362,297
C-section deliveries with RA 161,992
C-section deliveries with GA 12,384
Placenta previa
7.0 %
9.4 %
11.0 %
PROM
\0.1 %
\0.1 %
\0.1 %
Induction
0.5 %
0.4 %
0.4 %
Breech presentation
0.2 %
12.7 %
8.8 %
Meconium
1.8 %
1.4 %
1.4 %
Uterine bleeding
0.3 %
0.4 %
1.5 %
Prolong labor
0.1 %
5.2 %
2.6 %
Fetal distress
0.2 %
3.7 %
7.1 %
RA regional anesthesia, GA general anesthesia, PROM Premature rupture of membranes, SLE Systemic Lupus Erythematosus
Results
Table 2 The unadjusted incidence of autism (per 1,000 person-year) of births born via different modes of delivery
Basic Characteristics
Mode of delivery
Compared with vaginal deliveries, babies delivered by C-section with RA or GA were more likely to be boys or to have a 5-min Apgar score \7, and were less likely to have jaundice or to be carried to full term. Neonates delivered by C-section with RA or GA were also more likely to have older parents, married parents, or a mother who experienced risks and complications during pregnancy. Overall, 7.1 % of the C-sections were performed using GA (Table 1). Incidence of Autism The mean duration of follow-up was 4.3 years. The rates of autism diagnosis were 0.32 % (1,166/362 297), 0.38 % (615/161 992), and 0.56 % (69/12 384) for neonates delivered vaginally, by C-section with RA, and by C-section with GA, respectively. The incidence of autism per 1,000 person-years was 0.77 (95 % CI 0.73–0.81), 0.92 (95 % CI 0.85–1.00), and 1.34 (95 % CI 1.06–1.69) for vaginal deliveries, C-sections with RA, and C-sections with GA, respectively (Table 2). Therefore, the incidence of autism was highest in the neonates delivered by C-section with GA. After stratifying by sex, the incidence of autism was significantly higher in boys than in girls. The ratio of boys to girls ranged from 4.3 to 6.1 for the various modes of delivery. Regression Analysis The neonates delivered by C-section with GA had a 52 % higher risk of developing autism than did the neonates delivered vaginally (an adjusted HR of 1.52, 95 % CI 1.18–1.94, p = 0.001) (Table 3). After adjusting for neonatal characteristics, parental demographics, and maternal risks and
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Person-y
Autism
Incidence (95 % CI)
Vaginal deliveries
1,516,834
1,166
0.77 (0.73–0.81)
C-section deliveries with RA
665,430
615
0.92 (0.85–1.00)
C-section deliveries with GA
51,611
69
1.34 (1.06–1.69)
Overall
Boys Vaginal deliveries
783,203
1,006
1.28 (1.21–1.37)
C-section deliveries with RA
351,241
535
1.52 (1.40–1.66)
C-section deliveries with GA
27,263
57
2.09 (1.61–2.71)
Girls Vaginal deliveries
733,630
160
0.22 (0.19–0.25)
C-section deliveries with RA
314,189
80
0.25 (0.20–0.32)
C-section deliveries with GA
24,348
12
0.49 (0.28–0.87)
CI confidence interval, GA general anesthesia, RA regional anesthesia
complications, the results indicated nonsignificant differences in the risk of autism between neonates delivered by C-section with RA and those delivered vaginally. When we examined the effects of the mode of delivery on autism according to sex, we observed that boys and girls delivered by C-section with GA were more likely (44 and 96 %, respectively) to develop autism than those delivered vaginally. Appendix 6 of ESM shows the model for all risk factors. Kaplan–Meier Curves The risk of autism in neonates delivered by C-section with GA differed significantly from that in neonates delivered
J Autism Dev Disord Table 3 The hazard ratios (HR) of autism of births delivered by C-section with RA and C-section with GA compared to vaginal deliveries Cohort mode of delivery
Crude HR 95 % CI
Adjusted* P
HRs 95 % CI
p
Overall Vaginal deliveries (Ref.)
1.00
C-section deliveries with RA
1.21(1.10–1.33)
\0.001
1.07 (0.96–1.19)
1.00 0.213
C-section deliveries with GA
1.74 (1.36–2.22)
\0.001
1.52 (1.18–1.94)
0.001
Boys Vaginal deliveries (Ref.)
1.00
C-section deliveries with RA C-section deliveries with GA
1.19 (1.07–1.32) 1.62 (1.24–2.12)
1.00 0.001 \0.001
1.08 (0.96–1.21) 1.44 (1.10–1.90)
0.188 0.008
Girls Vaginal deliveries (Ref.)
1.00
C-section deliveries with RA
1.17 (0.90–1.53)
0.247
1.00 1.01 (0.75–1.36)
0.956
C-section deliveries with GA
2.26 (1.26–4.06)
0.006
1.96 (1.07–3.60)
0.030
CI confidence interval, GA general anesthesia, PROM premature rupture of membranes, RA regional anesthesia, SLE systemic lupus erythematous * Adjusted for neonatal characteristics (sex, gestational age, birth weight, Apgar score\7, residency urbanization, birth defect, jaundice, cerebral edema, and respiratory distress), parental characteristics (age, education, citizenship, married, aboriginal, insurance eligibility categories) and maternal risk (SLE, hyperthyroidism, hypertension, diabetes, epilepsy, asthma, allergic, gestational hypertension, gestational diabetes, preeclampsia, placenta previa, PROM, induce, breech presentation, meconium, uterine bleeding, prolonged labor, and fetal distress)
vaginally and the difference raised as the observational year increased. However, the risk of autism in neonates delivered by C-section with RA and in neonates delivered vaginally was nonsignificantly different (Fig. 2a). The risk of autism in boys and girls was also nonsignificantly different (Fig. 2b, c). Subgroup Analysis When we evaluated the sensitivity of our analysis by using the 290.xx ICD-9-CM diagnosis code as the clinical criterion for autism diagnosis, our initial results remained robust (Appendixes 3 and 4 of ESM). Compared with vaginal deliveries, the adjusted HRs for C-sections with GA for all births, boys, and girls were 1.48 (95 % CI 1.17–1.88, p = 0.001), 1.45 (95 % CI 1.12–1.87, p = 0.005), and 1.66 (95 % CI 0.91–3.05, p = 0.099), respectively. We repeated the analyses using a PS-matched cohort that included two groups with similar baseline characteristics. One group contained neonates delivered by C-section with GA and the other contained neonates delivered by C-section with RA (Appendix 4 of ESM). The majority of the covariates were balanced after PS matching, with the exception of the neonates delivered by C-section with RA, who had a higher gestational age (38.1 vs. 38.0 weeks), higher birth weight (3,075.2 vs. 3,063.1 g), and lower rate of meconium discharge (1.19 vs. 1.43 %) than did the neonates delivered by C-section with GA. After adjusting for covariates, the neonates delivered
by C-section with GA had a higher risk of autism than did those delivered by C-section with RA (HR 1.67, 95 % CI 1.21–2.31, p = 0.002).
Discussion According to our research, this study is the largest population-based birth cohort study to demonstrate an association between the mode of delivery and autism. Neonates delivered by C-section with GA were associated with a higher incidence of autism than neonates delivered vaginally or those delivered by C-section with RA. After adjusting for potential confounders, the risk of autism was 52 % higher in the neonates delivered by C-section with GA than in those delivered vaginally. When stratifying by sex, we observed stronger association between autism and girls than boys. However, when we used ICD-9-CM 290.xx diagnostic coding to identify autism, we only observed increased risk of autism in boys delivered by C-section with GA. The data for the PS-matched cohort, which had balanced potential confounders for RA and GA, also indicated higher risk of autism in neonates delivered by C-section with GA than in neonates delivered by C-section with RA. Our results suggest that the use of GA during C-section is associated with increased risk of neurological disorder in childhood. The PS-matched group analysis indicated a higher risk of autism than did the adjusted model estimate. The PS-
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Fig. 2 Cumulative Kaplan–Meier curves of the incidence of autism in neonates delivered by C-section with GA, C-section with RA, and vaginally, after adjusting for all risk factors. Panels a, b, and c represent the overall data and data from the boy and girl cohorts, respectively
matching method provides an alternative to regression analyses traditionally used to estimate treatment effects. However, PS and regression method estimates can differ considerably. A regression analysis produces a coefficient estimate that represents the average treatment effect, whereas the PS matching method provides an estimate of the effects of a treatment on a patient. The two estimates confer if the effects of a treatment do not vary between patients. Therefore, regression and PS-matching methods can yield conceptually and numerically differing estimates (Austin 2011). Previous studies have extensively evaluated the association between C-section and autism. Hultman et al. (2002) reported that neonates delivered by C-section in Sweden were 1.6 times more likely to develop autism than those delivered vaginally. Bilder et al. (2009) observed that neonates delivered by C-section were associated with increased risk of developing autism, but the association was eliminated after adjusting for breech presentation. In 2011, a Canadian study indicated that neonates delivered by C-section were 1.23 times more likely to develop autism than neonates delivered vaginally (Dodds et al. 2011). In
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our population-based study in Taiwan, we observed that increased risk of autism was associated with delivery by C-section with GA, but not with delivery by C-section with RA, after adjusting for potential risks. Neurotoxicity resulting from neonatal exposure to anesthesia might affect later neurodevelopment in children. Different regions of the brain are responsible for differing brain functions. Processes involved in brain development, such as neurogenesis, migration, synaptogenesis, apoptosis, and myelination, follow distinct timelines that vary among the various brain regions, resulting in different rates of neurocognitive maturation (Casey et al. 2005; Herschkowitz et al. 1997). Peak synaptogenesis in the primary sensorimotor cortex to the prefrontal cortex occurs from birth to approximately 3 years of age (Sun 2010). Early insult to brain development can affect a brain region undergoing peak synaptogenesis, thus delaying or affecting the future development of other brain regions (Rice and Barone 2000). Few studies have examined the risk of autism associated with the use of different types of anesthesia during delivery. These studies produced inconsistent results on the
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effects of GA on autism. Gardener et al. (2011) conducted a meta-analysis of studies investigating the association between autism and anesthesia during delivery, reporting that three studies had shown that GA increases the risk of autism compared with the risk in control births. However, this increase was nonsignificant (1.36, 95 % CI 0.87–2.13). According to our research, our study is the first to report a positive association between GA during delivery and autism in an Asian population. GA is predominantly used in emergency births, or because of maternal preference, inadequate RA, or failed RA attempts (Shroff et al. 2004). GA can also be recommended for women with pregnancy complications, such as preeclampsia, or women with illnesses or complications that could be associated with risk during an epidural or spinal anesthesia. Pregnancy complications tend to be associated with increased risk of autism. Although our model adjusted for as many confounders as possible, we were unable to completely eliminate the possibility that other unmeasured confounders or GA-indicated conditions contributed to the association between GA and risk of autism. It is possible that adjusting for all of the indications for GA could have eliminated the observed association between autism and C-section with GA. Besides, certain risks are inherent to anesthesia during delivery, and the neonate brain is vulnerable to the effects of anesthesia. Thus, whether GA directly contributes to the development of autism remains unclear. Because of associated maternal risk, the use of GA during C-sections has decreased in recent years (Palanisamy et al. 2011). Increasing evidence from animal models has shown that several GA techniques cause aberrant neuronal apoptosis and behavioral deficits later in life. Currently, the use of GA is limited primarily to cases of inadequate RA, failed attempts to administer RA, emergency deliveries, and deliveries in which the mother has requested GA (Palanisamy et al. 2011). Whether the risk of developing autism associated with epidurals and spinal anesthesia is lower than that associated with GA remains unclear. RA induces sympathetic blockade and vasodilatation, and also increases tissue oxygenation (Treschan et al. 2003). However, GA does not completely block afferent inputs or autonomic responses (Nishiyama et al. 2005), resulting in vasoconstriction, and subsequent impaired tissue perfusion and reduced tissue oxygen tension (Buggy 2000). In this study, indications for RA could not be determined based on the data available. Additional studies to examine the possible association between autism and RA during vaginal deliveries are warranted. Previous studies have shown that the rates of autism in boys and girls differ (Anello et al. 2009; Eaton et al. 2001), with a male-to-female patient ratio of approximately 4:1. Our results showed a similar sex-biased ratio in the
incidence of autism, irrespective of the mode of delivery. The incidence of autism among girls was two times higher in children delivered by C-section with GA than in those delivered vaginally. Girls might be more sensitive to the long-term effects of GA than boys. Additional studies are required to identify the mechanisms underlying the observed sex-related differences in risk of autism. Previous studies have investigated the possible associations between autism and parental characteristics, including parental age (Bilder et al. 2009; Glasson et al. 2004; Maimburg and Væth 2006; Reichenberg et al. 2006). In this study, maternal and paternal ages were both associated with risk of autism (Appendix 6 of ESM). Children born to mothers aged 35–44 years had a 26 % greater risk of developing autism than did those born to mothers aged 15–24 years, and children born to fathers aged 35–49 years had a 200 % greater risk of autism than did those born to fathers aged 15–24 years. Therefore, the effects of paternal age on risk of autism were greater than those of maternal age. This result was consistent with those of a recent study, which showed that paternal age is associated with risk of psychiatric and learning disorders, including autism and schizophrenia (D’Onofrio et al. 2014). These findings might be explained by a higher DNA mutation rate in sperm than in ova, which increases with increasing paternal age, resulting in higher frequencies of inherited genetic defects (Crow 1997). Autism has a strong genetic component (Bailey et al. 1995). Therefore, family-based cohort studies are useful for investigating the association between autism and obstetric anesthesia because they can eliminate the effects of genetic factors and maternal risks. In this study, we included only the first birth during the observational period in our analyses, which limited our sample size and might have influenced our results on the incidence of autism associated with the various modes of obstetric anesthesia. A power analysis indicated that we needed[120,000 births from multiple-birth families to detect differences in the incidence of autism; however, our cohort contained only 95,326 women who gave birth more than once during the study period. In addition, births within the same family during the same follow-up could have biased the estimation of the Cox regression analysis, which assumed that censoring times were independent and random across all variables (Cook et al. 2011). This study has limitations. First, it is a retrospective study using ICD-9-CM diagnosis codes to identify patients with autism. Although various clinicians in different clinical settings performed the autism diagnoses, physicians in Taiwan are required to follow the standardized criteria of the DSM-IV-TR for the diagnosis of autism, according to the recommendations of the Taiwan Society of Psychiatry. Second, the observed incidence of autism in Taiwan was considerably lower than that reported in the United States (1
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vs. 3–6 per 1,000 person-years) (Boulet et al. 2009; Bragg et al. 2010; Fombonne 2003). Autism is typically underdiagnosed in Taiwan because of stigmatization in Asian societies. This cultural difference could have influenced our results. However, although the true incidence of autism in Taiwan might be higher than that identified in this study, it is unlikely that this difference affected the validity of our risk estimates. Third, we were unable to assess the risks associated with anesthesia in neonates delivered vaginally because obstetric anesthesia during vaginal delivery is not covered by the NHI. These data were not thus included in the claims data analyzed. In addition, data on births resulting from the use of assisted reproductive technology, including single-embryo or blastocyst transfer, were unavailable and could have influenced our results. The strengths of this study include its retrospective design, which minimized the influence of clinician-related bias on the evaluation of the association between autism and mode of delivery, and minimized the potential for bias associated with medical surveillance. The majority of children with autism are first diagnosed between the ages of 2 and 3 years, and the number of autism diagnoses decreases gradually after the age of 4 years. In this study, the mean duration of follow-up was 4.3 years. Therefore, the majority of diagnoses of autism would have been detected prior to the end of the study evaluation period. In conclusion, the results from our population-based birth cohort study show that neonates delivered by C-section with GA are associated with higher incidence of autism than neonates delivered vaginally or by C-section with RA. The risk of autism in the children delivered by C-section with GA remained significantly higher than that in children delivered vaginally after adjusting for other risk factors in the prenatal, perinatal, and neonatal periods. Future investigations should include animal model experiments on the effects of exposure to GA in early infancy to determine the mechanisms underlying our results. We recommend that obstetricians consider the increased risk of autism in babies delivered by C-section with GA, and educate mothers to avoid C-section with GA, unless medically indicated. Neonates delivered by C-section with GA should undergo screening for autism during early childhood. Acknowledgments This work was supported by the Health Promotion Administration, Ministry of Health and Welfare, Taiwan (grant number 9910220P).
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ORIGINAL PAPER
Risk of Autism Associated With General Anesthesia During Cesarean Delivery: A Population-Based Birth-Cohort Analysis Li-Nien Chien • Hsiu-Chen Lin • Yu-Hsuan Joni Shao Shu-Ti Chiou • Hung-Yi Chiou
•
Ó Springer Science+Business Media New York 2014
Abstract The rates of Cesarean delivery (C-section) have risen to [30 % in numerous countries. Increased risk of autism has been shown in neonates delivered by C-section. This study examined the incidence of autism in neonates delivered vaginally, by C-section with regional anesthesia (RA), and by C-section with general anesthesia (GA) to evaluate the risk of autism associated with C-section and obstetric anesthesia. During a mean follow-up of 4.3 years, the incidence of autism was higher in neonates delivered by C-section with GA than in neonates delivered vaginally, with an adjusted risk of 1.52 (95 % confidence interval 1.18–1.94). However, the adjusted risk of autism in neonates delivered by C-section with RA and in neonates delivered vaginally was nonsignificantly different.
Introduction
Electronic supplementary material The online version of this article (doi:10.1007/s10803-014-2247-y) contains supplementary material, which is available to authorized users.
Cesarean deliveries (C-sections) have become increasingly common in numerous countries. The rate of C-section was 32.8 % of all births in the United States in 2010 (Hamilton et al. 2013) and 23.8 % of single births in the United Kingdom in 2008 (Bragg et al. 2010). During the past 10 years, the rates of C-section have risen to [30 % in numerous Asian, European, and Latin American countries (Declercq et al. 2011; Han et al. 2011; Harper and Odibo 2010; OECD 2011). Studies have reported that C-sections can harm fetuses and neonates, and do not necessarily benefit mothers. Therefore, The American College of Obstetricians and Gynecologists (2009) established strict guidelines for nonmedically indicated C-sections prior to 39 weeks’ gestation. However, the demand for planned elective C-sections has increased (Kottmel et al. 2012). A C-section is a major surgery associated with increased risk of intensive care (Murphy et al. 2001), breathing problems (Almqvist et al. 2012; Merenstein et al. 2011), low Apgar score (Burt et al. 1988), fetal injury (Lieberman et al. 1997), and asthma (Roduit et al. 2009). However,
L.-N. Chien School of Health Care Administration, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
S.-T. Chiou Health Promotion Administration, Ministry of Health and Welfare, Taipei, Taiwan
H.-C. Lin Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
S.-T. Chiou Institution of Public Health, School of Medicine, National YangMing University, Taipei, Taiwan
H.-C. Lin Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan
H.-Y. Chiou (&) School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wu-Hsing Street, Taipei City 110, Taiwan e-mail: [email protected]
Keywords Autism Cesarean delivery Obstetric anesthesia Population-based birth cohort Li-Nien Chien and Hsiu-Chen Lin contributed equally to this work.
Y.-H. J. Shao Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan
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C-section might be necessary because of medical conditions such as labor arrest disorders, multiple gestation, suspected macrosomia, preeclampsia, and other obstetric conditions (Barber et al. 2011). Whether autism is associated with C-section is unclear. The results from several studies have suggested increased risk of autism in neonates delivered by C-section (Bilder et al. 2009; Eaton et al. 2001; Glasson et al. 2004; Hultman et al. 2002; Maimburg and Væth 2006). Data from other studies have suggested that obstetric anesthesia administered to immature brains can cause histopathological changes that adversely affect development and behavior (DiMaggio et al. 2009; Wilder et al. 2009). Glasson et al. (2004) reported that the mothers of patients with autism were likely to have received anesthesia during labor, and that epidural caudal anesthesia was significantly associated with autism. Flick et al. (2011) reported that multiple exposures to anesthesia prior to the age of 2 years can adversely affect neurodevelopment in children, resulting in learning disabilities. Regional anesthesia (RA) and general anesthesia (GA) are both acceptable modes of anesthesia during C-section delivery; however, GA is less frequently provided than RA because of potential maternal and neonatal risks (Afolabi and Lesi 2012). Whether the C-section itself or obstetric anesthesia during the C-section is the risk factor associated with autism has yet to be established. Understanding the association between autism and C-section with anesthesia is crucial for the early detection and prevention of autism. However, few studies have investigated the association between obstetric anesthesia and autism (Glasson et al. 2004; Hattori et al. 1991). Therefore, this study aimed to determine whether the risk of developing autism in early childhood is associated with vaginal delivery, C-section delivery with RA, or C-section delivery with GA, based on data from a population-based birth cohort.
Methods Data Source The National Birth Reporting Database (NBRD), the National Health Insurance Research Database (NHIRD), and the Birth Certification Registry (BCR) were used as sources of population-based data in Taiwan. The NBRD is maintained by the Health Promotion Administration, and contains data on maternal risk during pregnancy and delivery, neonatal sex, gestational age, birth weight, and the mode of delivery reported by the attending obstetrician or pediatrician. Hospitals and clinics are obligated to report birth information to local health departments within 10 days of delivery. The NHIRD is maintained by the National Health Insurance Administration, and contains information on
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nearly all of the clinical diagnoses and treatments received by beneficiaries of the National Health Insurance (NHI) program. Since 1995, all Taiwanese citizens have been required by law to enroll with the NHI. The NHI coverage rate was 99 % in 2012 (National Health Insurance Administration 2013). Payments for vaginal deliveries and C-sections are covered by the NHI. The BCR is maintained by the Ministry of the Interior, and includes data on neonatal parity, residency, parental age, education, nationality, and aboriginal status, as well as encrypted identifiers for the parents and newborns, which allow the BCR, NBRD, and NHIRD databases to be linked. Because birth registration is mandatory, the data are considered accurate and complete. Ethics Statement Confidentiality was assured by abiding by the data regulations of the Collaboration Center of Health Information Application (CCHIA), Ministry of Health and Welfare, Executive Yuan, Taiwan. The CCHIA encrypts individual identifiers to protect privacy before releasing information to investigators for research purposes. This study was approved by the Taipei Medical University Joint Institutional Review Board (Approval no. 201305001). Participants More than 800,000 single births recorded in the NBRD between January 1, 2004 and December 31, 2007 were reviewed. Newborns of unknown sex, gestational age\20 or [42 weeks, and birth weight \500 g were excluded (n = 26,539). Newborns for whom the birth records could not be linked to the NHIRD or BCR because of erroneous encrypted identifiers, unknown parents, or the delivery not being covered by the NHI were also excluded (n = 93,165). Newborns with at least one parent aged\15 years, a mother aged [45 years, or a father aged [80 years were excluded, which accounted for \1 % of all patients reviewed (n = 400). In addition, newborns with missing data on the study variables were excluded (n = 87 621). When a mother gave birth more than once during the study period, only the first birth was included in the study sample. The associations between autism and the type of anesthesia used during C-section were investigated. Because the NHI does not cover RA for vaginal delivery, such as epidural anesthesia, data on whether obstetric anesthesia was administrated for vaginal delivery were unavailable. Therefore, patients who received epidural or spinal anesthesia were included in the C-section with RA group, and patients who received GA were included in the C-section with GA group. To evaluate the risk of autism specifically associated with obstetric anesthesia, the patients who received nonobstetric anesthesia during the observational period were excluded.
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Fig. 1 A flow diagram of participant selection
Thus, only three modes of delivery were considered when analyzing the incidence of autism: vaginal delivery (n = 362,297), C-section with RA (n = 161,992), and C-section with GA (n = 12,384) (Fig. 1). Study Variables Outcomes The primary outcome of interest was autism, a disorder that typically appears before the age of 3 years (Filipek et al.
2000). Children with autism, as defined by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code of 299.0 were selected, because it is the most common autism-related diagnosis in early childhood. In Taiwan, autism is usually diagnosed by a pediatrician or psychiatrist, and the diagnosis is confirmed based on the results of multiple tests, such as a multiphasic psychological test, a personality assessment, and an intelligence assessment. More than one diagnostic code was considered to ensure the validity of autism diagnoses. A recent study used an algorithm that
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included two or more types of claim for autism-spectrum disorders to generate a positive predictive value of 87.4 %, which indicates a high level of reliability for identifying cases of autism-spectrum disorders in claims data (Burke et al. 2014). Covariates Neonatal characteristics, parental demographics, and maternal risk factors were controlled for as potential confounders. The neonatal characteristics considered were sex, birth weight, gestational age, parity, 5-min Apgar score, level of urbanization of residence, previous or existing jaundice, cerebral edema, respiratory distress, and birth defects. The level of urbanization was estimated based on population density, the percentage of residents with a college-level education or higher, the percentage of residents aged [65 years, the percentage of agriculture workers among the residents, and the number of physicians per 100,000 residents. The parental demographics included age, education, nationality, aboriginal status, marital status, and insurance eligibility status. Data on insurance eligibility status were obtained from the enrollment records of the NHI, and were predominantly based on wage premiums. The maternal risks and complications during pregnancy and labor included systemic lupus erythematosus, hyperthyroidism, hypertension, diabetes, epilepsy, asthma, allergic rhinitis, gestational hypertension, gestational diabetes, preeclampsia, placenta previa, premature rupture of membranes, induction, breech presentation, presence of meconium, uterine bleeding, prolonged labor, and fetal distress. Appendix 1 of ESM lists detailed information on these variables and the ICD-9-CM diagnostic codes. Subgroup Analysis Two analyses were performed to evaluate the robustness of the initial findings. In the first analysis, the ICD-9-CM diagnosis code for autism was considered. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), the diagnosis of autistic-spectrum disorders includes autistic disorder, pervasive developmental disorder not otherwise specified, Asperger syndrome, Rett syndrome, and childhood disintegrative disorder (Filipek et al. 2000). However, distinguishing the diagnoses within the pervasive developmental disorders can be problematic and unreliable, even if the diagnostic criteria have been carefully adhered to. Therefore, the ICD-9-CM diagnosis code of 299.xx was used to broaden the range of diagnostic coding, and the data were reexamined. Appendixes 2 and 3 of ESM list the results.
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The use of GA or RA is influenced by various factors, such as the urgency of a procedure, maternal status, the presence of specific contraindications, and clinician and patient preferences. Neuraxial anesthesia for RA is generally preferred to GA for C-sections because it minimizes the risk of failed intubation, ventilation, and aspiration. However, obstetric indications, such as placenta previa, can be considered absolute indications for GA (McGlennan and Mustafa 2009). To ensure effective comparisons between C-sections with GA or RA, a propensity score (PS) matching technique was used to adjust for underlying risks. The PS cohort contained a group of C-section births and a control group of C-section births with similar baseline characteristics, on whom a method of obstetric anesthesia other than GA or RA had been used. This method has been used in numerous observational studies to reduce selection bias (Austin 2008, 2011; Rosenbaum and Rubin 1984; Stukel et al. 2007). The greedy match algorithm macro developed by the Mayo Clinic (http://ndc.mayo.edu/mayo/research/) for SAS software (SAS Institute, Cary, NC, USA), was used to match two C-section deliveries with RA to one C-section delivery with GA (Kosanke and Bergstralh 2004). The matched PS cohort consisted of 12,370 patients with C-section with GA, matched to 24,580 patients with C-section with RA, based on a probability of PS with a standard deviation of 0.1. The probability of being administered GA or RA was calculated for each birth by using a logistic regression model that addressed the covariates influencing the choice of obstetric anesthesia. Appendix 4 of ESM lists the baseline characteristics of the PS-matched cohort. Statistical Analysis Patients were followed-up from the date of birth to the date of the earliest clinic visit for autism, death (obtained from the death registry), withdrawal from the NHI (obtained from the enrollment file), or the end of the observational period (December 31, 2009). The duration of follow-up ranged from 2 to 6 years. Incidence rates of autism per 1,000 person-years with 95 % confidence intervals (CIs) were estimated. Cox proportional-hazards regression models were used to estimate the adjusted hazard ratios (HRs) for the mode of delivery and risk of autism. The models did not violate the assumption of proportional hazard. The cumulative hazard curves for the modes of delivery were constructed after adjusting for all of the risk factors. All statistical analyses were performed using SAS/ STAT, Version 9.3 and STATA 12 (StataCorp LP, College Station, TX, USA) software packages, and p \ 0.05 was considered statistically significant.
J Autism Dev Disord Table 1 Basic characteristics of births born via different modes of delivery Sample size
Vaginal deliveries 362,297
C-section deliveries with RA 161,992
C-section deliveries with GA 12,384
Male (%)
51.6 %
52.9 %
52.8 %
Gestational age (weeks), Mean(SD)
38.7 (1.4)
38.2 (1.5)
38.0 (2.0)
Birth weight (g), Mean(SD)
3,112.6 (393.7)
3,153.7 (454.8)
3,061.4 (519.6)
Apgar score \7 at 5 min
0.20 %
0.26 %
2.19 %
1 2
80.8 % 16.2 %
78.9 % 17.8 %
80.2 % 16.7 %
[=3
3.0 %
3.3 %
3.1 %
Level 1 (Most urbanized)
49.3 %
54.0 %
55.4 %
Level 2
39.7 %
36.3 %
35.1 %
Level 3
6.1 %
5.2 %
5.2 %
Level 4
4.9 %
4.5 %
4.4 %
Neonatal characteristics
Parity
Urbanization of residency
Risk factors Jaundice
4.6 %
4.0 %
3.5 %
Cerebral edema
\0.1 %
0.1 %
\0.1 %
Respiratory distress
0.3 %
0.4 %
0.8 %
Any birth defect
0.5 %
0.3 %
0.5 %
Age (year), Mean (SD)
28.5 (4.6)
30.2 (4.8)
30.1 (4.8)
Education (year), Mean (SD) Citizenship, not Taiwan
13.4 (2.8) 13.1 %
13.4 (2.7) 8.2 %
13.3 (2.7) 8.3 %
Maternal characteristics
Aboriginal status (yes)
2.2 %
2.4 %
1.8 %
Married
85.8 %
90.8 %
90.4 %
Level 1 (Highest)
19.0 %
20.2 %
17.3 %
Level 2
31.0 %
29.8 %
28.8 %
Level 3
17.0 %
16.1 %
17.6 %
Level 4
13.5 %
14.9 %
15.8 %
Level 5
7.8 %
7.3 %
7.8 %
Level 6
11.7 %
11.6 %
12.7 %
Age (year), Mean (SD)
32.4 (5.5)
33.3 (5.5)
33.3 (5.6)
Education (year), Mean (SD)
13.2 (3.0)
13.3 (2.8)
13.2 (2.7)
Citizenship, not Taiwan
0.6 %
0.8 %
0.8 %
Aboriginal status (yes)
2.1 %
2.2 %
1.7 %
Socioeconomics status
Paternal characteristics
Maternal risk/complication during pregnancy or labor SLE 0.2 %
0.2 %
0.4 %
Hyperthyroidism
0.1 %
0.2 %
0.1 %
Hypertension
0.4 %
0.2 %
0.2 %
Diabetes
1.8 %
2.7 %
2.8 %
Epilepsy
0.2 %
0.3 %
0.3 %
Asthma
\0.1 %
0.1 %
\0.1 %
Allergic rhinitis
0.1 %
0.1 %
0.2 %
Gestational hypertension
0.1 %
1.3 %
1.8 %
Gestational diabetes
0.6 %
0.8 %
0.7 %
Preeclampsia
\0.1 %
0.1 %
\0.1 %
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J Autism Dev Disord Table 1 continued Sample size
Vaginal deliveries 362,297
C-section deliveries with RA 161,992
C-section deliveries with GA 12,384
Placenta previa
7.0 %
9.4 %
11.0 %
PROM
\0.1 %
\0.1 %
\0.1 %
Induction
0.5 %
0.4 %
0.4 %
Breech presentation
0.2 %
12.7 %
8.8 %
Meconium
1.8 %
1.4 %
1.4 %
Uterine bleeding
0.3 %
0.4 %
1.5 %
Prolong labor
0.1 %
5.2 %
2.6 %
Fetal distress
0.2 %
3.7 %
7.1 %
RA regional anesthesia, GA general anesthesia, PROM Premature rupture of membranes, SLE Systemic Lupus Erythematosus
Results
Table 2 The unadjusted incidence of autism (per 1,000 person-year) of births born via different modes of delivery
Basic Characteristics
Mode of delivery
Compared with vaginal deliveries, babies delivered by C-section with RA or GA were more likely to be boys or to have a 5-min Apgar score \7, and were less likely to have jaundice or to be carried to full term. Neonates delivered by C-section with RA or GA were also more likely to have older parents, married parents, or a mother who experienced risks and complications during pregnancy. Overall, 7.1 % of the C-sections were performed using GA (Table 1). Incidence of Autism The mean duration of follow-up was 4.3 years. The rates of autism diagnosis were 0.32 % (1,166/362 297), 0.38 % (615/161 992), and 0.56 % (69/12 384) for neonates delivered vaginally, by C-section with RA, and by C-section with GA, respectively. The incidence of autism per 1,000 person-years was 0.77 (95 % CI 0.73–0.81), 0.92 (95 % CI 0.85–1.00), and 1.34 (95 % CI 1.06–1.69) for vaginal deliveries, C-sections with RA, and C-sections with GA, respectively (Table 2). Therefore, the incidence of autism was highest in the neonates delivered by C-section with GA. After stratifying by sex, the incidence of autism was significantly higher in boys than in girls. The ratio of boys to girls ranged from 4.3 to 6.1 for the various modes of delivery. Regression Analysis The neonates delivered by C-section with GA had a 52 % higher risk of developing autism than did the neonates delivered vaginally (an adjusted HR of 1.52, 95 % CI 1.18–1.94, p = 0.001) (Table 3). After adjusting for neonatal characteristics, parental demographics, and maternal risks and
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Person-y
Autism
Incidence (95 % CI)
Vaginal deliveries
1,516,834
1,166
0.77 (0.73–0.81)
C-section deliveries with RA
665,430
615
0.92 (0.85–1.00)
C-section deliveries with GA
51,611
69
1.34 (1.06–1.69)
Overall
Boys Vaginal deliveries
783,203
1,006
1.28 (1.21–1.37)
C-section deliveries with RA
351,241
535
1.52 (1.40–1.66)
C-section deliveries with GA
27,263
57
2.09 (1.61–2.71)
Girls Vaginal deliveries
733,630
160
0.22 (0.19–0.25)
C-section deliveries with RA
314,189
80
0.25 (0.20–0.32)
C-section deliveries with GA
24,348
12
0.49 (0.28–0.87)
CI confidence interval, GA general anesthesia, RA regional anesthesia
complications, the results indicated nonsignificant differences in the risk of autism between neonates delivered by C-section with RA and those delivered vaginally. When we examined the effects of the mode of delivery on autism according to sex, we observed that boys and girls delivered by C-section with GA were more likely (44 and 96 %, respectively) to develop autism than those delivered vaginally. Appendix 6 of ESM shows the model for all risk factors. Kaplan–Meier Curves The risk of autism in neonates delivered by C-section with GA differed significantly from that in neonates delivered
J Autism Dev Disord Table 3 The hazard ratios (HR) of autism of births delivered by C-section with RA and C-section with GA compared to vaginal deliveries Cohort mode of delivery
Crude HR 95 % CI
Adjusted* P
HRs 95 % CI
p
Overall Vaginal deliveries (Ref.)
1.00
C-section deliveries with RA
1.21(1.10–1.33)
\0.001
1.07 (0.96–1.19)
1.00 0.213
C-section deliveries with GA
1.74 (1.36–2.22)
\0.001
1.52 (1.18–1.94)
0.001
Boys Vaginal deliveries (Ref.)
1.00
C-section deliveries with RA C-section deliveries with GA
1.19 (1.07–1.32) 1.62 (1.24–2.12)
1.00 0.001 \0.001
1.08 (0.96–1.21) 1.44 (1.10–1.90)
0.188 0.008
Girls Vaginal deliveries (Ref.)
1.00
C-section deliveries with RA
1.17 (0.90–1.53)
0.247
1.00 1.01 (0.75–1.36)
0.956
C-section deliveries with GA
2.26 (1.26–4.06)
0.006
1.96 (1.07–3.60)
0.030
CI confidence interval, GA general anesthesia, PROM premature rupture of membranes, RA regional anesthesia, SLE systemic lupus erythematous * Adjusted for neonatal characteristics (sex, gestational age, birth weight, Apgar score\7, residency urbanization, birth defect, jaundice, cerebral edema, and respiratory distress), parental characteristics (age, education, citizenship, married, aboriginal, insurance eligibility categories) and maternal risk (SLE, hyperthyroidism, hypertension, diabetes, epilepsy, asthma, allergic, gestational hypertension, gestational diabetes, preeclampsia, placenta previa, PROM, induce, breech presentation, meconium, uterine bleeding, prolonged labor, and fetal distress)
vaginally and the difference raised as the observational year increased. However, the risk of autism in neonates delivered by C-section with RA and in neonates delivered vaginally was nonsignificantly different (Fig. 2a). The risk of autism in boys and girls was also nonsignificantly different (Fig. 2b, c). Subgroup Analysis When we evaluated the sensitivity of our analysis by using the 290.xx ICD-9-CM diagnosis code as the clinical criterion for autism diagnosis, our initial results remained robust (Appendixes 3 and 4 of ESM). Compared with vaginal deliveries, the adjusted HRs for C-sections with GA for all births, boys, and girls were 1.48 (95 % CI 1.17–1.88, p = 0.001), 1.45 (95 % CI 1.12–1.87, p = 0.005), and 1.66 (95 % CI 0.91–3.05, p = 0.099), respectively. We repeated the analyses using a PS-matched cohort that included two groups with similar baseline characteristics. One group contained neonates delivered by C-section with GA and the other contained neonates delivered by C-section with RA (Appendix 4 of ESM). The majority of the covariates were balanced after PS matching, with the exception of the neonates delivered by C-section with RA, who had a higher gestational age (38.1 vs. 38.0 weeks), higher birth weight (3,075.2 vs. 3,063.1 g), and lower rate of meconium discharge (1.19 vs. 1.43 %) than did the neonates delivered by C-section with GA. After adjusting for covariates, the neonates delivered
by C-section with GA had a higher risk of autism than did those delivered by C-section with RA (HR 1.67, 95 % CI 1.21–2.31, p = 0.002).
Discussion According to our research, this study is the largest population-based birth cohort study to demonstrate an association between the mode of delivery and autism. Neonates delivered by C-section with GA were associated with a higher incidence of autism than neonates delivered vaginally or those delivered by C-section with RA. After adjusting for potential confounders, the risk of autism was 52 % higher in the neonates delivered by C-section with GA than in those delivered vaginally. When stratifying by sex, we observed stronger association between autism and girls than boys. However, when we used ICD-9-CM 290.xx diagnostic coding to identify autism, we only observed increased risk of autism in boys delivered by C-section with GA. The data for the PS-matched cohort, which had balanced potential confounders for RA and GA, also indicated higher risk of autism in neonates delivered by C-section with GA than in neonates delivered by C-section with RA. Our results suggest that the use of GA during C-section is associated with increased risk of neurological disorder in childhood. The PS-matched group analysis indicated a higher risk of autism than did the adjusted model estimate. The PS-
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Fig. 2 Cumulative Kaplan–Meier curves of the incidence of autism in neonates delivered by C-section with GA, C-section with RA, and vaginally, after adjusting for all risk factors. Panels a, b, and c represent the overall data and data from the boy and girl cohorts, respectively
matching method provides an alternative to regression analyses traditionally used to estimate treatment effects. However, PS and regression method estimates can differ considerably. A regression analysis produces a coefficient estimate that represents the average treatment effect, whereas the PS matching method provides an estimate of the effects of a treatment on a patient. The two estimates confer if the effects of a treatment do not vary between patients. Therefore, regression and PS-matching methods can yield conceptually and numerically differing estimates (Austin 2011). Previous studies have extensively evaluated the association between C-section and autism. Hultman et al. (2002) reported that neonates delivered by C-section in Sweden were 1.6 times more likely to develop autism than those delivered vaginally. Bilder et al. (2009) observed that neonates delivered by C-section were associated with increased risk of developing autism, but the association was eliminated after adjusting for breech presentation. In 2011, a Canadian study indicated that neonates delivered by C-section were 1.23 times more likely to develop autism than neonates delivered vaginally (Dodds et al. 2011). In
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our population-based study in Taiwan, we observed that increased risk of autism was associated with delivery by C-section with GA, but not with delivery by C-section with RA, after adjusting for potential risks. Neurotoxicity resulting from neonatal exposure to anesthesia might affect later neurodevelopment in children. Different regions of the brain are responsible for differing brain functions. Processes involved in brain development, such as neurogenesis, migration, synaptogenesis, apoptosis, and myelination, follow distinct timelines that vary among the various brain regions, resulting in different rates of neurocognitive maturation (Casey et al. 2005; Herschkowitz et al. 1997). Peak synaptogenesis in the primary sensorimotor cortex to the prefrontal cortex occurs from birth to approximately 3 years of age (Sun 2010). Early insult to brain development can affect a brain region undergoing peak synaptogenesis, thus delaying or affecting the future development of other brain regions (Rice and Barone 2000). Few studies have examined the risk of autism associated with the use of different types of anesthesia during delivery. These studies produced inconsistent results on the
J Autism Dev Disord
effects of GA on autism. Gardener et al. (2011) conducted a meta-analysis of studies investigating the association between autism and anesthesia during delivery, reporting that three studies had shown that GA increases the risk of autism compared with the risk in control births. However, this increase was nonsignificant (1.36, 95 % CI 0.87–2.13). According to our research, our study is the first to report a positive association between GA during delivery and autism in an Asian population. GA is predominantly used in emergency births, or because of maternal preference, inadequate RA, or failed RA attempts (Shroff et al. 2004). GA can also be recommended for women with pregnancy complications, such as preeclampsia, or women with illnesses or complications that could be associated with risk during an epidural or spinal anesthesia. Pregnancy complications tend to be associated with increased risk of autism. Although our model adjusted for as many confounders as possible, we were unable to completely eliminate the possibility that other unmeasured confounders or GA-indicated conditions contributed to the association between GA and risk of autism. It is possible that adjusting for all of the indications for GA could have eliminated the observed association between autism and C-section with GA. Besides, certain risks are inherent to anesthesia during delivery, and the neonate brain is vulnerable to the effects of anesthesia. Thus, whether GA directly contributes to the development of autism remains unclear. Because of associated maternal risk, the use of GA during C-sections has decreased in recent years (Palanisamy et al. 2011). Increasing evidence from animal models has shown that several GA techniques cause aberrant neuronal apoptosis and behavioral deficits later in life. Currently, the use of GA is limited primarily to cases of inadequate RA, failed attempts to administer RA, emergency deliveries, and deliveries in which the mother has requested GA (Palanisamy et al. 2011). Whether the risk of developing autism associated with epidurals and spinal anesthesia is lower than that associated with GA remains unclear. RA induces sympathetic blockade and vasodilatation, and also increases tissue oxygenation (Treschan et al. 2003). However, GA does not completely block afferent inputs or autonomic responses (Nishiyama et al. 2005), resulting in vasoconstriction, and subsequent impaired tissue perfusion and reduced tissue oxygen tension (Buggy 2000). In this study, indications for RA could not be determined based on the data available. Additional studies to examine the possible association between autism and RA during vaginal deliveries are warranted. Previous studies have shown that the rates of autism in boys and girls differ (Anello et al. 2009; Eaton et al. 2001), with a male-to-female patient ratio of approximately 4:1. Our results showed a similar sex-biased ratio in the
incidence of autism, irrespective of the mode of delivery. The incidence of autism among girls was two times higher in children delivered by C-section with GA than in those delivered vaginally. Girls might be more sensitive to the long-term effects of GA than boys. Additional studies are required to identify the mechanisms underlying the observed sex-related differences in risk of autism. Previous studies have investigated the possible associations between autism and parental characteristics, including parental age (Bilder et al. 2009; Glasson et al. 2004; Maimburg and Væth 2006; Reichenberg et al. 2006). In this study, maternal and paternal ages were both associated with risk of autism (Appendix 6 of ESM). Children born to mothers aged 35–44 years had a 26 % greater risk of developing autism than did those born to mothers aged 15–24 years, and children born to fathers aged 35–49 years had a 200 % greater risk of autism than did those born to fathers aged 15–24 years. Therefore, the effects of paternal age on risk of autism were greater than those of maternal age. This result was consistent with those of a recent study, which showed that paternal age is associated with risk of psychiatric and learning disorders, including autism and schizophrenia (D’Onofrio et al. 2014). These findings might be explained by a higher DNA mutation rate in sperm than in ova, which increases with increasing paternal age, resulting in higher frequencies of inherited genetic defects (Crow 1997). Autism has a strong genetic component (Bailey et al. 1995). Therefore, family-based cohort studies are useful for investigating the association between autism and obstetric anesthesia because they can eliminate the effects of genetic factors and maternal risks. In this study, we included only the first birth during the observational period in our analyses, which limited our sample size and might have influenced our results on the incidence of autism associated with the various modes of obstetric anesthesia. A power analysis indicated that we needed[120,000 births from multiple-birth families to detect differences in the incidence of autism; however, our cohort contained only 95,326 women who gave birth more than once during the study period. In addition, births within the same family during the same follow-up could have biased the estimation of the Cox regression analysis, which assumed that censoring times were independent and random across all variables (Cook et al. 2011). This study has limitations. First, it is a retrospective study using ICD-9-CM diagnosis codes to identify patients with autism. Although various clinicians in different clinical settings performed the autism diagnoses, physicians in Taiwan are required to follow the standardized criteria of the DSM-IV-TR for the diagnosis of autism, according to the recommendations of the Taiwan Society of Psychiatry. Second, the observed incidence of autism in Taiwan was considerably lower than that reported in the United States (1
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vs. 3–6 per 1,000 person-years) (Boulet et al. 2009; Bragg et al. 2010; Fombonne 2003). Autism is typically underdiagnosed in Taiwan because of stigmatization in Asian societies. This cultural difference could have influenced our results. However, although the true incidence of autism in Taiwan might be higher than that identified in this study, it is unlikely that this difference affected the validity of our risk estimates. Third, we were unable to assess the risks associated with anesthesia in neonates delivered vaginally because obstetric anesthesia during vaginal delivery is not covered by the NHI. These data were not thus included in the claims data analyzed. In addition, data on births resulting from the use of assisted reproductive technology, including single-embryo or blastocyst transfer, were unavailable and could have influenced our results. The strengths of this study include its retrospective design, which minimized the influence of clinician-related bias on the evaluation of the association between autism and mode of delivery, and minimized the potential for bias associated with medical surveillance. The majority of children with autism are first diagnosed between the ages of 2 and 3 years, and the number of autism diagnoses decreases gradually after the age of 4 years. In this study, the mean duration of follow-up was 4.3 years. Therefore, the majority of diagnoses of autism would have been detected prior to the end of the study evaluation period. In conclusion, the results from our population-based birth cohort study show that neonates delivered by C-section with GA are associated with higher incidence of autism than neonates delivered vaginally or by C-section with RA. The risk of autism in the children delivered by C-section with GA remained significantly higher than that in children delivered vaginally after adjusting for other risk factors in the prenatal, perinatal, and neonatal periods. Future investigations should include animal model experiments on the effects of exposure to GA in early infancy to determine the mechanisms underlying our results. We recommend that obstetricians consider the increased risk of autism in babies delivered by C-section with GA, and educate mothers to avoid C-section with GA, unless medically indicated. Neonates delivered by C-section with GA should undergo screening for autism during early childhood. Acknowledgments This work was supported by the Health Promotion Administration, Ministry of Health and Welfare, Taiwan (grant number 9910220P).
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