Disease / Source / Description
Mode of delivery / NBRS / C-section and vaginal
Type of anesthesia / NHIRD / GA: general anesthesia
RA: regional anesthesia (included epidural and spinal)
Neonatal characteristics
Male / NBRS / Yes/No
Gestational age / NBRS / Continuous variables (ranged from 20 to 42 wk)
Birth weight / NBRS / Continuous variables (greater than 500 g)
Low Apgar score / NBRS / Apgar score <7
Parity / BCS / 1, 2 and ≥3
Jaundice / NHIRD / ICD-9-CM:773, 774
Cerebral edema / NHIRD / ICD-9-CM:3485
Respiratory distress / NHIRD / ICD-9-CM: 769, 7700, 7701, 7702, 7706, 7707, 7708
Birth defects / NBRS / Yes/No
Maternal and paternal characteristics
Age / NBRS / Continuous variable (ranged from 15 to 45)
Level of education / BCR / Continuous variable
Citizenship / NBRS / Not Taiwan (Yes/No)
Aboriginal status / BCR / Yes/No
Married / BCR / Yes/ No
Insurance eligibility groups / NHIRD / Six levels, highest to lowest
Maternal risk/complication during pregnancy or labor
SLE / NHIRD / ICD-9-CM: 6954, 7100
Hyperthyroidism / NHIRD / ICD-9-CM: 2429, 6481
Hypertension / NHIRD / ICD-9-CM: 401, 402, 403, 404, 405
Diabetes / NHIRD / ICD-9-CM: 250
Epilepsy / NHIRD / ICD-9-CM: 345, 7803
Asthma / NHIRD / ICD-9-CM: 493
Allergic rhinitis / NHIRD / ICD-9-CM: 477
Gestational hypertension / NHIRD / ICD-9-CM: 642, 6420, 6421, 6423, 6429
Gestational diabetes / NHIRD / ICD-9-CM: 648, 6480
Preeclampsia / NHIRD / ICD-9-CM: 6424, 6425, 6426, 6427
Placenta previa / NHIRD / ICD-9-CM: 641, 6661
PROM / NHIRD / ICD-9-CM: 6581
Induction / NBRS
Breech presentation / NBRS
Meconium / NBRS
Uterine bleeding / NBRS
Prolong labor / NBRS
Fetal distress / NBRS
BCR, Birth Certification Registry; ICD-9-CM, International Classification Disease Ninth Revision, Clinical Modification; NBRS, National Birth Reporting System; NHIRD, National Health Insurance Research Database; PROM, premature rupture of membranes; SLE,systemic lupus erythematous
Appendix 2. The incidence of autism (per 1000 person-y) of births born via vaginal and C-section with RA and C-section with GA (ICD-9-CM:299.xx)
Cohorts / Mode of delivery / Person-y / Autism / Incidence(95% CI)
Overall
Vaginal deliveries / 1516834 / 1315 / 0.87 / (0.82-0.92)
C-section deliveries with RA / 665430 / 693 / 1.04 / (0.97-1.21)
C-section deliveries with GA / 51611 / 75 / 1.45 / (1.16-1.82)
Boys
Vaginal deliveries / 783203 / 1128 / 1.44 / (1.36-1.53)
C-section deliveries with RA / 351241 / 604 / 1.72 / (1.59-1.86)
C-section deliveries with GA / 27263 / 63 / 2.31 / (1.80-2.96)
Girls
Vaginal deliveries / 733630 / 187 / 0.25 / (0.22-0.29)
C-section deliveries with RA / 314189 / 89 / 0.28 / (0.23-0.35)
C-section deliveries with GA / 24348 / 12 / 0.49 / (0.28-0.87)
Abbreviations: CI, confidence interval; GA, general anesthesia; RA, regional anesthesia
Appendix 3. The hazard ratios for autism of births delivered by C-section with RA and C-section with GA compared to vaginally deliveries (ICD-9: 299.xx)
Cohort / Mode of delivery / Crude / Adjusted*
HRs / (95% CI) / P / HRs / (95% CI) / P
Overall
Vaginal deliveries(Ref.) / 1.00 / 1.00
C-section deliveries with RA / 1.22 / (1.11-1.33) / <0.001 / 1.09 / (0.98-1.20) / 0.108
C-section deliveries with GA / 1.69 / (1.34-2.13) / <0.001 / 1.48 / (1.17-1.88) / 0.001
Boys
Vaginal deliveries(Ref.) / 1.00 / 1.00
C-section deliveries with RA / 1.21 / (1.10-1.34) / <0.001 / 1.10 / (0.99-1.23) / 0.078
C-section deliverieswith GA / 1.61 / (1.25-2.08) / <0.001 / 1.45 / (1.12-1.87) / 0.005
Girls
Vaginal deliveries(Ref.) / 1.00 / 1.00
C-section deliveries with RA / 1.12 / (0.87-1.45) / 0.362 / 0.99 / (0.75-1.31) / 0.948
C-section deliverieswith GA / 1.95 / (1.09-3.49) / 0.025 / 1.66 / (0.91-3.05) / 0.099
*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)
Abbreviations: CI, confidence interval; GA, general anesthesia; PROM, premature rupture of membranes; RA, regional anesthesia; SLE, systemic lupus erythematous
Appendix 4. Characteristics of C-section births delivered with RA and GA based on PS-matched cohort
Type of anesthesia / RA / GASample size / 24,580 / 12,370
Neonatal characteristics
Male (%) / 53.15% / 52.84%
Gestational age (wk), Mean (SD) / 38.1(1.8) / 38.0(2.0)
Birth weight (g), Mean (SD) / 3075.2(490.5) / 3063.1(516.9)
Parity
1 / 80.81% / 80.20%
2 / 16.31% / 16.72%
≥3 / 2.89% / 3.08%
Urbanization of residency
Level 1 (most urbanized) / 55.73% / 55.38%
Level 2 / 35.09% / 35.06%
Level 3 / 5.02% / 5.19%
Level 4 / 4.16% / 4.37%
Risk factors
Jaundice / 3.37% / 3.46%
Cerebral edema / 0.03% / 0.04%
Respiratory distress / 0.62% / 0.75%
Birth defects / 0.45% / 0.50%
Maternal characteristics
Age (y), Mean (SD) / 30.1(4.8) / 30.1(4.9)
Education (y), Mean (SD) / 13.34(2.7) / 13.3(2.7)
Citizenship, not Taiwanese / 7.96% / 8.26%
Aboriginal status (yes) / 1.67% / 1.78%
Married / 90.72% / 90.43%
Insurance eligibility groups
Level 1 (Highest) / 17.34% / 17.28%
Level 2 / 28.84% / 28.83%
Level 3 / 17.55% / 17.57%
Level 4 / 15.82% / 15.80%
Level 5 / 7.75% / 7.79%
Level 6 / 12.70% / 12.72%
Paternal characteristics
Age (y), Mean (SD) / 33.1(5.5) / 33.3(5.6)
Education (y), Mean (SD) / 13.3(2.7) / 13.2(2.7)
Citizenship, not Taiwanese / 0.78% / 0.77%
Aboriginal status (yes) / 1.75% / 1.71%
Maternal risk
SLE / 0.31% / 0.36%
Hyperthyroidism / 0.09% / 0.11%
Hypertension / 0.21% / 0.19%
Diabetes / 2.77% / 2.80%
Epilepsy / 0.27% / 0.32%
Asthma / 0.01% / 0.02%
Allergic rhinitis / 0.15% / 0.15%
Gestational hypertension / 1.71% / 1.80%
Gestational diabetes / 0.59% / 0.65%
Preeclampsia / 0.03% / 0.02%
Placenta Previa / 10.81% / 11.01%
PROM / 0.06% / 0.04%
Induction / 0.39% / 0.35%
Breech presentation / 8.45% / 8.77%
Meconium / 1.19% / 1.43%
Uterine bleeding / 1.46% / 1.45%
Prolong labor / 2.72% / 2.64%
Fetal distress / 6.61% / 7.03%
Abbreviations: GA, general anesthesia; PROM, premature rupture of membranes; RA, regional anesthesia; SLE, systemic lupus erythematous
Appendix 5. Incidences and hazard ratios of autism in a PS-matched C-section birthcohort according to obstetricanesthesia received
Sex / Anesthesia / Person-y / Autism / Incidence
(95% CI) / Adjusted HRs
(95% CI) / P value
Overall / RA / 102093 / 81 / 0.79 / (0.64-0.99) / -
GA / 51554 / 68 / 1.32 / (1.04-1.67) / 1.67 / (1.21-2.31) / 0.002
Boys / RA / 54215 / 71 / 1.31 / (1.04-1.65) / -
GA / 27251 / 56 / 2.06 / (1.58-2.67) / 1.57 / (1.11-2.24) / 0.011
Girls / RA / 47877 / 10 / 0.21 / (0.11-0.39) / -
GA / 24304 / 12 / 0.49 / (0.28-0.87) / 2.25 / (0.96-5.30) / 0.063
*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)
Abbreviations: GA, general anesthesia; HR, hazard ratio; CI, confidence interval; PS, propensity score; PROM, premature rupture of membranes; RA, regional anesthesia; SLE,systemic lupus erythematous
Appendix 6: Full model of hazard ratio for autism among overall births
Variables / HR / 95% CI / P_value
Vaginal birth / 1.00 / Ref.
C-section with RA / 1.07 / (0.96-1.19) / 0.213
C-section with GA / 1.52 / (1.18-1.94) / 0.001
Neonatal characteristics
Male / 5.76 / (5.04-6.59) / <0.001
Preterm: gestational age <= 36 weeks / 1.30 / (1.08-1.56) / 0.006
Late preterm: gestational age >=41 weeks / 1.03 / (0.82-1.30) / 0.792
VLBW: 500 to 1499 g / 1.70 / (0.94-3.08) / 0.077
LBW: 1500 to 2499 g / 1.04 / (0.83-1.32) / 0.716
OBW: >=4000 g / 1.01 / (0.90-1.13) / 0.883
APGAR score <7 / 1.30 / (0.67-2.52) / 0.437
Parity: 2 / 0.69 / (0.61-0.79) / <0.001
Parity>=3 / 0.47 / (0.32-0.69) / <0.001
Residency urbanization: level 2 / 2.09 / (1.52-2.86) / <0.001
Residency urbanization: level 2 / 1.38 / (1.00-1.90) / 0.051
Residency urbanization: level 4 / 1.04 / (0.69-1.57) / 0.855
Jaundice / 1.21 / (1.00-1.47) / 0.046
Cerebral edema / 1.99 / (0.48-8.34) / 0.345
Respiratory distress / 1.35 / (0.62-2.94) / 0.456
Any birth defect / 1.12 / (0.62-2.03) / 0.704
Parental characteristics
Maternal age: 15 to 24 / 1.00 / Ref.
Maternal age: 25 to 29 / 0.97 / (0.81-1.16) / 0.746
Maternal age: 30 to 34 / 1.10 / (0.91-1.34) / 0.312
Maternal age: 35 to 44 / 1.26 / (1.01-1.57) / 0.040
Mother's education: < 9 year / 1.00 / Ref.
Mother's education: 9 to 12 / 1.01 / (0.83-1.22) / 0.956
Mother's education: >12 / 1.21 / (0.99-1.49) / 0.067
Mother's citizenship: not Taiwan / 1.02 / (0.54-1.94) / 0.947
Marital status: unmarried / 1.00 / Ref.
Marital status: Married / 1.19 / (0.85-1.66) / 0.304
Marital status: unknown / 1.27 / (0.67-2.43) / 0.469
Insurance eligibility groups: level 1 / 1.00 / Ref.
Insurance eligibility groups: level 2 / 0.78 / (0.69-0.89) / <0.001
Insurance eligibility groups: level 3 / 0.74 / (0.63-0.87) / <0.001
Insurance eligibility groups: level 4 / 0.90 / (0.76-1.05) / 0.182
Insurance eligibility groups: level 5 / 0.75 / (0.59-0.96) / 0.024
Insurance eligibility groups: level 6 / 0.81 / (0.68-0.98) / 0.027
Paternal age: 15 to 24 / 1.00 / Ref.
Paternal age: 25 to 29 / 1.39 / (0.97-2.00) / 0.074
Paternal age: 30 to 34 / 1.65 / (1.15-2.38) / 0.007
Paternal age: 35 to 49 / 2.09 / (1.44-3.02) / <0.001
Paternal age: >=50 / 3.39 / (1.89-6.05) / <0.001
Fathers' education: < 9 year / 1.00 / Ref.
Fathers' education: 9 to 12 / 1.10 / (0.92-1.32) / 0.297
Fathers' education: >12 / 1.51 / (1.24-1.82) / <0.001
Father's citizenship: not Taiwan / 2.12 / (1.46-3.07) / <0.001
Maternal risk factors
SLE / 1.62 / (0.52-5.04) / 0.403
Hyperthyroidism / 1.37 / (0.44-4.26) / 0.586
Hypertension / 1.89 / (1.09-3.29) / 0.024
Diabetes / 1.26 / (0.96-1.65) / 0.091
Epilepsy / 1.27 / (0.53-3.05) / 0.598
Allergic rhinitis / 1.17 / (0.38-3.63) / 0.786
Gestational hypertension / 1.05 / (0.59-1.87) / 0.880
Gestational diabetes / 1.47 / (1.01-2.12) / 0.042
Preeclampsia / 0.84 / (0.12-5.99) / 0.858
Placentaprevia / 1.09 / (0.93-1.28) / 0.294
Induction / 1.07 / (0.59-1.93) / 0.832
Meconium / 0.99 / (0.71-1.40) / 0.965
Uterine bleeding / 1.61 / (0.93-2.79) / 0.087
Prolong labor / 1.07 / (0.76-1.50) / 0.705
Breech presentation / 1.17 / (0.94-1.45) / 0.153
Fetal distress / 1.00 / (0.71-1.40) / 0.978
Abbreviations: GA, general anesthesia; HR, hazard ratio; CI, confidence interval; LBW, low birth weight; OBW, over birth weight; PS, propensity score; PROM, premature rupture of membranes; RA, regional anesthesia; SLE,systemic lupus erythematous; VLBW, very low birth weight;