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BMJ Open
Does Cesarean Delivery Increase the Occurrence of

Neurodevelopmental Disorders, Asthma or Obesity in
Childhood?
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Journal: BMJ Open
Manuscript ID bmjopen-2017-017086
Article Type: Research

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Date Submitted by the Author: 30-Mar-2017
Complete List of Authors: Chen, Ginden; Institute of Health Policy and Management, College of Public
Health, National Taiwan University; Chung Shan Medical University
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Hospital, Department of Obstetrics and Gynecology

Chiang, Wan-Lin ; Institute of Health Policy and Management, College of
Public Health, National Taiwan University
Shu, Bih-Ching; National Cheng Kung University College of Medicine,
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Institute of Allied Health Sciences

Guo, Yueliang; National Taiwan University College of Medicine, Department
of Environmental and Occupational Medicine
Chiou, Shu-Ti; National Yang-Ming University,
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Chiang, Tung-liang; Institute of Health Policy and Management, College of

Primary Subject
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Paediatrics
Heading:
Secondary Subject Heading: Public health, Obstetrics and gynaecology

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Cesarean delivery, neurodevelopmental disorders, Asthma < THORACIC

Keywords:
MEDICINE, obesity, vaginal delivery
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For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 1 of 29 BMJ Open
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3 Does Cesarean Delivery Increase the Occurrence of Neurodevelopmental Disorders, Asthma or
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5 Obesity in Childhood?
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Ginden Chen MD, PhD1,2,3, Wan-Lin Chiang PhD1, Bih-Ching Shu PhD4, Yueliang Guo MD, PhD5
9 Shu-Ti Chiou PhD6, Tung-liang Chiang ScD1
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12 Affiliations:
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Institute of Health Policy and Management, College of Public Health, National Taiwan University,
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15 Taipei, Taiwan
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Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung,
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18 Taiwan
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Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
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21 Department of Institute of Allied Health Sciences, National Cheng Kung University, Tainan, Taiwan
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22 Department of Environmental and Occupational Medicine, National Taiwan University (NTU)
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College of Medicine and NTU Hospital, Taipei, Taiwan
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25 Health Promotion Administration, Ministry of Health & Welfare, Taipei, Taiwan
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27
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28 Address correspondence to:

29 Tung-liang Chiang, Institute of Health Policy and Management, College of Public Health, National
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31 Taiwan University, No. 17, Xu-Zhou Road, Taipei, 10055 Taiwan, [tlchiang@ntu.edu.tw],
32 886-2-33668059.
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34
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35 Keywords: Cesarean delivery, neurodevelopmental disorders, asthma, obesity, vaginal delivery

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Text word count: 2,810
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BMJ Open Page 2 of 29
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3 ABSTRACT
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5 Objectives Whether birth by Cesarean section (CS) increases the occurrence of neurodevelopmental
6 disorders, asthma or obesity in childhood is controversial. We used a cohort data to demonstrate the
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association between children born by CS and the occurrence of the above three diseases at the age of
9 5.5 years.
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12 Methods The database of the Taiwan Birth Cohort Study (TBCS) which was designed to assess the
13 developmental trajectories of children was used in this study. Associations between children born by
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15 CS and these three diseases were evaluated before and after controlling for gestational age (GA) at
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16 birth, children’s characteristics and disease-related predisposing factors.
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19 Results Children born by CS had significant increases in neurodevelopmental disorders (20%),
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21 asthma (14%), and obesity (18%) compared to children born by vaginal delivery. The association
22 between neurodevelopmental disorders and CS was attenuated after controlling for GA at birth (OR:
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1.15; 95% CI: 0.98-1.34). Occurrence of neurodevelopmental disorders steadily declined with
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25 increasing GA up to ≤40-42 weeks. CS and childhood asthma were not significantly associated after
26 controlling for parental history of asthma and GA at birth. Obesity in childhood remained
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28 significantly associated with cesarean delivery (OR: 1.19; 95% CI: 1.07-1.32) after controlling for
29 GA and disease-related factors.
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32 Conclusions Our results implied that the association between CS birth and children’s
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34 neurodevelopmental disorders is largely explained by GA. CS birth was weakly associated with
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35 childhood asthma since parental asthma and preterm births are stronger predisposing factors. The
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association between CS birth and childhood obesity was robust after controlling for disease-related
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3 STRENGTHS AND LIMITATIONS OF THIS STUDY
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5 Our database simultaneously demonstrates whether neurodevelopmental disorders, asthma, and
6 obesity are associated with modes of delivery after controlling for potential confounding
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factors.
9 We evaluated dose-dependent effects of gestation age on the occurrence of these diseases.
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Indications for Cesarean section were derived from self-reports by mothers or reports by
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12 primary care-givers, not from medical record.
13 We might ignore the possibility that these disorders might occur in combination because we
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15 looked at associations among these three disorders and modes of delivery mutually exclusive.
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4 INTRODUCTION
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7 With an escalating rate of cesarean sections worldwide, literature has demonstrated that infants
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10 born by Cesarean section (CS) may encounter different flora, and lack of compression in the birth
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13 canal may increase the risk of disturbed respiratory adaptation or neurological adaptation during their
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first days of life, compared to those delivered vaginally.[1-3] Cesarean delivery also alters gut
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microbiotic composition in early infancy.[4] However, whether modes of delivery also result in
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21 long-term physiological consequences in childhood or influence later physical well-being needs
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24 further investigation.
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27 Kapellou pointed out that the delivery of infants before 39 weeks can not only increase
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30 respiratory morbidity, but may also interrupt intrauterine brain maturation and have a significant
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33 impact on future neurodevelopment.[5] Animal studies have shown that CS may affect development
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36 of neurons and that some fetal brain developmental processes continue into the neonatal period.[6,7]
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39 In the past, mode of delivery has been shown to potentially affect normal intestinal colonization in
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42 infants as demonstrated by checking fecal flora.[8] However, the correlation between CS and later
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neurodevelopmental disorders is still controversial.
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Overweight children and increase of allergic diseases have been reported to be associated with
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50 CS delivery based on the hygiene hypothesis.[9-13] A meta-analysis demonstrated a 20% increase in
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53 the subsequent risk of asthma in children who had been delivered by CS.[9] A population-based
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56 cohort study found a moderately increased risk of asthma in the children delivered by CS and also
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4 found that this association was stronger for preterm children than for term children.[14] However,
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7 some longitudinal studies show no associations between subsequent risk of developing childhood
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10 asthma, wheeling episodes or atopic dermatitis and infants delivered by CS after controlling for their
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13 parental allergy history.[15,16] Epidemiological studies also revealed an association between CS and
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overweight or obese preschool age children.[10,11] Recently, a systematic review and meta-analysis
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indicated that CS is only moderately associated with overweight and obese children.[17] The
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21 inconsistent association between delivery modes and childhood allergies as well as
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24 overweight/obesity also needs clarification by further study.

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27 In this study, we used data from the Taiwan Birth Cohort Study (TBCS) to demonstrate whether
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30 neurodevelopmental disorders, asthma, and obesity at the age of 5.5 years are associated with modes
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33 of delivery after controlling for potential confounding factors. We also aimed to determine whether
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36 there are any dose-dependent effects of gestation age (GA) on the occurrence of these three diseases.
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39 MATERIALS AND METHODS
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42 Study population and setting
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Data used in this study were derived from the TBCS. The TBCS has been designed to assess the
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developmental trajectories of Taiwanese children and financially sponsored by the Health Promotion
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50 Administration in Taiwan. The study protocol and questionnaires were approved by the
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53 Directorate-General of Budget, Accounting and Statistics in the Executive Yuan, according to the
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56 Statistics Act of Taiwan. This study was approved by the Institutional Review Board at National
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4 Taiwan University Hospital (No. 201604055RINC).
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7 By using two-stage stratified random sampling, the TBCS selected a nationally representative
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10 sample of 24,200 children born in 2005 from the National Birth Report Database, with a sampling
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13 rate of approximately 11.7%. Before children reached school age, face-to-face survey interviews
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with mothers or primary caregivers were conducted at 6 months, 18 months, 36 months, and 5.5
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years of age, with response rates of 87.8%, 94.9%, 93.7%, and 92.8%, respectively. Our study
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21 sample included 19,721 children who participated the first and fourth surveys. The content of both
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24 surveys contains questions about the child’s developmental, behavioral, and health outcomes, as well
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27 as detailed information on family characteristics including socioeconomic conditions, parenting
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30 practices, and the parents’ health and well-being.
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33 Children’s health status, modes of delivery and gestational age
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36 In this study, we focused on childhood obesity, asthma and neurodevelopmental disorders.
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39 Childhood obesity was defined by the body mass index set by the Taiwan Bureau of Health
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42 Promotion for preschool children. Children with asthma were classified after a physician’s evaluation
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or diagnosis. Learning disabilities, developmental delay, attention deficit hyperactivity disorder,
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sensory integration disorder, and autism were diagnosed and evaluated by pediatric psychiatrists and
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50 clinical psychologists. Children with neurodevelopmental disorders were categorized as those having
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53 any or a combination of learning disabilities, developmental delay, attention deficit hyperactivity
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56 disorder, sensory integration disorder, or autism, according to the classification of the DSM-V
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4 published on May 27, 2013.[18]
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7 Information about the mode of delivery (vaginal or Cesarean delivery) and gestational age was
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10 also collected from Taiwanese birth certificates in 2005. GA was stratified as: preterm (< 37 weeks),
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13 term (37 to 41 weeks), and post-term (42 weeks or more). In order to evaluate the influence of GA on
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the associations of CS with the occurrence of the above three diseases, we further divided term
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pregnancy into 37 weeks, 38 weeks, 39 weeks, and 40-41 weeks for comparison.
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21 Parental characteristics used as control variables
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24 Mothers’ educational levels were classified as compulsory school (less than 9 years of
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27 schooling), senior high school, junior college, college and above. Household monthly income was
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30 categorized as less than 30,000 New Taiwan Dollars (NTD), 30,000-100,000 NTD, and more than
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33 100,000 NTD (30 NTD≒1 USD). Gestational weight gain among the mothers was regrouped as less
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36 than 11 kilograms and 11 kilograms or more. The occurrence of gestational diabetes diagnosed
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39 during prenatal care visits was also recorded. Parental history of asthma was recorded at the first
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Statistical analysis
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Children’s characteristics, obesity, asthma, and neurodevelopmental disorders were compared
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50 with Chi-square tests. Obesity, asthma, and neurodevelopmental disorders associated with Cesarean
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53 section were evaluated using logistic multiple regression analyses after controlling for GA and
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56 characteristics of children and parents. The Cochran-Armitage Trend Test was used to check
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4 dose-dependent effects on the occurrence of these three diseases across the preterm, early term
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7 period of 37-40 weeks (GA at 37 weeks - <38 weeks, 38 weeks - <39weeks, 39 weeks - <40 weeks)
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10 and ≧40 weeks. Alpha level was set as 0.01. All statistical analyses were performed using the
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13 Statistical Analysis Software package, SAS version 9.3.
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RESULTS
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In total, data of 19,721 children were successfully collected: neurodevelopmental disorders,
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21 19,717, asthma, 19,720 and obesity, 13,669. The children’s and parental characteristics are shown in
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24 Table 1. The prevalence of children’s neurodevelopmental disorders, asthma and obesity were
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27 significantly difference between birth by CS and vaginal delivery (4.7% vs. 3.8%, 7.3% vs. 6.3%,
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30 16.2% vs. 13.9%; respectively, all p < 0.01).
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33 Association between Neurodevelopmental Disorders and Cesarean Delivery
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36 Table 2 shows predisposing factors that might influence an association between
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39 neurodevelopmental disorders and birth by CS. The odds ratio (OR) and 95% confidence interval (CI)
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42 for Cesarean delivery were 1.22 and 1.05-1.42 after controlling for children’s and parental
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characteristics. Gender was significantly associated with children’s neurodevelopmental disorders
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(OR for male: 2.16). A young maternal age at childbirth was found to be a protective factor against
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50 neurodevelopmental disorders in the children. Monthly household income had an inverse association
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53 with the occurrence of children’s neurodevelopmental disorders.
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56 The association between neurodevelopmental disorders and birth by CS was attenuated after
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4 controlling for GA in regression model (OR: 1.15; 95% CI: 0.98-1.34). Children born at a gestational
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7 age of less than 37 weeks was significantly associated with more neurodevelopmental disorders (OR:
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10 1.94; 95% CI: 1.55-2.42).
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13 Association between Asthma and Cesarean Delivery
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Table 3 shows that asthma was associated with birth by CS (OR: 1.16; 95% CI: 1.03-1.30) after
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controlling for children’s and parental characteristics (Table 2). Gender and first-born children had a
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21 significant association with childhood asthma (ORs for males and first-born child: 1.40 and 1.23). A
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24 lower maternal educational level was a protective factor against childhood asthma. Children born in
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27 families with a lower monthly income had fewer occurrences of asthma.
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30 The association between asthma and children born by CS was attenuated after controlling for
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33 GA (OR: 1.11; 95% CI: 0.98-1.25). Children born at a GA of less than 37 weeks (OR: 1.27; 95% CI:
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36 1.03-1.56) had a significant association with more asthma. CS and childhood asthma were not
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39 significantly associated after further controlling parental history of asthma. However, children born
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42 at a GA of less than 37 weeks and a mother’s educational level were still associated with more
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asthma. Parental history of asthma was more significantly associated with childhood asthma (OR:
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3.62; 95% CI: 2.88-4.55).
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50 Association between Childhood Obesity and Cesarean Delivery
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53 Table 4 shows that childhood obesity was associated with birth by CS (OR: 1.19; 95% CI:
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56 1.08-1.32) after controlling for children’s and parental characteristics. Gender, first-born children and
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4 lower maternal education level were predisposing factors for childhood obesity. We found that
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7 obesity in childhood remained significantly associated with Cesarean delivery (OR: 1.19; 95% CI:
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10 1.07-1.32) after controlling for GA. Children born post-term had a significant association with
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13 childhood obesity. Male gender, first-born child and lower maternal educational level were also
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associated with obesity in childhood. Furthermore, birth by CS and childhood obesity were still
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associated when we included gestational diabetes (OR: 1.49) and maternal gestational weight gain
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21 (≧ 11kg; OR: 1.17) as control variables.
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24 Dose Effect of GA on These Three Disorders

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27 Further, we found that there was an association between CS at a GA of less than 37 weeks and
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30 neurodevelopmental disorders with a dose effect of GA until term. The association of premature birth
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33 and neurodevelopmental disorders also existed in the regression analysis while excluding the
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36 children born by primary CS due to mandatory medical factors. The risk of occurrence of
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39 neurodevelopmental disorders steadily declined with increasing GA up to 39 - <42 weeks (data not
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4 DISCUSSION
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7 In this study, children born by CS had significant increases in neurodevelopmental disorders
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10 (20%), asthma (14%), and obesity (18%) compared to children born by vaginal delivery. However,
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13 except for obesity, associations between CS births and children’s neurodevelopmental disorders or
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asthma were attenuated after controlling for GA and potential disease-related predisposing factors.
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Effect of GA on These Three Disorders
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21 Our results are consistent with the findings of MacKay et al.[19] We found that the risk of
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24 occurrence of neurodevelopmental disorders was significantly associated with a GA of less than 37

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27 weeks and steadily declined with increasing GA up to ≤40 - <42 weeks and with a dose effect of the
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30 gestation until term. These results support the hypothesis proposed by Kapellou which implies that
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33 the fetal brain develops and matures toward the end of gestation.[5] Our results also seem to
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36 indirectly provide data to support that neurodevelopmental outcomes are affected by premature
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39 interruption of intrauterine life.[20,21]
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42 Literature has revealed that preterm births, a younger GA at birth and low birth weight are
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associated with childhood asthma.[14,22] Tollanes et al. reported that an association between birth
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by CS and increased risk of asthma was stronger for preterm children than for term children.
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50 Sonnenschein-van der Voort et al. further found that “the association of lower birth weight with
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53 childhood asthma was largely explained by younger gestational age at birth”. Our results revealed
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4 controlling for parental history of asthma.
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7 Our results also showed that there were no associations between preterm, late-preterm, or term
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10 at birth and childhood obesity. But childhood obesity was significantly associated with children born
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13 post-term before and after controlling for gestational diabetes mellitus and gestational weight gain.
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Association between Neurodevelopmental Disorders and Cesarean Delivery
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Our results do not support the association between CS and neurodevelopmental disorders in
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21 childhood after controlling for GA. GA at birth, especially preterm births, largely explained the
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27 consistent with the viewpoint of Kapellou et al.[20] and Woythaler et al.[21]
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30 In addition to GA at birth, we also found that neurodevelopmental disorders occurred more in
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33 boys than in girls. However, recent literature has revealed that the increased risk of
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36 neurodevelopmental disorders in boys cannot exclude sex bias.[23,24] In this study, children with
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39 neurodevelopmental disorders were diagnosed and evaluated by pediatric psychiatrists and clinical
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Associations between maternal age and neurodevelopmental disorders in longitudinal or cohort
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studies are controversial.[25,26] Our study showed that a young maternal age at childbirth is as a
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50 protective factor. Literature showed that parental socioeconomic status such as low familial income
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53 is associated with an increased risk of neurodevelopmental disorders.[27-29] We found that a higher
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56 familial income is a protective factor against the occurrence of children’s neurodevelopmental
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10 A study in the UK in 2004 showed that an adjusted OR of delivery by CS is not associated with
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13 the subsequent development of physician-diagnosed asthma, wheezing or atopy in later childhood.
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[15] Another population-based cohort study conducted by Juhn et al. in the USA also revealed that
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mode of delivery is not associated with subsequent risk of developing childhood asthma or wheezing
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21 episodes after calculating their cumulative incidence rate and adjusting hazard ratios.[16] In this
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27 and parental history of asthma.
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30 Kolokotroni et al. reported that children with a family history of allergies enhance the positive
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33 association between CS delivery and asthma outcomes.[12] Xu et al. revealed that maternal history
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36 of asthma (hazard ratio: 3.71) was strongly associated with offspring asthma.[30] In this study,
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39 children born to a parent with a history of asthma was significantly associated with children’s asthma.
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42 Our results concur with the findings of Delbley et al. They noted that in addition to the hygiene
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hypothesis, factors including genetics, intrauterine environment and premature birth might also
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influence the association between birth by CS and childhood asthma.[31]
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50 In this study, boys and first-born child were also positively associated with and maternal
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53 educational level was negatively associated with the occurrence of childhood asthma other than CS
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56 and parental history of asthma. Mersha et al. showed that both genetic and gene expression data have
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4 sex-based differences in the genomic association with asthma.[32] A significant association between
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7 first-born children and childhood asthma might be consistent with the hypothesis of “in utero
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10 ‘birth-order’ T-cell programming” postulated by Kragh et al. which does not support the hygiene
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13 hypothesis. Kragh et al. revealed that first-born infants display a reduced anti-inflammatory profile in
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T cells at birth which may contribute to later development of immune-mediated diseases by
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increasing overall immune reactivity in first-born children compared to younger siblings.[33]
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21 However, negative associations between maternal educational levels and childhood asthma are
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24 inconsistent with other studies. Renz-Polster et al. did not find that maternal education levels
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27 influenced the occurrence of childhood asthma.[34] Hermann et al. reported that lower parental
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30 educational levels result in a higher prevalence of childhood asthma.[35]
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36 The association between CS births and childhood obesity was robust after including GA,
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39 gestational diabetes and maternal gestational weight gain as potential predisposing factors. Our
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42 findings were consistent with the epidemiological study conducted by Huh et al.[11] and a systematic
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review and meta-analysis by Li et al.[17] However, Pei et al. only found a greater likelihood of
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obesity at the age of 2 years in their CS group, but not at the ages of 6 and 10 years in a prospective
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50 cohort study in Germany which were inconsistent with our results.[36]
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53 In addition, boys, first-born children and lower maternal educational levels were also
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56 significantly associated with childhood obesity in current study. Matthiessen et al. reported that
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4 maternal educational level is inversely associated with childhood obesity, especially in boys.[37]
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7 Fradkin et al. found that children growing up with a high socioeconomic status are associated with a
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10 lower risk of childhood obesity, but with variations across race/ethnicity and gender.[38]
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13 Literature reveals that children born to mothers with excessive gestational weight gain and
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gestational diabetes mellitus are associated with a higher risk of childhood obesity.[39,40] Our
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results also showed that children born to mothers with gestational diabetes mellitus and higher
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27 There are several limitations in this study. First, we did not evaluate relationships of childhood
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30 obesity and parental body mass index which is included in the TBCS. We used gestational weight
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33 gain as an associated factor instead of parental body mass index since parental body mass index may
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36 be influenced by other lifestyle habits. Second, indications for CS in this study were derived from
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39 self-reports by mothers or reports by primary care-givers, not from medical record. Some
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42 information related to these disorders might be omitted. Last, we looked at associations among these
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three disorders and modes of delivery mutually exclusive, but we may have ignored the possibility
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that these disorders might occur in combination.
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4 CONCLUSIONS
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7 Our results implied that the association between CS birth and children’s neurodevelopmental
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10 disorders is largely explained by GA. CS birth was weakly associated with childhood asthma since
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13 parental asthma and preterm labor are stronger predisposing factors. The association between CS
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birth and childhood obesity is robust after controlling for related factors.
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3 Acknowledgements We appreciate Dr. Jeng-Dau Tsai from the Department of Pediatrics and Dr.
4
5 Vincent Chin-Hung Chen from the Department of Psychiatry at Chung Shan Medical University
6 Hospital for kindly providing their expert opinion to help us interpret and classify our findings on
7
8
neurodevelopmental disorders. We thank all the children and their parents who participated in this
9 study, the interviewers who helped with data collection and all of the study groups who participated
10
in the Taiwan Birth Cohort Study (TBCS).
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13 Contributor’s statements:
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15 Ginden Chen interpreted data, wrote drafts, revised the manuscript and approved the final manuscript
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16 as submitted.
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18 Wan-Lin Chiang carried out the initial analyses, analyzed research data and approved the final
19 manuscript as submitted.
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21 Bih-Ching Shu, Yue-Liang Guo and Shu-Ti Chiou interpreted research data and approved the final
23
Tung-liang Chiang conceptualized and designed the study, revised the initial manuscript and
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25 approved the final manuscript as submitted.
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27
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28 All authors approved the final manuscript as submitted and agree to be accountable for all aspects of
29 the work.
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32 Funding source: sponsored by the Health Promotion Administration, Department of Health and
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34 Welfare in Taiwan (DOH94-HP-1802, DOH95-HP-1802, DOH96-HP-1702, and DOH99-HP-1702).
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Conflicts of Interest: The authors declare that they have no conflict of interest.
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Data Sharing Statement: No additional data available.
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3 REFERENCES
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56 34. Renz-Polster H, David MR, Buist AS, et al. Caesarean section delivery and the risk of allergic
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10 Danish five-year-olds. Acta Paediatr 2006;95:1182–90.
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13 36. Pei Z, Heinrich J, Fuertes E, Flexeder C, et al. Cesarean delivery and risk of childhood obesity. J
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3 Table 1. Characteristics of cohort members by child health at 5 years (sample 19,721)
4
5 Total, n (%) Vaginal delivery, Cesarean delivery,
6 n (%) n (%)
7 ＊＊＊＊
8 Neurodevelopmental disorders 804 (4.1) 497 (3.8) 307 (4.7)
9 Learning disabilities 290 (1.5) 179 (1.4) 111 (1.7)
10 ＊＊＊＊
Developmental delay 525 (2.7) 322 (2.5) 203 (3.1)
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12 ADHD 183 (0.9) 112 (0.9) 71 (1.1)
13 147 (1.1) ＊＊
107 (1.6) ＊＊
Sensory integration disorder 254 (1.3)
14
15 Autism 88 (0.4) 52 (0.4) 36 (0.5)
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16 Asthma 1311 (6.7) 831 (6.3)
＊
478 (7.3)
＊
17 ＊＊＊＊＊＊
18 Obesity 2012 (14.7) 1269 (13.9) 737 (16.2)
19 Gender
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20 ＊＊＊＊＊＊
21 male 10358 (52.6) 6785 (51.6) 3561 (54.3)
22 Birth order
23 ＊＊＊＊＊＊
first-born child 9918 (50.4) 6833 (52.0) 3085 (47.1)
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＊＊＊
25 Gestational age
26
<37 weeks 1644 (8.3) 784 (6.0) 857 (13.1)
27
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28 37 weeks 2557 (13.0) 1348 (10.3) 1206 (18.4)

29 38 weeks 5282 (26.8) 3124 (23.8) 2152 (32.8)
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31 39 weeks 5601 (28.4) 4250 (32.3) 1343 (20.5)

32 40-41weeks 4580 (23.2) 3603 (27.4) 975 (14.9)
33
34 ≧42 weeks 57 (0.3) 34 (0.3) 23 (0.4)
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＊＊＊
35 Mother's age at birth of child
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<25 years 2882 (14.6) 2288 (17.4) 591 (9.0)
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38 25-29 years 6401 (32.5) 4514 (34.3) 1880 (28.7)
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30-34 years 7032 (35.7) 4522 (34.4) 2503 (38.2)
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41 >=35 years 3406 (17.3) 1819 (13.8) 1582 (24.1)

42 ＊＊＊
Mother's education level
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44 Compulsory school 2846 (14.5) 2061 (15.7) 780 (11.9)
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45 Senior high school 7908 (40.2) 5147 (39.2) 2756 (42.1)

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47 Junior college 4959 (25.2) 3277 (25.0) 1675 (25.6)
48 College and above 3974 (20.2) 2636 (20.1) 1333 (20.4)
49 ＊＊＊
50 Family monthly income
51 <30,000 2745 (14.1) 1860 (14.3) 881 (13.5)
52
53 30,000-100,000 13729 (70.3) 9211 (70.8) 4502 (69.2)
54 >100,000 3065 (15.7) 1944 (14.9) 1119 (17.2)
55
56
Missing data in birth order: 0.2%, gestational age: 0.1%, mother’s age at birth of child:
57 0.1%, mother’s educational levels: 0.3%, and family monthly income: 1.0%
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23
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1
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3 Number of mothers or main care-givers who completed the questions regarding the three
4
5 children’s health issues: neurodevelopmental disorders: 19,695, allergic diseases: 19,696,
6 and overweight/obesity: 13,653
7
8
Data of modes of delivery from birth registration
9 Chi square for analyzing differences of overweight/obesity, allergic diseases, neurodevelopmental
10
disorders, gender and birth order between vaginal and Cesarean delivery
11 ＊＊＊＊＊＊
12 p<0.05; p <0.01; p <0.001
13
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15
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3 Table 2. Association between Cesarean delivery and the occurrence of children’s
4
5 neurodevelopmental disorders after controlling gestational age, children’s and parental
6 characteristics
7
8 OR 95% CI OR 95% CI
9 Cesarean delivery 1.22 1.05-1.42 1.15 0.98-1.34
10
11
Gestational age (ref: 39-41 weeks)
12 <37 weeks 1.94 1.55-2.42
13
37 weeks 1.24 1.00-1.55
14
15 38 weeks 0.97 0.81-1.17
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16 ≧42 weeks 1.63 0.58-4.59
17
18 Gender, male (ref: female) 2.16 1.85-2.52 2.13 1.83-2.49
19 First-born child (ref: not first-born child) 1.13 0.97-1.31 1.17 1.00-1.36
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20
21 Mother’s age at birth of child (ref: ≧35 years)
22 <25 years 0.75 0.58-0.98 0.76 0.58-1.00
23
25-29 years 0.79 0.64-0.98 0.81 0.65-0.99
ee
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25 30-34 years 0.78 0.63-0.95 0.79 0.64-0.96
26
Mother’s education levels (ref: college or above)
27
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28 ≤ Compulsory school 1.09 0.82-1.44 1.07 0.81-1.41

29 Senior high school 0.97 0.78-1.22 0.97 0.77-1.21
30
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31 Junior college 0.96 0.76-1.21 0.96 0.76-1.21

32 Family monthly income (NTD) (ref: >100,000)
33
34 <30,000 2.23 1.66-3.00 2.23 1.66-3.00
ie
35 30,000-100,000 1.33 1.04-1.69 1.34 1.05-1.71

36
NTD: New Taiwan Dollar, 1 USD≒30 NTD
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38 Logistic regression was used for analysis
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3 Table 3. Association between Cesarean delivery and the occurrence of children’s asthma after
4
5 controlling gestational age, children’s and parental characteristics
6 OR 95% CI OR 95% CI OR 95% CI
7
8 Cesarean delivery 1.16 1.03-1.30 1.11 0.98-1.25 1.11 0.98-1.25
9 Gestational age (ref:
10
39-41 weeks)
11
12 <37 weeks 1.27 1.03-1.56 1.23 1.00-1.52
13
37 weeks 1.18 0.99-1.41 1.17 0.98-1.40
14
15 38 weeks 1.19 1.04-1.37 1.19 1.03-1.36
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16 ≧42 weeks 1.98 0.84-4.65 2.05 0.87-4.84
17
18 Gender, male 1.40 1.25-1.57 1.39 1.24-1.56 1.40 1.24-1.57
19 First-born child 1.23 1.09-1.38 1.26 1.12-1.42 1.27 1.13-1.44
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21 Mother’s age at birth of
22 child (ref: ≧35 years)
23
<25 years 0.90 0.71-1.15 0.90 0.71-1.15 0.88 0.69-1.12
ee
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25 25-29 years 1.14 0.95-1.36 1.14 0.96-1.36 1.13 0.94-1.34
26
30-34 years 1.03 0.88-1.22 1.04 0.88-1.23 1.02 0.87-1.21
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28 Mother’s education
29 levels (ref: college or
30
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31 above)
32 ≤ Compulsory school 0.67 0.53-0.85 0.67 0.53-0.85 0.68 0.54-0.86
33
34 Senior high school 0.72 0.61-0.85 0.72 0.61-0.85 0.72 0.61-0.86
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35 Junior college 0.81 0.69-0.95 0.81 0.69-0.95 0.81 0.69-0.96

36
Family monthly income
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38 (NTD; ref: >100,000)
39
40
<30,000 0.67 0.52-0.86 0.66 0.52-0.85 0.67 0.53-0.86
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41 30,000-100,000 0.87 0.74-1.02 0.87 0.74-1.02 0.88 0.75-1.04

42
Parental asthma history 3.62 2.88-4.55
43
44 (ref: no)
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45 NTD: New Taiwan Dollar, 1 USD≒30 NTD

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3 Table 4. Association between Cesarean delivery and the occurrence of children’s obesity after
4
5 controlling gestational age, children’s and parental characteristics
6 OR 95% CI OR 95% CI OR 95% CI
7
9 Gestational age (ref:
10
39-41 weeks)
11
12 <37 weeks 1.07 0.89-1.28 1.09 0.91-1.31
13
37 weeks 0.97 0.83-1.13 0.98 0.84-1.14
14
15 38 weeks 0.97 0.86-1.09 0.96 0.85-1.08
Fo
16 ≧42 weeks 2.11 1.03-4.29 2.10 1.03-4.29
17
18 Gender, male (ref: 1.90 1.72-2.10 1.90 1.72-2.10 1.90 1.72-2.10
19 female)
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20
21 First-born child (ref: 1.17 1.05-1.29 1.16 1.05-1.29 1.14 1.03-1.26
22 not first-born child)
23
Mother’s age at birth
ee
24
25 of child (ref: ≧35 years)
26
<25 years 1.01 0.84-1.22 1.01 0.84-1.22 1.02 0.84-1.23
27
rr
28 25-29 years 1.01 0.87-1.17 1.01 0.87-1.17 1.02 0.88-1.19

29 30-34 years 0.88 0.77-1.02 0.88 0.77-1.02 0.89 0.77-1.02
30
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31 Mother’s education
33
34 above)
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36
Senior high school 1.48 1.26-1.72 1.48 1.27-1.73 1.48 1.27-1.73
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38 Junior college 1.27 1.08-1.49 1.27 1.09-1.49 1.28 1.09-1.50
39
40
Family monthly
on
41 income (NTD) (ref:

42 >100,000)
43
44 <30,000 1.14 0.92-1.39 1.13 0.92-1.38 1.15 0.93-1.41
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45 30,000-100,000 1.11 0.95-1.29 1.11 0.95-1.29 1.11 0.95-1.29

46
47 Gestational diabetes 1.49 1.12-1.99
48 mellitus (ref: no)
49
50 Gestational weight 1.17 1.04-1.32
51 gain (ref: < 11 kg)
52
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27
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1
2 STROBE Statement—checklist of items that should be included in reports of observational studies
3
4
Item Reported
5
No Recommendation on page #
6
7 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the 1-2
8 abstract
9 (b) Provide in the abstract an informative and balanced summary of what was 2-3
10 done and what was found
11
12 Introduction
13 Background/rationale 2 Explain the scientific background and rationale for the investigation being 4-5
14 reported
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Objectives 3 State specific objectives, including any prespecified hypotheses 5
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17 Methods
18 Study design 4 Present key elements of study design early in the paper 5
19
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Setting 5 Describe the setting, locations, and relevant dates, including periods of 5-6
20
21 recruitment, exposure, follow-up, and data collection
22 Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of 5-6
23 selection of participants. Describe methods of follow-up
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24 Case-control study—Give the eligibility criteria, and the sources and methods
25
of case ascertainment and control selection. Give the rationale for the choice of
26
27 cases and controls
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28 Cross-sectional study—Give the eligibility criteria, and the sources and

29 methods of selection of participants
30
(b) Cohort study—For matched studies, give matching criteria and number of 6
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32 exposed and unexposed
33 Case-control study—For matched studies, give matching criteria and the
34 number of controls per case
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35 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and 6-8
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effect modifiers. Give diagnostic criteria, if applicable
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38 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 6-8
39 measurement assessment (measurement). Describe comparability of assessment methods if
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there is more than one group

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Bias 9 Describe any efforts to address potential sources of bias 7
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43 Study size 10 Explain how the study size was arrived at 6
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Statistical methods 12 (a) Describe all statistical methods, including those used to control for 7-8
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estimates and their precision (eg, 95% confidence interval). Make clear which
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unexposed groups in cohort and cross-sectional studies.
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54 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely
55 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
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http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is
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2
BMJ Open
Associations of Cesarean Delivery and the Occurrence of

Childhood Based on Taiwan Birth Cohort Study
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Journal: BMJ Open
Manuscript ID bmjopen-2017-017086.R1

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Date Submitted by the Author: 21-Jun-2017
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Primary Subject
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Paediatrics
Heading:

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Keywords:
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3 Associations of Cesarean Delivery and the Occurrence of Neurodevelopmental Disorders, Asthma or
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5 Obesity in Childhood Based on Taiwan Birth Cohort Study
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9 Ginden Chen MD, PhD1,2,3, Wan-Lin Chiang PhD1, Bih-Ching Shu PhD4, Yueliang Guo MD, PhD5
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Shu-Ti Chiou PhD6, Tung-liang Chiang ScD1
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13 Affiliations:
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15 Institute of Health Policy and Management, College of Public Health, National Taiwan University,
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16 Taipei, Taiwan
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18 Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung,
19 Taiwan
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21 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
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Department of Environmental and Occupational Medicine, National Taiwan University (NTU)
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25 College of Medicine and NTU Hospital, Taipei, Taiwan
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Health Promotion Administration, Ministry of Health & Welfare, Taipei, Taiwan
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34 886-2-33668059.
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Keywords: Cesarean delivery, neurodevelopmental disorders, asthma, obesity, vaginal delivery
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Abstract word count: 250
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3 ABSTRACT
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5 Objectives Whether birth by cesarean section (CS) increases the occurrence of neurodevelopmental
6 disorders, asthma or obesity in childhood is controversial. We tried to demonstrate the association
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between children born by CS and the occurrence of the above three diseases at the age of 5.5 years.
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Methods The database of the Taiwan Birth Cohort Study (TBCS) which was designed to assess the
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12 developmental trajectories of 24,200 children born in 2005 was used in this study. Associations
13 between children born by CS and these three diseases were evaluated before and after controlling for
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15 gestational age (GA) at birth, children’s characteristics and disease-related predisposing factors.
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22 1.15; 95% CI: 0.98-1.34). Occurrence of neurodevelopmental disorders steadily declined with
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increasing GA up to ≤40-42 weeks. CS and childhood asthma were not significantly associated after
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26 significantly associated with CS (OR: 1.13; 95% CI: 1.04-1.24) after controlling for GA and
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28 disease-related factors.
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32 neurodevelopmental disorders was significantly influenced by GA. CS birth was weakly associated
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34 with childhood asthma since parental asthma and preterm births are stronger predisposing factors.
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35 The association between CS birth and childhood obesity was robust after controlling for
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disease-related factors.
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factors.
9 We evaluated dose-dependent effects of gestational age on the occurrence of these diseases.
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Some information such as maternal/fetal conditions that indicate CS or precise indications of
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12 CS that might be more related to these disorders were not evaluated because indications for CS
13 were derived from self-reports by mothers or reports by primary care-givers, not from medical
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15 records.
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16 We might have missed the possibility that these disorders might occur in combination because
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18 we looked at associations among these three disorders and modes of delivery as mutually
19 exclusive.
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4 INTRODUCTION
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7 With an escalating rate of cesarean sections (CS) worldwide, literature has revealed that
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10 cesarean delivery might delay neurological adaptation in infants and can also alter gut microbiotic
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13 composition in early infancy. [1,2] Recent studies demonstrate that different delivery modes shape
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the diversity in the human microbiome’s successional development in different body habitats and
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might alter gut the microbiotic composition which might have associated effects on infant health.
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21 [3,4] However, whether modes of delivery also result in long-term physiological consequences in
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24 childhood or influence later physical well-being needs further investigation.

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42 infants as demonstrated by checking fecal flora.[4] Collins et al. revealed that intestinal microbiota
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could communicate with the brain via the gut-brain axis to influence brain development and behavior.
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[8] However, the correlation between CS and later neurodevelopmental disorders is still
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50 controversial.
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53 Overweight children and increase of allergic diseases have been reported to be associated with
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asthma, wheezing episodes or atopic dermatitis in infants delivered by CS after controlling for their
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parental allergy history.[15,16] Epidemiological studies also revealed an association between CS and
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21 overweight or obese preschool age children.[10,11] Recently, a systematic review and meta-analysis
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24 indicated that CS is only moderately associated with overweight and obese children.[17] The
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39 of delivery after controlling for potential confounding factors. Except for the basic demographic
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42 factors of children and socioeconomic status of parents, the potential confounding factors also
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include specific factors that might be related to the occurrence of neurodevelopmental disorders,
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asthma, and obesity.
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10 Data used in this study were derived from the TBCS. The TBCS has been designed to assess the
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13 developmental trajectories of Taiwanese children and was financially sponsored by the Health
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Promotion Administration in Taiwan. The study protocol and questionnaires were approved by the
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Directorate-General of Budget, Accounting and Statistics in the Executive Yuan, according to the
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21 Statistics Act of Taiwan. This study was approved by the Institutional Review Board at the National
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36 with mothers or primary caregivers were conducted at 6 months, 18 months, 36 months, and 5.5
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39 years of age, with response rates of 87.8%, 94.9%, 93.7%, and 92.8%, respectively. Our study
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surveys contains questions about the child’s developmental, behavioral, and health outcomes, as well
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as detailed information on family characteristics including socioeconomic conditions, parenting
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7 Promotion for preschool children. Children categorized with asthma were those who had been
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10 diagnosed by a physician as described by Wen et al.[18] Learning disabilities, developmental delay,
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13 attention deficit hyperactivity disorder, sensory integration disorder, and autism were diagnosed and
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evaluated by pediatric psychiatrists and clinical psychologists. Children with neurodevelopmental
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disorders were categorized as those having any or a combination of learning disabilities,
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24 according to the classification of the DSM-V published on May 27, 2013.[19]

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27 Information about the mode of delivery (vaginal or cesarean delivery) and gestational age (GA)
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30 was also collected from Taiwanese birth certificates in 2005. GA was stratified as: preterm (< 37
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33 weeks), term (37 to 41 weeks), and post-term (42 weeks or more). In order to evaluate the influence
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36 of GA on the associations of CS with the occurrence of the above three diseases, we further divided
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Mothers’ educational levels were classified as compulsory school (less than 9 years of
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schooling), senior high school, junior college, college and above. Household monthly income was
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53 100,000 NTD (30 NTD≒1 USD). Gestational weight gain among the mothers was grouped as less
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7 survey.
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10 Statistical analysis
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13 Children’s characteristics, obesity, asthma, and neurodevelopmental disorders were compared
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with Chi-square tests. Logistic multiple regression analyses were used to evaluate obesity, asthma,
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and neurodevelopmental disorders associated with CS after controlling for characteristics of children
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21 (i.e. GA, gender, birth order) and parents (i.e. mother’s age at birth of child, mother’s education
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24 levels, family monthly income). We also included disease-specific factors such as parental asthma
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27 history for children’s asthma, gestational diabetes mellitus and gestational weight gain of mother for
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30 children’s obesity as controlling factors to demonstrate their effects on these disorders. The
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36 three diseases across the preterm, early term period of 37-40 weeks (GA at 37 weeks - <38 weeks, 38
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39 weeks - <39weeks, 39 weeks - <40 weeks) and ≧40 weeks. Alpha level was set as 0.05. All
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RESULTS
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In total, data of 19,721 children (cohort cesarean rate: 33.2 %) were successfully collected:
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50 neurodevelopmental disorders, 19,717, asthma, 19,720 and obesity, 19,269. The children’s and
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53 parental characteristics are shown in Table 1. The prevalence of children’s neurodevelopmental
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56 disorders, asthma and obesity were significantly different between birth by CS and vaginal delivery
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4 (4.7% vs. 3.8%, 7.3% vs. 6.3%, 15.9% vs. 14.0%; respectively, all p < 0.05).
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for cesarean delivery were 1.22 and 1.05-1.42 after controlling for children’s and parental
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21 (OR for male: 2.16). A young maternal age at childbirth was found to be a protective factor against
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33 controlling for GA in a regression model (OR: 1.15; 95% CI: 0.98-1.34). Children born by CS at a
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36 GA of less than 38 weeks were significantly associated with more neurodevelopmental disorders
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39 (GA less than 37 weeks: OR: 1.94; 95% CI: 1.55-2.42; GA at 37 weeks: OR: 1.24; 95% CI: 1.0-1.55;
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Association between Asthma and Cesarean Delivery
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significantly associated after further controlling parental history of asthma. However, children born
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at a GA of less than 37 weeks and a mother’s educational level were still associated with more
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21 asthma. Parental history of asthma was more significantly associated with childhood asthma (OR:
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24 3.62; 95% CI: 2.88-4.55).

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39 obesity in childhood remained significantly associated with cesarean delivery (OR: 1.15; 95% CI:
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childhood obesity. Male gender, first-born child and lower maternal educational level were also
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neurodevelopmental disorders steadily declined with increasing GA up to 39 - <42 weeks (data not
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shown). However, there was no dose effect of the GA until term on childhood asthma and obesity.
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21 childhood after controlling for GA. GA at birth, especially preterm births, significantly influenced
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24 the association between CS births and neurodevelopmental disorders in childhood. This phenomenon
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27 is consistent with the viewpoint of Kapellou et al.[21] and Woythaler et al.[22]
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studies are controversial.[26,27] Our study showed that a young maternal age at childbirth is a
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50 protective factor. Literature has shown that parental socioeconomic status such as low familial
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53 income is associated with an increased risk of neurodevelopmental disorders.[28-30] We found that
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4 neurodevelopmental disorders compared to children with a lower familial income.
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36 of asthma (hazard ratio: 3.71) was strongly associated with offspring asthma.[31] In this study,
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hypothesis, factors including genetics, intrauterine environment and premature birth might also
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influence the association between birth by CS and childhood asthma.[32]
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50 In this study, in addition to parental asthma history being significantly associated with child
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53 asthma, boys and first-born children were also positively associated with the occurrence of childhood
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56 asthma and maternal educational level was negatively associated with the occurrence of childhood
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4 asthma. Mersha et al. showed that both genetic and gene expression data have sex-based differences
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10 childhood asthma might be consistent with the hypothesis of “in utero ‘birth-order’ T-cell
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revealed that first-born infants display a reduced anti-inflammatory profile in T cells at birth which
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may contribute to later development of immune-mediated diseases by increasing overall immune
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21 reactivity in first-born children compared to younger siblings.[34] However, negative associations
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27 Renz-Polster et al. did not find that maternal education levels influenced the occurrence of childhood
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39 The association between CS births and childhood obesity was robust after including GA,
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42 gestational diabetes and maternal gestational weight gain as potential predisposing factors. Our
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findings were consistent with the epidemiological study conducted by Huh et al.[11] and a systematic
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review and meta-analysis by Li et al.[17] However, Pei et al. only found a greater likelihood of
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50 obesity at the age of 2 years in their CS group, but not at the ages of 6 and 10 years in a prospective
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53 cohort study in Germany which was inconsistent with our results.[37]
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4 significantly associated with childhood obesity in the current study. Matthiessen et al. reported that
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10 Fradkin et al. found that children growing up with a high socioeconomic status are associated with a
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13 lower risk of childhood obesity, but with variations across race/ethnicity and gender.[39]
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Literature reveals that children born to mothers with excessive gestational weight gain and
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gestational diabetes mellitus are associated with a higher risk of childhood obesity.[40,41] Our
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39 be influenced by other lifestyle habits. Second, indications for CS in this study were derived from
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information such as maternal/fetal conditions that indicate CS or precise indications for CS that
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might be more related to these disorders were not evaluated. Last, we looked at associations among
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4 CONCLUSIONS
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7 Our results implied that CS birth was associated with the occurrence of children’s
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10 neurodevelopmental disorders. However, children born before 38 weeks of GA by CS had
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13 significantly more children’s neurodevelopmental disorders. CS birth was weakly associated with
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childhood asthma since parental asthma and preterm labor are stronger predisposing factors. The
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association between CS birth and childhood obesity is robust after controlling for related factors.
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Conflicts of Interest: none.
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3 REFERENCES
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5 1. Otamiri G, Berg G, Ledin T, et al. Delayed neurological adaptation in infants delivered by
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8 elective cesarean section and the relation to catecholamine levels. Early Hum Dev 1991;26:51–
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11 60.
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20 3. Dominguez-Belloa MG, Costellob EK, Contrerasc M, et al. Delivery mode shapes the acquisition
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23 and structure of the initial microbiota across multiple body habitats in newborn. Proc Natl Acad
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26 Sci U S A 2010;107:11971–5.
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20-45 weeks’ gestation. Semin Fetal Neonatal Med 2006;11:415–22.

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55 8. Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain.
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antibiotics. Int J Obes 2011;35:522–29.
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11. Huh SY, Rifas-Shiman SL, Zera CA, et al. Delivery by caesarean section and risk of obesity in
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53 142:731–8.
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56 26. Lampi KM, Hinkka-Yli-Salomäki S, Lehti V, et al. Parental age and risk of autism spectrum
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4 disorders in a Finnish national birth cohort. J Autism Dev Disord 2013;43:2526–35.
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spectrum disorders in a Swedish population-based study. J Am Acad Child Adolesc Psychiatry
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2015;8:51–61.
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32. Debley JS, Smith JM, Redding GJ, et al. Childhood asthma hospitalization risk after cesarean
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56 Genomics 2015;106:15–22.
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4 34. Kragh M, Larsen JM, Thysen AH, et al. Divergent response profile in activated cord blood T
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10 2016;71:323–32.
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disorders in childhood. Clin Exp Allergy 2005;35:1466–72.
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36. Hermann C, Olivarius NDF, Høst A, et al. Prevalence, severity and determinants of asthma in
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27 Pediatr 2014;164:1068–73.
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30 38. Matthiessen J, Stockmarr A, Fagt S, et al. Danish children born to parents with lower levels of
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40. Lau et al., 2014 Lau EY, Liu J, Archer E, et al. Maternal weight gain in pregnancy and risk of
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obesity among offspring: a systematic review. J Obes 2014;2014:524939.
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6 n (%) n (%)
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8 Total 19721 (100.0) 13143 (66.6) 6556 (33.2)
9 Neurodevelopmental disorders 804 (4.1) 497 (3.8) 307 (4.7) **
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Learning disabilities 290 (1.5) 179 (1.4) 111 (1.7)
12 Developmental delay 525 (2.7) 322 (2.5) 203 (3.1) **
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ADHD 183 (0.9) 112 (0.9) 71 (1.1)
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15 Sensory integration disorder 254 (1.3) 147 (1.1) 107 (1.6) **
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16 Autism 88 (0.4) 52 (0.4) 36 (0.5)
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18 Asthma 1311 (6.7) 831 (6.3) 478 (7.3) *
19 Obesity 2896 (14.7) 1844 (14.0) 1046 (15.9) ***
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21 Gender
22 male 10358 (52.6) 6785 (51.6) 3561 (54.3) ***
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Birth order
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25 first-born child 9918 (50.4) 6833 (52.0) 3085 (47.1) ***
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Gestational age, weeks ***
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28 <37 1644 (8.3) 784 (6.0) 857 (13.1)

29 37 2557 (13.0) 1348 (10.3) 1206 (18.4)
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31 38 5282 (26.8) 3124 (23.8) 2152 (32.8)

32 39 5601 (28.4) 4250 (32.3) 1343 (20.5)
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34 40-41 4580 (23.2) 3603 (27.4) 975 (14.9)
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35 ≧42 57 (0.3) 34 (0.3) 23 (0.4)

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Maternal age at birth of child, ***
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38 years
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<25 2882 (14.6) 2288 (17.4) 591 (9.0)
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41 25-29 6401 (32.5) 4514 (34.3) 1880 (28.7)

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30-34 7032 (35.7) 4522 (34.4) 2503 (38.2)
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44 ≧35 3406 (17.3) 1819 (13.8) 1582 (24.1)
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45 Maternal education level ***

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50 Junior college 4959 (25.2) 3277 (25.0) 1675 (25.6)
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53 Family monthly income ***
54 <30,000 2745 (14.1) 1860 (14.3) 881 (13.5)
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30,000-100,000 13729 (70.3) 9211 (70.8) 4502 (69.2)
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57 >100,000 3065 (15.7) 1944 (14.9) 1119 (17.2)
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3 Parental asthma history 518 (2.6) 328 (2.5) 190 (2.9)
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5 Gestational diabetes mellitus 435 (2.2) 200 (1.5) 234 (3.6) ***
6 Gestational weight gain, kg ***
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< 11 4766 (24.4) 3309 (25.4) 1449 (22.3)
9 11-13 4697 (24.0) 3306 (25.4) 1385 (21.3)
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14-16 4631 (23.7) 3138 (24.1) 1491 (22.9)
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12 ≧17 5448 (27.9) 3272 (25.1) 2171 (33.4)
13 Missing data in modes of delivery: 0.2%, birth order: 0.2%, gestational age: 0.1%,
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15 maternal age at birth of child: 0.1%, maternal educational levels: 0.3%, and family
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16 monthly income: 1.0%, parental asthma history: 0.5%, gestational diabetes mellitus:
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18 0.2%, gestational weight gain: 0.9%
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21 children’s health issues: neurodevelopmental disorders: 19,717, asthma: 19,720, and
22 obesity: 19,269
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25 Chi square for analyzing differences of obesity, asthma, neurodevelopmental disorders, gender and
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birth order between vaginal and cesarean delivery
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28 p<0.05; ＊＊ p <0.01; ＊＊＊ p <0.001
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3 Table 2. Association between cesarean delivery and the occurrence of children’s
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5 neurodevelopmental disorders after controlling for gestational age, children’s and parental
6 characteristics
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8 Adjusted 95% CI Adjusted 95% CI
9 OR OR
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Cesarean delivery 1.22 1.05-1.42 1.15 0.98-1.34
12 Gestational age (ref: 39-41 weeks)
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<37 weeks 1.94 1.55-2.42
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15 37 weeks 1.24 1.00-1.55
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16 38 weeks 0.97 0.81-1.17
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18 ≧42 weeks 1.63 0.58-4.59
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22 Maternal age at birth of child (ref: ≧35 years)
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<25 years 0.75 0.58-0.98 0.76 0.58-1.00
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25 25-29 years 0.79 0.64-0.98 0.81 0.65-0.99
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30-34 years 0.78 0.63-0.95 0.79 0.64-0.96
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28 Maternal education levels (ref: college or above)

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32 Junior college 0.96 0.76-1.21 0.96 0.76-1.21
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35 <30,000 2.23 1.66-3.00 2.23 1.66-3.00

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30,000-100,000 1.33 1.04-1.69 1.34 1.05-1.71
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3 Table 3. Association between cesarean delivery and the occurrence of children’s asthma after
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5 controlling for gestational age, children’s and parental characteristics
6 Adjusted 95% CI Adjusted 95% CI Adjusted 95% CI
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8 OR OR OR
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Gestational age (ref:
12 39-41 weeks)
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<37 weeks 1.27 1.03-1.56 1.23 1.00-1.52
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15 37 weeks 1.18 0.99-1.41 1.17 0.98-1.40
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16 38 weeks 1.19 1.04-1.37 1.19 1.03-1.36
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18 ≧42 weeks 1.98 0.84-4.65 2.05 0.87-4.84
19 Gender, male 1.40 1.25-1.57 1.39 1.24-1.56 1.40 1.24-1.57
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21 First-born child 1.23 1.09-1.38 1.26 1.12-1.42 1.27 1.13-1.44
22 Maternal age at birth of
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child (ref: ≧35 years)
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25 <25 years 0.90 0.71-1.15 0.90 0.71-1.15 0.88 0.69-1.12
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25-29 years 1.14 0.95-1.36 1.14 0.96-1.36 1.13 0.94-1.34
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28 30-34 years 1.03 0.88-1.22 1.04 0.88-1.23 1.02 0.87-1.21

29 Maternal education
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32 above)
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Junior college 0.81 0.69-0.95 0.81 0.69-0.95 0.81 0.69-0.96
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(NTD; ref: >100,000)
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30,000-100,000 0.87 0.74-1.02 0.87 0.74-1.02 0.88 0.75-1.04
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44 Parental asthma history 3.62 2.88-4.55
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3 Table 4. Association between cesarean delivery and the occurrence of children’s obesity after
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8 OR OR OR
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12 39-41 weeks)
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<37 weeks 1.03 0.89-1.20 1.04 0.90-1.21
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15 37 weeks 1.04 0.91-1.18 1.04 0.91-1.18
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16 38 weeks 1.00 0.90-1.10 1.00 0.90-1.10
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18 ≧42 weeks 2.28 1.26-4.13 2.29 1.26-4.15
19 Gender, male (ref:
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20 1.88 1.73-2.05 1.88 1.73-2.05 1.88 1.73-2.04
21 female)
22 First-born child (ref:
23 1.11 1.02-1.21 1.11 1.02-1.21 1.09 0.99-1.18
not first-born child)
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25 Maternal age at birth
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of child (ref: ≧35 years)
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28 <25 years 0.97 0.83-1.14 0.97 0.83-1.14 1.00 0.85-1.16

29 25-29 years 0.99 0.87-1.12 0.99 0.87-1.12 1.00 0.88-1.13
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31 30-34 years 0.91 0.81-1.03 0.91 0.81-1.03 0.92 0.82-1.04

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35 above)
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≤ Compulsory school 1.70 1.44-2.00 1.69 1.43-2.00 1.71 1.45-2.02
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Junior college 1.36 1.19-1.56 1.36 1.19-1.55 1.35 1.18-1.55
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41 Family monthly
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income (NTD) (ref:
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44 >100,000)
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45 <30,000 1.04 0.88-1.24 1.04 0.87-1.23 1.05 0.89-1.25

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47 30,000-100,000 1.06 0.93-1.21 1.06 0.93-1.21 1.07 0.94-1.22
48 Gestational diabetes
49 1.53 1.20-1.95
51 Gestational weight
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54 ≧ 11kg 1.18 1.07-1.30
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Item Reported
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8 abstract
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12 Introduction
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17 Methods
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Setting 5 Describe the setting, locations, and relevant dates, including periods of 6
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22 Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of 6
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Bias 9 Describe any efforts to address potential sources of bias 6-8
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48 confounding
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3 Results
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14 interest
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17 Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over 8-11
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23 measures
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Discussion
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37 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias 16
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43 Generalisability 21 Discuss the generalisability (external validity) of the study results 6
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Other information
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BMJ Open
Associations of Cesarean Delivery and the Occurrence of

Childhood Based on Taiwan Birth Cohort Study
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Journal: BMJ Open
Manuscript ID bmjopen-2017-017086.R2

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Date Submitted by the Author: 18-Aug-2017
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Primary Subject
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Paediatrics
Heading:

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Keywords:
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3 Associations of Cesarean Delivery and the Occurrence of Neurodevelopmental Disorders, Asthma or
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5 Obesity in Childhood Based on Taiwan Birth Cohort Study
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9 Ginden Chen MD, PhD1,2,3, Wan-Lin Chiang PhD1, Bih-Ching Shu PhD4, Yueliang Guo MD, PhD5
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Shu-Ti Chiou PhD6, Tung-liang Chiang ScD1
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13 Affiliations:
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15 Institute of Health Policy and Management, College of Public Health, National Taiwan University,
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16 Taipei, Taiwan
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18 Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung,
19 Taiwan
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21 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
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Department of Environmental and Occupational Medicine, National Taiwan University (NTU)
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25 College of Medicine and NTU Hospital, Taipei, Taiwan
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Health Promotion Administration, Ministry of Health & Welfare, Taipei, Taiwan
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34 886-2-33668059.
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Keywords: Cesarean delivery, neurodevelopmental disorders, asthma, obesity, vaginal delivery
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Abstract word count: 250
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3 ABSTRACT
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5 Objectives Whether birth by cesarean section (CS) increases the occurrence of neurodevelopmental
6 disorders, asthma or obesity in childhood is controversial. We tried to demonstrate the association
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between children born by CS and the occurrence of the above three diseases at the age of 5.5 years.
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Methods The database of the Taiwan Birth Cohort Study (TBCS) which was designed to assess the
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12 developmental trajectories of 24,200 children born in 2005 was used in this study. Associations
13 between children born by CS and these three diseases were evaluated before and after controlling for
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15 gestational age (GA) at birth, children’s characteristics and disease-related predisposing factors.
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22 1.15; 95% CI: 0.98-1.34). Occurrence of neurodevelopmental disorders steadily declined with
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increasing GA up to ≤40-42 weeks. CS and childhood asthma were not significantly associated after
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26 significantly associated with CS (OR: 1.13; 95% CI: 1.04-1.24) after controlling for GA and
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28 disease-related factors.
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32 neurodevelopmental disorders was significantly influenced by GA. CS birth was weakly associated
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34 with childhood asthma since parental asthma and preterm births are stronger predisposing factors.
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35 The association between CS birth and childhood obesity was robust after controlling for
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disease-related factors.
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factors.
9 We evaluated dose-dependent effects of gestational age on the occurrence of these diseases.
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Some information such as maternal/fetal conditions that indicate CS or precise indications of
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12 CS that might be more related to these disorders were not evaluated because indications for CS
13 were derived from self-reports by mothers or reports by primary care-givers, not from medical
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15 records.
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16 We might have missed the possibility that these disorders might occur in combination because
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18 we looked at associations among these three disorders and modes of delivery as mutually
19 exclusive.
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4 INTRODUCTION
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7 With an escalating rate of cesarean sections (CS) worldwide, literature has revealed that
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10 cesarean delivery might delay neurological adaptation in infants and can also alter gut microbiotic
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13 composition in early infancy. [1,2] Recent studies demonstrate that different delivery modes shape
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the diversity in the human microbiome’s successional development in different body habitats and
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might alter gut the microbiotic composition which probably has associated effects on infant health.
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21 [3] However, whether modes of delivery also result in long-term physiological consequences in
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42 infants as demonstrated by checking fecal flora.[7] Collins et al. revealed that intestinal microbiota
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could communicate with the brain via the gut-brain axis to influence brain development and behavior.
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[8] However, the correlation between CS and later neurodevelopmental disorders is still
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50 controversial.
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53 Overweight children and increase of allergic diseases have been reported to be associated with
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asthma, wheezing episodes or atopic dermatitis in infants delivered by CS after controlling for their
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parental allergy history.[15,16] Epidemiological studies also revealed an association between CS and
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21 overweight or obese preschool age children.[10,11] Recently, a systematic review and meta-analysis
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39 of delivery after controlling for potential confounding factors. Except for the basic demographic
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42 factors of children and socioeconomic status of parents, the potential confounding factors also
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include specific factors that might be related to the occurrence of neurodevelopmental disorders,
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asthma, and obesity.
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10 Data used in this study were derived from the TBCS. The TBCS has been designed to assess the
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13 developmental trajectories of Taiwanese children and was financially sponsored by the Health
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Promotion Administration in Taiwan. The study protocol and questionnaires were approved by the
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Directorate-General of Budget, Accounting and Statistics in the Executive Yuan, according to the
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36 with mothers or primary caregivers were conducted at 6 months, 18 months, 36 months, and 5.5
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39 years of age, with response rates of 87.8%, 94.9%, 93.7%, and 92.8%, respectively. Our study
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surveys contains questions about the child’s developmental, behavioral, and health outcomes, as well
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as detailed information on family characteristics including socioeconomic conditions, parenting
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7 Promotion for preschool children. Children categorized with asthma were those who had been
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10 diagnosed by a physician as described by Wen et al.[18] Learning disabilities, developmental delay,
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13 attention deficit hyperactivity disorder, sensory integration disorder, and autism were diagnosed and
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evaluated by pediatric psychiatrists and clinical psychologists. Children with neurodevelopmental
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disorders were categorized as those having any or a combination of learning disabilities,
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21 developmental delay, attention deficit hyperactivity disorder, sensory integration disorder, or autism,
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27 Information about the mode of delivery (vaginal or cesarean delivery) and gestational age (GA)
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36 of GA on the associations of CS with the occurrence of the above three diseases, we further divided
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Mothers’ educational levels were classified as compulsory school (less than 9 years of
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schooling), senior high school, junior college, college and above. Household monthly income was
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7 survey.
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10 Statistical analysis
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13 Children’s characteristics, obesity, asthma, and neurodevelopmental disorders were compared
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with Chi-square tests. Logistic multiple regression analyses were used to evaluate obesity, asthma,
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and neurodevelopmental disorders associated with CS after controlling for characteristics of children
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21 (i.e. GA, gender, birth order) and parents (i.e. mother’s age at birth of child, mother’s education
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24 levels, family monthly income). We also included disease-specific factors such as parental asthma
25
26
27 history for children’s asthma, gestational diabetes mellitus and gestational weight gain of mother for
rr
28
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30 children’s obesity as controlling factors to demonstrate their effects on these disorders. The
ev
31
32
33 Cochran-Armitage Trend Test was used to check dose-dependent effects on the occurrence of these
34
ie
35
36 three diseases across the preterm, early term period of 37-40 weeks (GA at 37 weeks - <38 weeks, 38
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39 weeks - <39weeks, 39 weeks - <40 weeks) and ≧40 weeks. Alpha level was set as 0.05. All
40
on
41
42 statistical analyses were performed using the Statistical Analysis Software package, SAS version 9.3.
43
44
ly
45
RESULTS
46
47
In total, data of 19,721 children (cohort cesarean rate: 33.2 %) were successfully collected:
48
49
50 neurodevelopmental disorders, 19,717, asthma, 19,720 and obesity, 19,269. The children’s and
51
52
53 parental characteristics are shown in Table 1. The prevalence of children’s neurodevelopmental
54
55
56 disorders, asthma and obesity were significantly different between birth by CS and vaginal delivery
57
58
59
8
60
1
2
3
4 (4.7% vs. 3.8%, 7.3% vs. 6.3%, 15.9% vs. 14.0%; respectively, all p < 0.05).
5
6
8
9
11
12
14
15
for cesarean delivery were 1.22 and 1.05-1.42 after controlling for children’s and parental
Fo
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17
18
19
rp
20
21 (OR for male: 2.16). A young maternal age at childbirth was found to be a protective factor against
22
23
ee
25
26
rr
28
29
ev
31
32
33 controlling for GA in a regression model (OR: 1.15; 95% CI: 0.98-1.34). Children born by CS at a
34
ie
35
36 GA of less than 38 weeks were significantly associated with more neurodevelopmental disorders
w
37
38
39 (GA less than 37 weeks: OR: 1.94; 95% CI: 1.55-2.42; GA at 37 weeks: OR: 1.24; 95% CI: 1.0-1.55;
40
on
41
42 All p <0.05)
43
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ly
45
Association between Asthma and Cesarean Delivery
46
47
48
49
50 controlling for children’s and parental characteristics. Gender and first-born children had a
51
52
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55
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59
9
60
1
2
3
5
6
8
9
11
12
14
15
significantly associated after further controlling parental history of asthma. However, children born
Fo
16
17
18
at a GA of less than 37 weeks, at 38 weeks, boys, first born children and mother’s educational level
19
rp
20
21 were still associated with more asthma. Parental history of asthma was more significantly associated
22
23
ee
24 with childhood asthma (OR: 3.62; 95% CI: 2.88-4.55).

25
26
rr
28
29
ev
31
32
34
ie
35
w
37
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39 obesity in childhood remained significantly associated with cesarean delivery (OR: 1.15; 95% CI:
40
on
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44
ly
45
childhood obesity. Male gender, first-born child and lower maternal educational level were also
46
47
48
49
50 associated when we included gestational diabetes (OR: 1.53; 95% CI: 1.20-1.95) and maternal
51
52
53 gestational weight gain (≧ 11kg; OR: 1.18; 95% CI: 1.07-1.30) as control variables.
54
55
57
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10
60
1
2
3
5
6
8
9
11
12
14
15
neurodevelopmental disorders steadily declined with increasing GA up to 39 - <42 weeks (data not
Fo
16
17
18
shown). However, there was no dose effect of the GA until term on childhood asthma and obesity.
19
rp
20
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22
23
ee
24
25
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27
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28
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30
ev
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on
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ly
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11
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4 DISCUSSION
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Fo
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rp
20
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23
ee

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ie
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on
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ly
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50 Sonnenschein-van der Voort et al.[23] further found that “the association of lower birth weight with
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59
12
60
1
2
3
5
6
8
9
11
12
14
15
Fo
16
17
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19
rp
20
21 childhood after controlling for GA. GA at birth, especially preterm births, significantly influenced
22
23
ee
24 the association between CS births and neurodevelopmental disorders in childhood. This phenomenon
25
26
27 is consistent with the viewpoint of Kapellou et al.[21] and Woythaler et al.[22]
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ev
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on
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studies are controversial.[26,27] Our study showed that a young maternal age at childbirth is a
48
49
50 protective factor. Literature has shown that parental socioeconomic status such as low familial
51
52
53 income is associated with an increased risk of neurodevelopmental disorders.[28-30] We found that
54
55
56 children who have a higher familial income have less risk for the occurrence of children’s
57
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13
60
1
2
3
4 neurodevelopmental disorders compared to children with a lower familial income.
5
6
8
9
11
12
14
15
Fo
16
17
18
19
rp
20
22
23
ee
24 study, children’s asthma was not significantly associated with CS births after further controlling for
25
26
27 GA and parental history of asthma.
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28
29
ev
31
32
34
ie
35
36 of asthma (hazard ratio: 3.71) was strongly associated with offspring asthma.[31] In our study,
w
37
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39 children born to a parent with a history of asthma was significantly associated with childhood asthma.
40
on
41
42 However, Delbley et al. found that CS births are associated with subsequent asthma hospitalization
43
44
ly
45
only in premature and mothers with asthma have increased rates of CS and premature delivery. They
46
47
noted that in addition to the hygiene hypothesis, factors including genetics, intrauterine environment
48
49
50 and premature birth might also influence the association between birth by CS and childhood
51
52
53 asthma.[32]
54
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56 In this study, in addition to parental asthma history being significantly associated with child
57
58
59
14
60
1
2
3
4 asthma, boys and first-born children were also positively associated with the occurrence of childhood
5
6
7 asthma and maternal educational level was negatively associated with the occurrence of childhood
8
9
10 asthma. Mersha et al. showed that both genetic and gene expression data have sex-based differences
11
12
13 in the genomic association with asthma.[33] A significant association between first-born children and
14
15
childhood asthma might be consistent with the hypothesis of “in utero ‘birth-order’ T-cell
Fo
16
17
18
programming” postulated by Kragh et al. which does not support the hygiene hypothesis. Kragh et al.
19
rp
20
21 revealed that first-born infants display a reduced anti-inflammatory profile in T cells at birth which
22
23
ee
24 may contribute to later development of immune-mediated diseases by increasing overall immune

25
26
27 reactivity in first-born children compared to younger siblings.[34] However, negative associations
rr
28
29
30 between maternal educational levels and childhood asthma are inconsistent with other studies.
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33 Renz-Polster et al. did not find that maternal education levels influenced the occurrence of childhood
34
ie
35
36 asthma.[35] Hermann et al. reported that lower parental educational levels result in a higher
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37
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39 prevalence of childhood asthma.[36]
40
on
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ly
45
The association between CS births and childhood obesity was robust after including GA,
46
47
gestational diabetes and maternal gestational weight gain as potential predisposing factors. Our
48
49
50 findings were consistent with the epidemiological study conducted by Huh et al.[11] and a systematic
51
52
53 review and meta-analysis by Li et al.[17] However, Pei et al. only found a greater likelihood of
54
55
56 obesity at the age of 2 years in their CS group, but not at the ages of 6 and 10 years in a prospective
57
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59
15
60
1
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3
4 cohort study in Germany which was inconsistent with our results.[37]
5
6
8
9
10 significantly associated with childhood obesity in the current study. Matthiessen et al. reported that
11
12
14
15
Fradkin et al. found that children growing up with a high socioeconomic status are associated with a
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16
17
18
lower risk of childhood obesity, but with variations across race/ethnicity and gender.[39]
19
rp
20
21 Literature reveals that children born to mothers with excessive gestational weight gain and
22
23
ee
24 gestational diabetes mellitus are associated with a higher risk of childhood obesity.[40,41] Our
25
26
27 results also showed that children born to mothers with gestational diabetes mellitus and higher
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28
29
ev
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32
34
ie
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on
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ly
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be influenced by other lifestyle habits. Second, indications for CS in this study were derived from
46
47
self-reports by mothers or reports by primary care-givers, not from medical records. Some
48
49
50 information such as maternal/fetal conditions that indicate CS or precise indications for CS that
51
52
53 might be more related to these disorders were not evaluated. For example, whether there was a trial
54
55
56 of labor before CS was not available. The infant might have exposed to some of the flora, even in the
57
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16
60
1
2
3
4 absence of vaginal delivery. Third, we looked at associations among these three disorders and modes
5
6
7 of delivery as mutually exclusive, but we might have missed the possibility that these disorders
8
9
10 might occur in combination. Last, any or in combination of learning disabilities, developmental delay,
11
12
13 attention deficit hyperactivity disorder, sensory integration disorder, or autism were categorized as
14
15
neurodevelopment disorders might distorted our outcomes because each of them may have different
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18
underlying risk factors.
19
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17
60
1
2
3
4 CONCLUSIONS
5
6
7 Our results implied that CS birth was associated with the occurrence of children’s
8
9
10 neurodevelopmental disorders. However, children born before 38 weeks of GA by CS had
11
12
13 significantly more children’s neurodevelopmental disorders. CS birth was weakly associated with
14
15
childhood asthma since parental asthma and preterm labor are stronger predisposing factors. The
Fo
16
17
18
association between CS birth and childhood obesity is robust after controlling for related factors.
19
rp
20
21
22
23
ee
24
25
26
27
rr
28
29
30
ev
31
32
33
34
ie
35
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on
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ly
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60
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7
8
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16 as submitted.
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24
26
27
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29 the work.
30
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Conflicts of Interest: none.
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5 1. Otamiri G, Berg G, Ledin T, et al. Delayed neurological adaptation in infants delivered by
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11. Huh SY, Rifas-Shiman SL, Zera CA, et al. Delivery by caesarean section and risk of obesity in
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16. Juhn YJ, Weaver A, Katusic S, et al. Mode of delivery at birth and development of asthma: a
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50 population-based cohort study. J Allergy Clin Immunol 2005;116:510–6.
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53 17. Li HT, Zhou YB, Liu JM. The impact of Cesarean section on offspring overweight and obesity: a
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20. MacKay DF, Smith GC, Dobbie R, et al. Gestational age at delivery and special education need:
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56 26. Lampi KM, Hinkka-Yli-Salomäki S, Lehti V, et al. Parental age and risk of autism spectrum
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56 2014;9:10–6.
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4
6 n (%) n (%)
7
8 Total 19721 (100.0) 13143 (66.6) 6556 (33.2)
9 Neurodevelopmental disorders 804 (4.1) 497 (3.8) 307 (4.7) **
10
11
Learning disabilities 290 (1.5) 179 (1.4) 111 (1.7)
12 Developmental delay 525 (2.7) 322 (2.5) 203 (3.1) **
13
ADHD 183 (0.9) 112 (0.9) 71 (1.1)
14
15 Sensory integration disorder 254 (1.3) 147 (1.1) 107 (1.6) **
Fo
16 Autism 88 (0.4) 52 (0.4) 36 (0.5)
17
18 Asthma 1311 (6.7) 831 (6.3) 478 (7.3) *
19 Obesity 2896 (14.7) 1844 (14.0) 1046 (15.9) ***
rp
20
21 Gender
22 male 10358 (52.6) 6785 (51.6) 3561 (54.3) ***
23
Birth order
ee
24
25 first-born child 9918 (50.4) 6833 (52.0) 3085 (47.1) ***
26
Gestational age, weeks ***
27
rr
28 <37 1644 (8.3) 784 (6.0) 857 (13.1)

29 37 2557 (13.0) 1348 (10.3) 1206 (18.4)
30
ev
31 38 5282 (26.8) 3124 (23.8) 2152 (32.8)

32 39 5601 (28.4) 4250 (32.3) 1343 (20.5)
33
34 40-41 4580 (23.2) 3603 (27.4) 975 (14.9)
ie
35 ≧42 57 (0.3) 34 (0.3) 23 (0.4)

36
Maternal age at birth of child, ***
w
37
38 years
39
40
<25 2882 (14.6) 2288 (17.4) 591 (9.0)
on
41 25-29 6401 (32.5) 4514 (34.3) 1880 (28.7)

42
30-34 7032 (35.7) 4522 (34.4) 2503 (38.2)
43
44 ≧35 3406 (17.3) 1819 (13.8) 1582 (24.1)
ly
45 Maternal education level ***

46
49
50 Junior college 4959 (25.2) 3277 (25.0) 1675 (25.6)
52
53 Family monthly income ***
54 <30,000 2745 (14.1) 1860 (14.3) 881 (13.5)
55
30,000-100,000 13729 (70.3) 9211 (70.8) 4502 (69.2)
56
57 >100,000 3065 (15.7) 1944 (14.9) 1119 (17.2)
58
59
25
60
1
2
3 Parental asthma history 518 (2.6) 328 (2.5) 190 (2.9)
4
5 Gestational diabetes mellitus 435 (2.2) 200 (1.5) 234 (3.6) ***
6 Gestational weight gain, kg ***
7
8
< 11 4766 (24.4) 3309 (25.4) 1449 (22.3)
9 11-13 4697 (24.0) 3306 (25.4) 1385 (21.3)
10
14-16 4631 (23.7) 3138 (24.1) 1491 (22.9)
11
12 ≧17 5448 (27.9) 3272 (25.1) 2171 (33.4)
13 Missing data in modes of delivery: 0.2%, birth order: 0.2%, gestational age: 0.1%,
14
15 maternal age at birth of child: 0.1%, maternal educational levels: 0.3%, and family
Fo
16 monthly income: 1.0%, parental asthma history: 0.5%, gestational diabetes mellitus:
17
18 0.2%, gestational weight gain: 0.9%
rp
20
21 children’s health issues: neurodevelopmental disorders: 19,717, asthma: 19,720, and
22 obesity: 19,269
23
ee
24
25 Chi square for analyzing differences of obesity, asthma, neurodevelopmental disorders, gender and
26
birth order between vaginal and cesarean delivery
27
rr
＊
28 p<0.05; ＊＊ p <0.01; ＊＊＊ p <0.001
29
30
ev
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33
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ie
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36
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on
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26
60
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3 Table 2. Association between cesarean delivery and the occurrence of children’s
4
5 neurodevelopmental disorders after controlling for gestational age, children’s and parental
6 characteristics
7
8 Adjusted 95% CI Adjusted 95% CI
9 OR OR
10
11
Cesarean delivery 1.22 1.05-1.42 1.15 0.98-1.34
12 Gestational age (ref: 39-41 weeks)
13
<37 weeks 1.94 1.55-2.42
14
15 37 weeks 1.24 1.00-1.55
Fo
16 38 weeks 0.97 0.81-1.17
17
18 ≧42 weeks 1.63 0.58-4.59
rp
20
22 Maternal age at birth of child (ref: ≧35 years)
23
<25 years 0.75 0.58-0.98 0.76 0.58-1.00
ee
24
25 25-29 years 0.79 0.64-0.98 0.81 0.65-0.99
26
30-34 years 0.78 0.63-0.95 0.79 0.64-0.96
27
rr
28 Maternal education levels (ref: college or above)

30
ev

32 Junior college 0.96 0.76-1.21 0.96 0.76-1.21
33
ie
35 <30,000 2.23 1.66-3.00 2.23 1.66-3.00

36
30,000-100,000 1.33 1.04-1.69 1.34 1.05-1.71
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27
60
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3 Table 3. Association between cesarean delivery and the occurrence of children’s asthma after
4
7
8 OR OR OR
10
11
12 39-41 weeks)
13
<37 weeks 1.27 1.03-1.56 1.23 1.00-1.52
14
15 37 weeks 1.18 0.99-1.41 1.17 0.98-1.40
Fo
16 38 weeks 1.19 1.04-1.37 1.19 1.03-1.36
17
18 ≧42 weeks 1.98 0.84-4.65 2.05 0.87-4.84
19 Gender, male 1.40 1.25-1.57 1.39 1.24-1.56 1.40 1.24-1.57
rp
20
21 First-born child 1.23 1.09-1.38 1.26 1.12-1.42 1.27 1.13-1.44
22 Maternal age at birth of
23
child (ref: ≧35 years)
ee
24
25 <25 years 0.90 0.71-1.15 0.90 0.71-1.15 0.88 0.69-1.12
26
25-29 years 1.14 0.95-1.36 1.14 0.96-1.36 1.13 0.94-1.34
27
rr
28 30-34 years 1.03 0.88-1.22 1.04 0.88-1.23 1.02 0.87-1.21

30
ev

32 above)
33
ie

36
Junior college 0.81 0.69-0.95 0.81 0.69-0.95 0.81 0.69-0.96
w
37
39
40
(NTD; ref: >100,000)
on
41 <30,000 0.67 0.52-0.86 0.66 0.52-0.85 0.67 0.53-0.86

42
30,000-100,000 0.87 0.74-1.02 0.87 0.74-1.02 0.88 0.75-1.04
43
44 Parental asthma history 3.62 2.88-4.55
ly
45 (ref: no)
46
49
50
51
52
53
54
55
56
57
58
59
28
60
1
2
3 Table 4. Association between cesarean delivery and the occurrence of children’s obesity after
4
7
8 OR OR OR
10
11
12 39-41 weeks)
13
<37 weeks 1.03 0.89-1.20 1.04 0.90-1.21
14
15 37 weeks 1.04 0.91-1.18 1.04 0.91-1.18
Fo
16 38 weeks 1.00 0.90-1.10 1.00 0.90-1.10
17
18 ≧42 weeks 2.28 1.26-4.13 2.29 1.26-4.15
19 Gender, male (ref:
rp
20 1.88 1.73-2.05 1.88 1.73-2.05 1.88 1.73-2.04
21 female)
22 First-born child (ref:
23 1.11 1.02-1.21 1.11 1.02-1.21 1.09 0.99-1.18
not first-born child)
ee
24
25 Maternal age at birth
26
of child (ref: ≧35 years)
27
rr
28 <25 years 0.97 0.83-1.14 0.97 0.83-1.14 1.00 0.85-1.16

29 25-29 years 0.99 0.87-1.12 0.99 0.87-1.12 1.00 0.88-1.13
30
ev
31 30-34 years 0.91 0.81-1.03 0.91 0.81-1.03 0.92 0.82-1.04

33
ie
35 above)
36
≤ Compulsory school 1.70 1.44-2.00 1.69 1.43-2.00 1.71 1.45-2.02
w
37
39
40
Junior college 1.36 1.19-1.56 1.36 1.19-1.55 1.35 1.18-1.55
on
41 Family monthly
42
income (NTD) (ref:
43
44 >100,000)
ly
45 <30,000 1.04 0.88-1.24 1.04 0.87-1.23 1.05 0.89-1.25

46
47 30,000-100,000 1.06 0.93-1.21 1.06 0.93-1.21 1.07 0.94-1.22
48 Gestational diabetes
49 1.53 1.20-1.95
51 Gestational weight
52
54 ≧ 11kg 1.18 1.07-1.30
55
56
58
59
29
60
1
3
4
Item Reported
5
6
8 abstract
11
12 Introduction
14 reported
15
Fo
16
17 Methods
19
rp
Setting 5 Describe the setting, locations, and relevant dates, including periods of 6
20
22 Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of 6
ee
25
26
rr

30
ev
31
ie
36
w
37
40
on

41
Bias 9 Describe any efforts to address potential sources of bias 6-8
42
ly

46
47
48 confounding
49 (b) Describe any methods used to examine subgroups and interactions 8
51 (d) Cohort study—If applicable, explain how loss to follow-up was addressed 6
52
54 was addressed
57
58
60
1
1
2
3 Results
4
5
9
10
14 interest
15
Fo
17 Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over 8-11
18 time
19 Case-control study—Report numbers in each exposure category, or summary NA
rp
20
21
23 measures
ee
25
26
rr
28 (b) Report category boundaries when continuous variables were categorized 25-26
30
ev
31
34
ie
Discussion
35
w
37 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias 16-17
40
on

41
43 Generalisability 21 Discuss the generalisability (external validity) of the study results 6
44
ly
Other information
45
48
50
51
52
56
57
59
60
2

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BMJ Open is committed to open peer review.

As part of this commitment we make the peer review

Does Cesarean Delivery Increase the Occurrence of

Article Type: Research

Date Submitted by the Author: 30-Mar-2017

Hospital, Department of Obstetrics and Gynecology

Institute of Allied Health Sciences

Chiang, Tung-liang; Institute of Health Policy and Management, College of

Secondary Subject Heading: Public health, Obstetrics and gynaecology

Cesarean delivery, neurodevelopmental disorders, Asthma < THORACIC

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

28 Address correspondence to:

35 Keywords: Cesarean delivery, neurodevelopmental disorders, asthma, obesity, vaginal delivery

24 overweight/obesity also needs clarification by further study.

24 Dose Effect of GA on These Three Disorders

24 occurrence of neurodevelopmental disorders was significantly associated with a GA of less than 37

24 association between CS births and neurodevelopmental disorders in childhood. This phenomenon is

24 Limitations of this study

20-45 weeeks gestation. Semin Fetal Neonatal Med 2006;11:415–22.

28 37 weeks 2557 (13.0) 1348 (10.3) 1206 (18.4)

31 39 weeks 5601 (28.4) 4250 (32.3) 1343 (20.5)

41 >=35 years 3406 (17.3) 1819 (13.8) 1582 (24.1)

45 Senior high school 7908 (40.2) 5147 (39.2) 2756 (42.1)

28 ≤ Compulsory school 1.09 0.82-1.44 1.07 0.81-1.41

31 Junior college 0.96 0.76-1.21 0.96 0.76-1.21

35 30,000-100,000 1.33 1.04-1.69 1.34 1.05-1.71

35 Junior college 0.81 0.69-0.95 0.81 0.69-0.95 0.81 0.69-0.96

41 30,000-100,000 0.87 0.74-1.02 0.87 0.74-1.02 0.88 0.75-1.04

45 NTD: New Taiwan Dollar, 1 USD≒30 NTD

28 25-29 years 1.01 0.87-1.17 1.01 0.87-1.17 1.02 0.88-1.19

35 ≤ Compulsory school 1.45 1.19-1.78 1.45 1.19-1.77 1.47 1.20-1.80

41 income (NTD) (ref:

45 30,000-100,000 1.11 0.95-1.29 1.11 0.95-1.29 1.11 0.95-1.29

28 Cross-sectional study—Give the eligibility criteria, and the sources and

there is more than one group

45 describe which groupings were chosen and why

28 (b) Report category boundaries when continuous variables were categorized 10

limitations, multiplicity of analyses, results from similar studies, and other

Associations of Cesarean Delivery and the Occurrence of

Article Type: Research

Date Submitted by the Author: 21-Jun-2017

Hospital, Department of Obstetrics and Gynecology

Institute of Allied Health Sciences

Chiang, Tung-liang; Institute of Health Policy and Management, College of

Secondary Subject Heading: Public health, Obstetrics and gynaecology

Cesarean delivery, neurodevelopmental disorders, Asthma < THORACIC

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

41 Text word count: 2,991

24 childhood or influence later physical well-being needs further investigation.

24 Taiwan University Hospital (No. 201604055RINC).

24 according to the classification of the DSM-V published on May 27, 2013.[19]

24 3.62; 95% CI: 2.88-4.55).

24 occurrence of neurodevelopmental disorders was significantly associated with a GA of less than 37

24 gestational weight gain have a higher risk of childhood obesity.

20-45 weeks’ gestation. Semin Fetal Neonatal Med 2006;11:415–22.

24 shown by altered allometric scaling of brain growth. PLoS Med 2006;3:e265.

28 <37 1644 (8.3) 784 (6.0) 857 (13.1)

31 38 5282 (26.8) 3124 (23.8) 2152 (32.8)

35 ≧42 57 (0.3) 34 (0.3) 23 (0.4)

41 25-29 6401 (32.5) 4514 (34.3) 1880 (28.7)

45 Maternal education level ***

28 Maternal education levels (ref: college or above)