Maternal and Perinatal Factors Associated With Kawasaki Disease Among Offspring in Taiwan | Cardiology | JAMA Network Open | JAMA Network
[Skip to Navigation]
Sign In
Table 1.  Characteristics of Study Participants and Factors Associated With KD
Characteristics of Study Participants and Factors Associated With KD
Table 2.  Multivariable Analysis of Autoimmune Diseases Associated With Kawasaki Disease
Multivariable Analysis of Autoimmune Diseases Associated With Kawasaki Disease
1.
Onouchi  Y, Ozaki  K, Burns  JC,  et al; Japan Kawasaki Disease Genome Consortium; US Kawasaki Disease Genetics Consortium.  A genome-wide association study identifies three new risk loci for Kawasaki disease.   Nat Genet. 2012;44(5):517-521. doi:10.1038/ng.2220PubMedGoogle ScholarCrossref
2.
McCrindle  BW, Rowley  AH, Newburger  JW,  et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention.  Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.   Circulation. 2017;135(17):e927-e999. doi:10.1161/CIR.0000000000000484PubMedGoogle ScholarCrossref
3.
Hayward  K, Wallace  CA, Koepsell  T.  Perinatal exposures and Kawasaki disease in Washington State: a population-based, case-control study.   Pediatr Infect Dis J. 2012;31(10):1027-1031. doi:10.1097/INF.0b013e31825eaed0PubMedGoogle ScholarCrossref
4.
Belkaibech  S, Potter  BJ, Kang  H, Lee  GE, Bilodeau-Bertrand  M, Auger  N.  Maternal autoimmune disorders and risk of Kawasaki disease in offspring.   J Pediatr. 2020;222:240-243.e1. doi:10.1016/j.jpeds.2020.02.016PubMedGoogle ScholarCrossref
5.
Yang  SW, Kernic  MA, Mueller  BA, Simon  GE, Chan  KCG, Vander Stoep  A.  Association of parental mental illness with child injury occurrence, hospitalization, and death during early childhood.   JAMA Pediatr. 2020;174(8):e201749. doi:10.1001/jamapediatrics.2020.1749PubMedGoogle Scholar
6.
Wong  WS, Solomon  BD, Bodian  DL,  et al.  New observations on maternal age effect on germline de novo mutations.   Nat Commun. 2016;7:10486. doi:10.1038/ncomms10486PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Views 2,853
    Citations 0
    Research Letter
    Pediatrics
    March 26, 2021

    Maternal and Perinatal Factors Associated With Kawasaki Disease Among Offspring in Taiwan

    Author Affiliations
    • 1Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
    • 2Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
    • 3Department of Pediatrics, Cathay General Hospital, Hsinchu, Taiwan
    • 4School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
    • 5Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan
    • 6School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
    • 7Department of Food and Nutrition, Providence University, Taichung, Taiwan
    • 8School of Medicine, Chung Shan Medical University, Taichung, Taiwan
    • 9Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
    • 10Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung, Taiwan
    • 11Department of Health Care Management, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
    • 12Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
    • 13Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
    • 14Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan
    • 15Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
    • 16Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
    • 17Center For Intelligent Drug Systems and Smart Bio-devices, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
    • 18Drug Development and Value Creation Research Center, Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
    JAMA Netw Open. 2021;4(3):e213233. doi:10.1001/jamanetworkopen.2021.3233
    Introduction

    Kawasaki disease (KD) is the most recognized childhood vasculitis and the leading cause of pediatric-acquired heart disease in developed countries.1 Increased KD incidence among East Asian children, a high risk among siblings and twins, and familial occurrence suggest a genetic predisposition.1,2 However, genetic factors alone cannot explain seasonal variations, periodic outbreaks, or the continued increase in KD incidence.2 Many other factors, including exposure to infectious agents, pollution, and elevated atmospheric biological particle concentrations, are associated with KD.2

    Several studies3,4 have suggested that maternal and perinatal factors might be associated with KD development. This case-control study investigated the role of perinatal factors and maternal autoimmune diseases in the development of KD using the Taiwan Maternal and Child Health Database.

    Methods

    The institutional review board of the Cathay General Hospital approved this study and waived the need for informed consent because the data are publicly available and deidentified. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for case-control studies.

    We collected data of patients who were younger than 5 years, had KD, and were born between 2004 and 2010, from the original claims data of the Taiwan National Health Insurance Research Database, which was established in 1995 and covered 99.9% of the population by 2003.5 KD diagnosis (International Classification of Diseases, Ninth Revision code 446.1) was confirmed by receipt of intravenous immunoglobulins (Anatomic Therapeutic Chemical code J06BA02) and hospitalization. Age-matched and index date–matched individuals were collected as a control group. Every citizen in Taiwan is assigned a unique national identification number. The Taiwan Maternal and Child Health Database, which contains national identification numbers of children and their parents, was used to link parents and children.5 The child’s birth history, maternal comorbidities, and maternal autoimmune diseases were analyzed (see the eAppendix in the Supplement).

    Differences in categorical and continuous variables were assessed using χ2 and t tests, respectively. P values were 2-sided, and statistical significance was set at P <.05. Analyses were performed using SAS Enterprise Guide statistical software version 9.4 (SAS Institute). The analyses were conducted from May 1 to August 6, 2020.

    Results

    We enrolled 4197 patients with KD (2601 boys [62.0%]; 1717 [40.9%] younger than 1 year; 1261 [30.0%] aged 1 year) and 16 788 matched individuals without KD (8832 boys [52.6%]) from 1 280 374 children in the database. Male sex (odds ratio [OR], 1.47; 95% CI, 1.37-1.57; P < .001), maternal age 35 years or older (OR, 1.18; 95% CI, 1.07-1.30; P < .001), maternal Sjögren syndrome (OR, 1.75; 95% CI, 1.03-2.95; P = .04), and maternal ankylosing spondylitis (OR, 2.01; 95% CI, 1.17-3.43; P = .01) were associated with increased KD risk in the offspring. However, low birth weight, preterm delivery, other maternal autoimmune diseases, and maternal comorbidities showed no associations with risk of developing KD (Table 1). In the multivariable analysis, maternal ankylosing spondylitis was associated with a 2.02 times higher odds of KD in the offspring (95% CI, 1.18-3.47; P = .01) (Table 2).

    Discussion

    Given that the age of KD onset is between 6 months and 5 years, and it is most severe during the first year of life, it is possible that the child’s immature immune system and maternal and perinatal factors might be associated with KD development. However, the identification of maternal associations, especially when investigating perinatal factors associated with pediatric diseases, is the challenge when integrating different large databases to link maternal health information with the child’s clinical phenotypes.5 In this study, we found that advanced maternal age was significantly associated with KD development in the offspring. This association may partly explain the increasing KD incidence in developed countries because ages at marriage and childbearing are increasing. The advanced parental age may be associated with more germline de novo variants, which may lead to KD in the offspring.6 Furthermore, we demonstrated that maternal ankylosing spondylitis and Sjögren syndrome may be perinatal factors associated with increased risk of KD. This suggests that a maternal autoimmune disease or its associated medical treatment might induce an epigenetic predisposition to developing KD in the offspring.

    The main limitation of the study was the unavailability of the genetic and environmental confounders.1,2 Moreover, our findings are based on data of patients who were younger than 5 years. Therefore, the role of maternal factors in increasing the risk of KD in offspring requires further investigation, especially in older patients.

    Back to top
    Article Information

    Accepted for Publication: February 4, 2021.

    Published: March 26, 2021. doi:10.1001/jamanetworkopen.2021.3233

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Chang C-L et al. JAMA Network Open.

    Corresponding Authors: Tai-Ming Ko, PhD, Department of Biological Science and Technology, National Chiao Tung University, 75 Boai St, Hsinchu 300, Taiwan, ROC (tmko@nctu.edu.tw); Ching-Heng Lin, PhD, Department of Medical Research, Taichung Veterans General Hospital, 1650 Taiwan Blvd, Section 4, Taichung, Taiwan, ROC (epid@vghtc.gov.tw).

    Author Contributions: Dr C.-H. Lin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: All authors.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Chang, Ko.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: C.-H. Lin.

    Obtained funding: Ko.

    Administrative, technical, or material support: M.-C. Lin, C.-H. Lin, Ko.

    Supervision: M.-C. Lin, Ko.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This study was funded by grants VGHUST108-G2-2-1 and VGHUST109-V2-1-2 from the University System of Taiwan Joint Research Program and by grants MOST-107-2314-B-009-005-MY2, MOST-109-2314-B-009-003-MY3, and MOST-109-2321-B-009-007 from the Ministry of Science and Technology in Taiwan.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    References
    1.
    Onouchi  Y, Ozaki  K, Burns  JC,  et al; Japan Kawasaki Disease Genome Consortium; US Kawasaki Disease Genetics Consortium.  A genome-wide association study identifies three new risk loci for Kawasaki disease.   Nat Genet. 2012;44(5):517-521. doi:10.1038/ng.2220PubMedGoogle ScholarCrossref
    2.
    McCrindle  BW, Rowley  AH, Newburger  JW,  et al; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention.  Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.   Circulation. 2017;135(17):e927-e999. doi:10.1161/CIR.0000000000000484PubMedGoogle ScholarCrossref
    3.
    Hayward  K, Wallace  CA, Koepsell  T.  Perinatal exposures and Kawasaki disease in Washington State: a population-based, case-control study.   Pediatr Infect Dis J. 2012;31(10):1027-1031. doi:10.1097/INF.0b013e31825eaed0PubMedGoogle ScholarCrossref
    4.
    Belkaibech  S, Potter  BJ, Kang  H, Lee  GE, Bilodeau-Bertrand  M, Auger  N.  Maternal autoimmune disorders and risk of Kawasaki disease in offspring.   J Pediatr. 2020;222:240-243.e1. doi:10.1016/j.jpeds.2020.02.016PubMedGoogle ScholarCrossref
    5.
    Yang  SW, Kernic  MA, Mueller  BA, Simon  GE, Chan  KCG, Vander Stoep  A.  Association of parental mental illness with child injury occurrence, hospitalization, and death during early childhood.   JAMA Pediatr. 2020;174(8):e201749. doi:10.1001/jamapediatrics.2020.1749PubMedGoogle Scholar
    6.
    Wong  WS, Solomon  BD, Bodian  DL,  et al.  New observations on maternal age effect on germline de novo mutations.   Nat Commun. 2016;7:10486. doi:10.1038/ncomms10486PubMedGoogle ScholarCrossref
    ×