The association between Mycoplasma pneumoniae infection and speech and language impairment: A nationwide population-based study in Taiwan

Abstract

Manifestations of Mycoplasma pneumoniae infection can range from self-limiting upper respiratory symptoms to various neurological complications, including speech and language impairment. But an association between Mycoplasma pneumoniae infection and speech and language impairment has not been sufficiently explored. In this study, we aim to investigate the association between Mycoplasma pneumoniae infection and subsequent speech and language impairment in a nationwide population-based sample using Taiwan’s National Health Insurance Research Database. We identified 5,406 children with Mycoplasma pneumoniae infection (International Classification of Disease, Revision 9, Clinical Modification code 4830) and compared to 21,624 age-, sex-, urban- and income-matched controls on subsequent speech and language impairment. The mean follow-up interval for all subjects was 6.44 years (standard deviation = 2.42 years); the mean latency period between the initial Mycoplasma pneumoniae infection and presence of speech and language impairment was 1.96 years (standard deviation = 1.64 years). The results showed that Mycoplasma pneumoniae infection was significantly associated with greater incidence of speech and language impairment [hazard ratio (HR) = 1.49, 95% CI: 1.23–1.80]. In addition, significantly increased hazard ratio of subsequent speech and language impairment in the groups younger than 6 years old and no significant difference in the groups over the age of 6 years were found (HR = 1.43, 95% CI:1.09–1.88 for age 0–3 years group; HR = 1.67, 95% CI: 1.25–2.23 for age 4–5 years group; HR = 1.14, 95% CI: 0.54–2.39 for age 6–7 years group; and HR = 0.83, 95% CI:0.23–2.92 for age 8–18 years group). In conclusion, Mycoplasma pneumoniae infection is temporally associated with incident speech and language impairment.

About the Authors:

Ching-Shu Tsai

Contributed equally to this work with: Ching-Shu Tsai, Yao-Hsu Yang

Roles Conceptualization, Investigation, Methodology, Project administration, Writing – original draft

Affiliations Department of Psychiatry, Chang Gung Memorial Hospital and University, Chiayi, Taiwan, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan, Chang Gung Institute of Technology, Taoyuan, Taiwan

Vincent Chin-Hung Chen

Roles Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Writing – review & editing

Affiliations Department of Psychiatry, Chang Gung Memorial Hospital and University, Chiayi, Taiwan, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan

Yao-Hsu Yang

Contributed equally to this work with: Ching-Shu Tsai, Yao-Hsu Yang

Roles Data curation, Software

Affiliations Department for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan, Center of Excellence for Chang Gung Research Datalink, Chang Gung Memorial Hospital, Chiayi, Taiwan, Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

Tai-Hsin Hung

Roles Funding acquisition, Methodology

Affiliations Department of Psychiatry, Chang Gung Memorial Hospital and University, Chiayi, Taiwan, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan, Chang Gung Institute of Technology, Taoyuan, Taiwan

Mong-Liang Lu

Roles Formal analysis, Validation, Writing – review & editing

Affiliation: Department of Psychiatry, Wan-Fang Hospital and School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

Kuo-You Huang

Roles Conceptualization, Supervision, Validation, Writing – review & editing

* E-mail: [email protected]

Affiliation: Department of Speech Language Pathology and Audiology, Chung Shan Medical University and Hospital, Taichung, Taiwan

Michael Gossop

Roles Formal analysis, Validation, Writing – review & editing

Affiliation: National Addiction Centre, King’s College, London, United Kingdom

Introduction

Mycoplasma pneumoniae (M. pneumoniae), belonging to the class Mollicutes, is a ubiquitous and well-established pathogen of the respiratory tract. Manifestations of M. pneumoniae infection can range from self-limiting upper respiratory illness to severe pneumonia. Between 10% and 20% of radiologically proven pneumonia cases in endemic periods and up to 50% of all cases in epidemic periods are caused by M. pneumoniae [1, 2].

About 25% of M. pneumoniae infected persons may be complicated by the involvements of various extrapulmonary systems, and the central nervous system (CNS) is the most frequently affected [3, 4]. Within hospitalized patients with serologically confirmed M. pneumoniae infection, approximately 1–10% is associated with neurological manifestations [5]. Cerebellar syndrome, polyradiculitis, cranial nerve palsies, aseptic meningitis, encephalitis, meningoencephalitis, acute disseminated encephalomyelitis, optic neuritis, diplopia, cranial nerve palsy, ataxia, choreoathetosis, and ascending paralysis (Guillain-Barre syndrome) are examples of neurological complications in M. pneumoniae infection [6]. More than 80% of patients with CNS findings have prior or concomitant respiratory illness [7]. The time interval between the onset of respiratory symptoms and neurological symptoms varies from 2 to 14 days [8, 9]. But late onset encephalitis after several days to a few weeks was also reported [5].

M. pneumoniae infections can occur in children of all ages. Many M. pneumoniae infections are subclinical, a finding that is particularly common in children younger than 5 years of age [10]. But age-specific attack rates for M. pneumoniae pneumonia could be observed. The rate among children aged five to nine years was about two times for younger children and four times for adults [11]. Within hospitalized pediatric patients with M. pneumoniae infection, 25% have neurological symptoms [12]. And 5–10% of childhood encephalitis is attributed to M. pneumoniae [13]. Although there was a self-limited course and favorable outcome after an acute M. pneumoniae infection, significant neurological sequelae in 45% of hospitalized pediatric patients have been reported [12].

There were only two case reports of subsequent speech and language impairment after M. pneumoniae infection in our literature review [14, 15]. To our knowledge, there is no large scale study to explore the association between M. pneumoniae infection and speech and language impairment. This study investigates the association between M. pneumoniae infection and subsequent speech and language impairment in a nationwide population-based sample.

Materials and methods

Database

Data used were obtained from the Taiwan National Health Insurance Research Database (NHIRD). The NHIRD was launched on March 1, 1995 and is maintained by the Department of Health and the National Health Research Institutes (NHRI). It covers more than ninety-nine per cent of the national population of Taiwan [16] and provides comprehensive patient data, including demographic data, dates and numbers of clinical visits, dates of admission and discharge, the names of prescribed drugs, dosages, and prescription duration, operations, examinations, diagnostic codes in the format of the International Classification of Disease, Revision 9, Clinical Modification (ICD-9-CM), and physician specialties: these provide valuable information for epidemiological study [17]. The NHRI has provided these data to scientists for research purposes since 2000. In concert with the Bureau of the National Health Insurance, the NHRI extracted a randomly sampled representative database of 1,000,000 people from the registry of all enrolees via a systemic sampling method to form the Longitudinal Health Insurance Database in 2005 (LHID 2005). The LHID contained all reimbursement claims records from 1996 to 2013. There are no statistically significant differences in age, sex, or health care costs between this sample and all enrollees [18].

Study subjects and design

For the difficult incubation and limited application of the polymerase chain reaction (PCR) techniques for M. pneumoniae in the clinical settings, the serological diagnosis is widely used. The sensitivity of the serological diagnosis is similar to that of the PCR methods [19]. In Taiwan, M. pneumoniae infection is diagnosed by clinical evaluation and serologic test results [20], including specific IgM present or a greater than 4-fold increase in specific IgG levels in a blood sample [21].

The study subjects were comprised of insured children under 18 years of age between 1998 and 2011. Inclusion criteria for the M. pneumoniae infection group included at least two ambulatory claims within one year or at least one inpatient claim with a diagnosis of M. pneumoniae infection (ICD-9-CM code 4830). The foregoing definition is consistent with previous research using this database [22]. Children who have diagnostic codes of developmental speech or language disorder (ICD-9-CM codes 315.3, 315.31–39), aphasia (ICD-9-CM code 784.3), voice and resonance disorders (ICD-9-CM codes 784.4, 784.40–49), and other speech disturbance (ICD-9-CM codes 784.5, 784.51–59) or received speech therapy before M. pneumoniae infection were excluded from the analysis. A total of 5,406 children with M. pneumoniae infection were eligible. The children matching on age, sex, urban and income from the remaining subjects as comparison group were randomly sampled at a 1:4 ratio. The process is shown in Fig 1.

[Figure omitted. See PDF.]

Fig 1. Flow chart of data collection.

https://doi.org/10.1371/journal.pone.0180402.g001

Case identification of speech and language impairment

Adult onset fluency disorder (ICD-9-CM code 307.0), developmental speech or language disorder (ICD-9-CM codes 315.3, 315.31–39), aphasia (ICD-9-CM code 784.3), voice and resonance disorders (ICD-9-CM codes 784.4, 784.40–49), and other speech disturbance (ICD-9-CM codes 784.5, 784.51–59) were operationalized as speech and language impairment. Cases that had at least two ambulatory claims within one year or at least one inpatient claim with these diagnostic codes were identified and collected for analysis. In addition, cases of speech therapy without above-mentioned diagnostic codes were also classified as the group of speech and language impairment.

Confounding factors

The analyses were adjusted for potential confounders which had been reported in relation to speech and language impairment in previous studies, including preterm labor and small for gestational age (ICD-9-CM codes 765–765.19) [23, 24], perinatal complications (ICD-9-CM codes 760–764, 766–779 and V137) [24], autistic spectrum disorder (ICD-9-CM codes 299) [25, 26], intellectual disability (ICD-9-CM codes 317, 318, 319) [26, 27], other disorders of the CNS (ICD-9-CM codes 340–349) including cerebral palsy (ICD-9-CM codes 343) [28], attention deficit hyperactivity disorder (ICD-9-CM codes 314) [29], otitis media (ICD-9-CM codes 381.0–381.4 and 382) [30, 31], hearing loss (ICD-9-CM codes 389) [24, 26], and traumatic brain injury (ICD-9-CM codes 800–804 and 850–854) [32].

Statistical analysis

The distribution of demographic factors and comorbidities were compared between the M. pneumoniae infection group and the comparison group. We used the Kaplan–Meier methods to estimate cumulative incidences of speech and language impairment and the log-rank tests to examine the differences. Finally, Cox proportional hazards models were used to compute the hazard ratios accompanying 95% confidence intervals (CIs) after adjustment for age, sex, urban, income, and other confounders. Two-tailed p value = 0.05 was considered significant. Individuals who were deceased during the study period and/or were from the beneficiaries register lost to follow-up were omitted from the analysis. All analyses were conducted using SAS statistical software (Version 9.4; SAS Institute, Cary, NC, USA).

Ethics statement

The study was approved by the Institutional Review Board of Chang Gung Memorial Hospital. Written informed consent was exempted.

Results

Characteristics of subjects

The study sample comprised 5,406 individuals with M. pneumoniae infection and 21,624 age-, sex-, urban- and income-matched individuals ascertained from the database. The characteristics are described and compared in Table 1. Compared to the comparison group, individuals with M. pneumoniae infection had more perinatal complications, other disorders of the CNS, otitis media, traumatic brain injury and subsequent speech and language impairment, and less autistic spectrum disorder. The mean follow-up interval for all subjects was 6.44 years (standard deviation = 2.42 years). Mean latency period between the initial M. pneumoniae infection and presence of speech and language impairment was 1.96 years (standard deviation = 1.64 years).

[Figure omitted. See PDF.]

Table 1. Characteristics of M. pneumoniae infection cases and their matched controls.

https://doi.org/10.1371/journal.pone.0180402.t001

Association between potential risk factors and risk of speech and language impairment

As shown in Table 2, the hazard ratio of speech and language impairment in boys was higher than the ratio in girls (hazard ratio = 2.00, 95% CI: 1.67–2.39). Compared to the children aged eight to eighteen years, children aged from zero to three years have the highest risk (hazard ratio = 24.25, 95% CI: 14.78–39.78), followed by the children aged 4–5 years (hazard ratio = 11.19, 95% CI: 6.82–18.37) and the children aged 6–7 years (hazard ratio = 2.98, 95% CI: 1.69–5.24). There were significant increased hazard ratios among the prior history of preterm labor and small for gestational age (hazard ratio = 2.05, 95% CI: 1.35–3.13), intellectual disability (hazard ratio = 4.26, 95% CI: 1.91–9.51), or other disorders of the CNS (hazard ratio = 1.97, 95% CI: 1.34–2.89).

[Figure omitted. See PDF.]

Table 2. Hazard ratios of factors associated with speech and language impairment via Cox regression analysis.

https://doi.org/10.1371/journal.pone.0180402.t002

Association between M. pneumoniae infection and risk of speech and language impairment

Analyses of associations of interest are summarized in Table 2 and shown in Fig 2. In the fully adjusted Cox regression model, M. pneumoniae infection was associated with a greater incidence of speech and language impairment (hazard ratio = 1.49, 95% CI: 1.23–1.80) after adjusting for age, sex, urban, income, preterm labor and small for gestational age, perinatal complications, autistic spectrum disorder, intellectual disability, other disorders of the CNS, attention deficit hyperactivity disorder, otitis media, hearing loss and traumatic brain injury.

[Figure omitted. See PDF.]

Fig 2. Cumulative incidence of speech and language impairment in cohorts with/without Mycoplasma pneumoniae infection.

https://doi.org/10.1371/journal.pone.0180402.g002

Association between the age of M. pneumoniae infection and risk of speech and language impairment

The present study also showed that the hazard ratios of subsequent speech and language impairment were modified in different ages of M. pneumoniae infection. Compared with the same age groups without M. pneumoniae infection, the hazard ratio of subsequent speech and language impairment in the groups younger than 6 years old was significantly increased, and there was no significant difference in the groups over the age of 6 years. The hazard ratio of M. pneumoniae infection in the age 0–3 years group, age 4–5 years group, age 6–7 years group and age 8–18 years group was 1.43 (95% CI:1.09–1.88), 1.67 (95% CI: 1.25–2.23), 1.14 (95% CI: 0.54–2.39) and 0.83 (95% CI:0.23–2.92), respectively (Table 3).

[Figure omitted. See PDF.]

Table 3. Hazard ratios for speech and language impairment in subgroups of different age groups of M. pneumoniae infection.

https://doi.org/10.1371/journal.pone.0180402.t003

Discussion

To our knowledge, this is the first study to investigate the relationship between M. pneumoniae infection and speech and language impairment using a nationwide longitudinal dataset. The results identified a greater risk for speech and language impairment with M. pneumoniae infection, after adjusting for age, sex, urban, income, preterm labor and small for gestational age, perinatal complications, autistic spectrum disorder, intellectual disability, other disorders of the CNS, attention deficit hyperactivity disorder, otitis media, hearing loss and traumatic brain injury. In the present study, the mean latency period from initial M. pneumoniae infection to subsequent speech and language impairment was 1.96 years.

To our knowledge, there were only two case reports about speech and language impairment after M. pneumoniae infection [14, 15]. One reported two female children of 5 and 8 years of age with an apparent M. pneumoniae infection, and both showed symptoms of cerebellar syndrome, including ataxia, hypotonia, dysarthric speech and dysmetria initially. An initial brain MRI in one girl of 5-year-old was normal, but evident signs of global cerebellar atrophy in follow-up brain MRI performed at 6 and 24 months were present. Incomplete resolution of cerebellar dysfunction with speech problem and fine motor impairment was found three years later. The other girl of 8-year-old displayed striking cerebellar swelling in initial brain MRI. The follow-up brain MRI performed at two months showed normal signal in the cerebellum, but a loss of the volume of both cerebellum hemispheres with preservation of vermis. She was asymptomatic one year after the event [14]. Another case report was 5-year-old boy with a confirmed M. pneumoniae infection. He was admitted due to right lower lobe pneumonia with pleural effusion. But prolonged generalized tonic or tonic-clonic convulsion on the seventh day was observed. Brain imaging showed bilateral thalamic lesions without striatal or white-matter involvement. Even almost complete neurological recovery by 2 months, significant dysarthria was still present and persisted at 9 months [15]. Results from these case reports indicated that M. pneumoniae infection was associated with speech and language impairment, but the presence or not of such neurological impairment could not be totally judged from brain image. Results from our study based on longitudinal, representative population-based design provided support that previous M. pneumoniae infection is associated with incident speech and language impairment.

Previous studies reported that several factors may be involved with speech and language impairment, including male [24], perinatal factors [23, 24], hearing status [24, 26], medical conditions [30, 31], multiple birth [33, 34], oral sucking habits [35], temperament [36], family history of speech and language problems [37, 38], educational level of mother and father [39], parental mental health [40], maternal age at birth of child [33], birth order [41, 42], and neighborhood disadvantage [42, 43]. Mental handicap [26, 27], autism [25, 26], and attention deficit hyperactivity disorder [29] were also related to speech and language impairment. The findings in this study that boy, preterm labor and small for gestational age, intellectual disability, and other disorders of the CNS were associated with speech and language impairment are comparable with previous studies. But the results of this study that perinatal complications, autistic spectrum disorder, attention deficit hyperactivity disorder, otitis media, hearing loss and traumatic brain injury were not statistically related to speech and language impairment are inconsistent with previous studies. Differences in the size and nature of the samples, the case definition of speech and language impairment and the range and number of possible predictor variables included in the analyses may be the main reasons for the observed differences in study results [24]. Further research is needed to study the effects of factors which are inconsistent with previous studies on speech and language impairment, including perinatal complications, autistic spectrum disorder, otitis media, hearing loss and traumatic brain injury.

Although most of the M. pneumoniae infection in children younger than 5 years of age were subclinical [10], the influence on speech and language impairment was worthy of attention. In this study, children at the age of M. pneumoniae infection less than 6 years old have significant risk to have subsequent speech and language impairment.

In most of the M. pneumoniae infected cases reviewed, respiratory illness are usually mild and has preceded or coincided with the CNS findings [5]. And the development of several neurological findings is indicative of focal or diffuse CNS injury. The definite etiopathogenic mechanism is unknown. Several pathogenic theories have been put forth in recent years, including direct neuroinvasion, neurotoxin elaboration, hypercoagulable state and infection leading to immune dysfunction, such as autoantibodies production [5, 44–46]. It is possible that multiple mechanisms may be occurring simultaneously. For our study, immune complex mediated injury may be one of the pathogenic mechanisms. Through this mechanism, M. pneumoniae derived antigenic elements may act as molecular mimics and initiate complex immune reactions which subsequently generate neurological injury. A variety of autoantibodies production, such as antibodies against the mitotic spindle apparatus, the centriole, cardiolipin, smooth muscle cells, and lung, liver, and brain antigens (e.g. anti-neuronal antibodies) and IgM-class cold agglutinins have been reported after M. pneumoniae infection [47–51]. Another possible mechanism is the hypercoagulable state which could result in neurological injury from intravascular coagulation and thromboembolic phenomena of the cerebral vasculature. And immune mediated vascular injury and the development of a vasculitis could further contribute to such effects [52, 53]. It requires further empirical study to explore the putative mechanism of M. pneumoniae -induced immune response and its influence on speech and language impairment.

Strength and limitations

The large, nationally representative sample population and longitudinal dataset are key strengths in this study. But there are also several limitations. First, we could not rule out the possible influence of other previously proposed confounding variables not assessed and adjusted for, such as multiple birth, oral sucking habits, temperament, family history of speech and language problems, educational level of mother and father, parental mental health, maternal age at birth of child, birth order, and neighborhood disadvantage. Second, the period of follow-up is insufficient to confirm all possible cases. Speech and language impairment may manifest after the end of the study period in some subjects. Third, the diagnosis of M. pneumoniae infection and speech and language impairment was established by board physicians and registered in the database. Differences between healthcare providers in their diagnosis of M. pneumoniae infection and speech and language impairment cannot be controlled for. However, the accuracy of disease diagnoses in national health insurance system could reach up to 85% [54]. Fourth, because of lack of brain imaging data in this study, it could not explore whether the emergence of speech and language impairment was due to brain damage after M. pneumoniae infection or not.

Conclusions

M. pneumoniae infection is temporally associated with incident speech and language impairment. Clinicians should advise parents of children with M. pneumoniae infection to attend to symptoms that are associated with the development of speech and language impairment, especially when the child is less than 6 years old.

Acknowledgments

The authors would like to thank Center of Excellence for Chang Gung Research Datalink for the comments and assistance in data analysis. This study was supported by a grant from Chang Gung Memorial Hospital, Chiayi Branch (CMRPG6F0281), and based on the National Health Insurance Research Database provided by the Central Bureau of National Health Insurance, the Department of Health, and managed by the National Health Research Institutes. Due that this study is based in part on data from the National Health Insurance Research Database, the interpretation and conclusions contained herein do not represent those of National Health Insurance Administration, Ministry of Health and Welfare or National Health Research Institutes.

Citation: Tsai C-S, Chen VC-H, Yang Y-H, Hung T-H, Lu M-L, Huang K-Y, et al. (2017) The association between Mycoplasma pneumoniae infection and speech and language impairment: A nationwide population-based study in Taiwan. PLoS ONE 12(7): e0180402. https://doi.org/10.1371/journal.pone.0180402

References

1. Foy HM, Kenny GE, McMahan R, Mansy AM, Grayston JT. Mycoplasma pneumoniae pneumonia in an urban area. Five years of surveillance. JAMA. 1970;214(9):1666–72. pmid:5536528.

2. Mansel JK, Rosenow EC 3rd, Smith TF, Martin JW Jr. Mycoplasma pneumoniae pneumonia. Chest. 1989;95(3):639–46. pmid:2646077.

3. Chaudhry R, Ghosh A, Chandolia A. Pathogenesis of Mycoplasma pneumoniae: An update. Indian J Med Microbiol. 2016;34(1):7–16. pmid:26776112.

4. Koskiniemi M. CNS manifestations associated with Mycoplasma pneumoniae infections: summary of cases at the University of Helsinki and review. Clin Infect Dis. 1993;17 Suppl 1:S52–7. pmid:8399938.

5. Tsiodras S, Kelesidis I, Kelesidis T, Stamboulis E, Giamarellou H. Central nervous system manifestations of Mycoplasma pneumoniae infections. J Infect. 2005;51(5):343–54. pmid:16181677.

6. Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev. 2004;17(4):697–728, table of contents. pmid:15489344;

7. Yimenicioglu S, Yakut A, Ekici A, Bora Carman K, Cagri Dinleyici E. Mycoplasma pneumoniae infection with neurologic complications. Iran J Pediatr. 2014;24(5):647–51. pmid:25793076;

8. Lin WC, Lee PI, Lu CY, Hsieh YC, Lai HP, Lee CY, et al. Mycoplasma pneumoniae encephalitis in childhood. J Microbiol Immunol Infect. 2002;35(3):173–8. pmid:12380790.

9. Socan M, Ravnik I, Bencina D, Dovc P, Zakotnik B, Jazbec J. Neurological symptoms in patients whose cerebrospinal fluid is culture- and/or polymerase chain reaction-positive for Mycoplasma pneumoniae. Clin Infect Dis. 2001;32(2):E31–5. pmid:11170938.

10. Fernald GW, Collier AM, Clyde WA Jr. Respiratory infections due to Mycoplasma pneumoniae in infants and children. Pediatrics. 1975;55(3):327–35. pmid:1143973.

11. Foy HM, Kenny GE, Cooney MK, Allan ID. Long-term epidemiology of infections with Mycoplasma pneumoniae. J Infect Dis. 1979;139(6):681–7. pmid:448195.

12. Kammer J, Ziesing S, Davila LA, Bultmann E, Illsinger S, Das AM, et al. Neurological Manifestations of Mycoplasma pneumoniae Infection in Hospitalized Children and Their Long-Term Follow-Up. Neuropediatrics. 2016;47(5):308–17. pmid:27299367.

13. Bitnun A, Ford-Jones EL, Petric M, MacGregor D, Heurter H, Nelson S, et al. Acute childhood encephalitis and Mycoplasma pneumoniae. Clin Infect Dis. 2001;32(12):1674–84. pmid:11360206.

14. Roses-Noguer F, Raspall-Chaure M, Macaya-Ruiz A, del Toro-Riera M, Vazquez-Mendez E, Roig-Quilis M. [Cerebellar atrophy following acute Mycoplasma pneumoniae cerebellitis]. Rev Neurol. 2006;42(8):466–70. pmid:16625508.

15. Ashtekar CS, Jaspan T, Thomas D, Weston V, Gayatri NA, Whitehouse WP. Acute bilateral thalamic necrosis in a child with Mycoplasma pneumoniae. Dev Med Child Neurol. 2003;45(9):634–7. pmid:12948332.

16. Chen CY, Liu CY, Su WC, Huang SL, Lin KM. Factors associated with the diagnosis of neurodevelopmental disorders: a population-based longitudinal study. Pediatrics. 2007;119(2):e435–43. pmid:17272605.

17. Tsai CJ, Loh el W, Lin CH, Yu TM, Chan CH, Lan TH. Correlation of antidepressive agents and the mortality of end-stage renal disease. Nephrology (Carlton). 2012;17(4):390–7. pmid:22260522.

18. NHIRD. National Health Insurance Research Database, Taiwan. http://nhird.nhri.org.tw/en/index.htm.

19. Waites KB. New concepts of Mycoplasma pneumoniae infections in children. Pediatr Pulmonol. 2003;36(4):267–78. pmid:12950038.

20. Bebear CM. [Pathogenesis and laboratory diagnosis of Mycoplasma pneumoniae infections]. Arch Pediatr. 2008;15(7):1253–6. pmid:18406582.

21. Ma YJ, Wang SM, Cho YH, Shen CF, Liu CC, Chi H, et al. Clinical and epidemiological characteristics in children with community-acquired mycoplasma pneumonia in Taiwan: A nationwide surveillance. J Microbiol Immunol Infect. 2015;48(6):632–8. pmid:25311405.

22. Yeh JJ, Wang YC, Hsu WH, Kao CH. Incident asthma and Mycoplasma pneumoniae: A nationwide cohort study. J Allergy Clin Immunol. 2015. pmid:26586037.

23. Prathanee B, Thinkhamrop B, Dechongkit S. Factors associated with specific language impairment and later language development during early life: a literature review. Clin Pediatr (Phila). 2007;46(1):22–9. pmid:17164505.

24. Harrison LJ, McLeod S. Risk and protective factors associated with speech and language impairment in a nationally representative sample of 4- to 5-year-old children. J Speech Lang Hear Res. 2010;53(2):508–29. pmid:19786704.

25. Buschmann A, Jooss B, Rupp A, Dockter S, Blaschtikowitz H, Heggen I, et al. Children with developmental language delay at 24 months of age: results of a diagnostic work-up. Dev Med Child Neurol. 2008;50(3):223–9. pmid:18266869.

26. Gurgel LG, Vidor DC, Joly MC, Reppold CT. Risk factors for proper oral language development in children: a systematic literature review. Codas. 2014;26(5):350–6. pmid:25388066.

27. Goertzen SM. Speech and the mentally retarded child. Am J Ment Defic. 1957;62(2):244–53. pmid:13458222.

28. Nordberg A, Miniscalco C, Lohmander A. Consonant production and overall speech characteristics in school-aged children with cerebral palsy and speech impairment. Int J Speech Lang Pathol. 2014;16(4):386–95. pmid:24910255.

29. Korrel H, Mueller KL, Silk T, Anderson V, Sciberras E. Research Review: Language problems in children with Attention-Deficit Hyperactivity Disorder—a systematic meta-analytic review. J Child Psychol Psychiatry. 2017. pmid:28186338.

30. Paradise JL, Dollaghan CA, Campbell TF, Feldman HM, Bernard BS, Colborn DK, et al. Language, speech sound production, and cognition in three-year-old children in relation to otitis media in their first three years of life. Pediatrics. 2000;105(5):1119–30. pmid:10790473.

31. Mody M, Schwartz RG, Gravel JS, Ruben RJ. Speech perception and verbal memory in children with and without histories of otitis media. J Speech Lang Hear Res. 1999;42(5):1069–79. pmid:10515506.

32. Marini A, Galetto V, Zampieri E, Vorano L, Zettin M, Carlomagno S. Narrative language in traumatic brain injury. Neuropsychologia. 2011;49(10):2904–10. pmid:21723304.

33. Stanton-Chapman TL, Chapman DA, Bainbridge NL, Scott KG. Identification of early risk factors for language impairment. Res Dev Disabil. 2002;23(6):390–405. pmid:12426008.

34. Horwitz SM, Irwin JR, Briggs-Gowan MJ, Bosson Heenan JM, Mendoza J, Carter AS. Language delay in a community cohort of young children. J Am Acad Child Adolesc Psychiatry. 2003;42(8):932–40. pmid:12874495.

35. Fox AV, Dodd B, Howard D. Risk factors for speech disorders in children. Int J Lang Commun Disord. 2002;37(2):117–31. pmid:12012611.

36. Hauner KK, Shriberg LD, Kwiatkowski J, Allen CT. A subtype of speech delay associated with developmental psychosocial involvement. J Speech Lang Hear Res. 2005;48(3):635–50. pmid:16197278.

37. Spitz RV, Tallal P, Flax J, Benasich AA. Look who's talking: a prospective study of familial transmission of language impairments. J Speech Lang Hear Res. 1997;40(5):990–1001. pmid:9328871.

38. Rice ML, Haney KR, Wexler K. Family histories of children with SLI who show extended optional infinitives. J Speech Lang Hear Res. 1998;41(2):419–32. pmid:9570593.

39. Dollaghan CA, Campbell TF, Paradise JL, Feldman HM, Janosky JE, Pitcairn DN, et al. Maternal education and measures of early speech and language. J Speech Lang Hear Res. 1999;42(6):1432–43. pmid:10599625.

40. Weindrich D, Jennen-Steinmetz C, Laucht M, Esser G, Schmidt MH. Epidemiology and prognosis of specific disorders of language and scholastic skills. Eur Child Adolesc Psychiatry. 2000;9(3):186–94. pmid:11095041.

41. Zubrick SR, Taylor CL, Rice ML, Slegers DW. Late language emergence at 24 months: an epidemiological study of prevalence, predictors, and covariates. J Speech Lang Hear Res. 2007;50(6):1562–92. pmid:18055773;

42. Reilly S, Wake M, Bavin EL, Prior M, Williams J, Bretherton L, et al. Predicting language at 2 years of age: a prospective community study. Pediatrics. 2007;120(6):e1441–9. pmid:18055662.

43. Reilly S, Eadie P, Bavin EL, Wake M, Prior M, Williams J, et al. Growth of infant communication between 8 and 12 months: a population study. J Paediatr Child Health. 2006;42(12):764–70. pmid:17096710.

44. Guleria R, Nisar N, Chawla TC, Biswas NR. Mycoplasma pneumoniae and central nervous system complications: a review. J Lab Clin Med. 2005;146(2):55–63. pmid:16099235.

45. Nishimura M, Saida T, Kuroki S, Kawabata T, Obayashi H, Saida K, et al. Post-infectious encephalitis with anti-galactocerebroside antibody subsequent to Mycoplasma pneumoniae infection. J Neurol Sci. 1996;140(1–2):91–5. pmid:8866432.

46. Fernandez CV, Bortolussi R, Gordon K, Lee SH, Gatien JG, Shahdrabadi MS. Mycoplasma pneumoniae infection associated with central nervous system complications. J Child Neurol. 1993;8(1):27–31. pmid:8445168.

47. Biberfeld G. Antibodies to brain and other tissues in cases of Mycoplasma pneumoniae infection. Clin Exp Immunol. 1971;8(2):319–33. pmid:4995565;

48. Lind K. Manifestations and complications of Mycoplasma pneumoniae disease: a review. Yale J Biol Med. 1983;56(5–6):461–8. pmid:6433567;

49. Lind K, Hoier-Madsen M, Wiik A. Autoantibodies to the mitotic spindle apparatus in Mycoplasma pneumoniae disease. Infect Immun. 1988;56(3):714–5. pmid:3277919;

50. Cimolai N. Mycoplasma pneumoniae. Arch Dis Child. 1994;71(3):281. pmid:7979510;

51. Behan PO, Feldman RG, Segerra JM, Draper IT. Neurological aspects of mycoplasmal infection. Acta Neurol Scand. 1986;74(4):314–22. pmid:2949478.

52. Mulder LJ, Spierings EL. Stroke in a young adult with Mycoplasma pneumoniae infection complicated by intravascular coagulation. Neurology. 1987;37(8):1430–1. pmid:3614676.

53. Fu M, Wong KS, Lam WW, Wong GW. Middle cerebral artery occlusion after recent Mycoplasma pneumoniae infection. J Neurol Sci. 1998;157(1):113–5. pmid:9600687.

54. Yeoh C, Davies H. Clinical coding: completeness and accuracy when doctors take it on. BMJ. 1993;306(6883):972. pmid:8490474;