Skip to content

Advertisement

  • Research
  • Open Access

Infection with Trichomonas vaginalis increases the risk of psychiatric disorders in women: a nationwide population-based cohort study

Parasites & Vectors201912:88

https://doi.org/10.1186/s13071-019-3350-x

  • Received: 12 October 2018
  • Accepted: 26 February 2019
  • Published:

Abstract

Background

Trichomonas vaginalis is a protozoan parasite that causes trichomoniasis and annually infects approximately 276 million people worldwide. We observed an ambiguously higher probability of trichomoniasis in patients from the psychiatric department of Tri-Service General Hospital. Herein, we aimed to investigate the association between trichomoniasis and the risk of developing psychiatric disorders.

Methods

The nationwide population-based study utilized the database of the National Health Insurance (NHI) programme in Taiwan. A total of 46,865 subjects were enrolled in this study from 2000–2013, comprising 9373 study subjects with trichomoniasis and 37,492 subjects without trichomoniasis as the control group. Cox proportional hazards regression analysis was performed to calculate the hazard ratio (HR) of psychiatric disorders during the 14 years of follow-up.

Results

Of the study subjects with trichomoniasis, 875 (9.34%) developed psychiatric disorders compared with 1988 (5.30%) in the control group (P < 0.001). The adjusted hazard ratio (aHR) of overall psychiatric disorders in the study subjects was 1.644 (95% confidence interval, CI: 1.514–1.766; P < 0.001). More specifically, the study subjects had a higher risk for developing an individual psychiatric disorder, including depression, anxiety, bipolar disorder, schizophrenia and substance abuse. Although metronidazole treatment reduced the risk for developing several subgroups of psychiatric disorders, significant reduction was detected for depression only. Furthermore, refractory trichomoniasis (trichomoniasis visits ≥ 2) enhanced the risk of psychiatric disorders.

Conclusions

We show herein that T. vaginalis infection increases the overall risk for psychiatric disorders. The novel role of T. vaginalis in developing psychiatric disorders deserves more attention, and the control of such a neglected pathogen is of urgent public health importance.

Keywords

  • Trichomonas vaginalis
  • Neglected tropical diseases
  • Psychiatric disorders

Background

Human trichomoniasis, caused by Trichomonas vaginalis, is the most widespread non-viral sexually transmitted infection, with approximately 276 million cases reported annually worldwide [1]. Trichomonas vaginalis infects both women and men, although 89% of trichomoniasis patients are women as a result of their higher occurrence of symptoms [2]. Men are often asymptomatic carriers of T. vaginalis infection, although dysuria, discharge and increased risk of infertility and prostate cancer have been reported [3]. Infected women may develop vaginitis, urethritis and cervicitis, potentially leading to serious health outcomes, such as infertility, preterm delivery, low-birth-weight infants, susceptibility to herpes simplex virus and human papillomavirus infection, and cervical cancer [4]. Trichomoniasis has been associated with an increased risk of human immunodeficiency virus (HIV) transmission [5].

In addition to the symptoms and signs, direct microscopic examination, including the wet mount test and Pap smear test, and traditional culture are the most common diagnostic methods for T. vaginalis infection. Moreover, rapid antigen detection and nucleic acid amplification test are also used for T. vaginalis diagnosis [6].

Current treatments for trichomoniasis include a single oral dose of metronidazole (MTZ; 2 g), a single oral dose of tinidazole (2 g), or a 7-day oral course of MTZ (500 mg twice daily) [7]. The prevalence of trichomoniasis varies among different subpopulations, ranging from 5.4% in family planning clinics and 17.3% in patients presenting to sexually transmitted disease clinics, to 32% among incarcerated women [8, 9]. The prevalence of T. vaginalis in women with recurrent urinary tract infections in Taiwan was 16.9% [10]. However, no large-scale epidemiological study of trichomoniasis in Taiwan has been conducted. Hence, it is necessary to understand the prevalence of trichomoniasis for women in Taiwan to improve their sexual and reproductive health.

Psychiatric disorders, also called mental disorders, are defined as clinically significant behavioral or psychological syndromes, with a high level of individual distress, anxiety and premature mortality [11]. In the USA, the regional disease burden attributable to mental disorders, neurological disorders, substance use disorders and self-harm comprises 19% of total disability-adjusted life-years and 34% of total years lived with disability in 2015 [12]. Mental health problems thereby represent important public health challenges worldwide. There is a growing interest in the role of microbes, such as viruses and protozoan parasites, in some psychiatric disorders [1315]. For instance, several studies have shown impaired cognitive functions among individuals with schizophrenia exposed to neurotropic herpes simplex virus type 1 [16]. Additionally, it has been reported that prenatal maternal exposure to influenza, rubella, genital-reproductive infections and other pathogens are associated with schizophrenia and autism [17, 18]. The protozoan parasite Toxoplasma gondii is an extensively studied candidate that is associated with various psychiatric disorders, such as schizophrenia [19, 20]. Having a neurotropic nature and brain-damaging characteristic, T. gondii is a potential causative agent for mental and behavioral disorders [14]. However, there is limited evidence for the association of other protists and psychiatric disorders, especially those whose colonization sites are not directly linked to the central nervous system.

Recently, we observed an unexpected trend that trichomoniasis patients were accompanied by some psychiatric disorders in the Tri-Service General Hospital, raising the possibility that there is an association between T. vaginalis infection and the risk of psychiatric disorders. Hence, we conducted a nationwide population-based cohort study to verify whether T. vaginalis infection may lead to psychiatric disorders. Our findings underscore the potential risk of T. vaginalis for developing psychiatric disorders, providing a novel and clinically important role of this neglected protozoan parasite.

Methods

Data sources

The National Health Insurance (NHI) programme began in Taiwan in 1995 and covers more than 99% of entire population, with approximately 23 million beneficiaries [21]. The data were collected from the NHI Research Database (NHIRD) of Taiwan. The NHRID uses the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to record diagnoses [22]. A subset of the NHIRD, the Longitudinal Health Insurance Database 2000 (LHID 2000), was utilized to investigate the association between trichomoniasis and psychiatric disorders. The LHID 2000 provided a million individuals randomly selected from the entire NHI enrollee population in the year 2000. The ICD-9-CM codes of trichomoniasis-related diagnoses were included in the study group, such as trichomonal vulvovaginitis (ICD-9-CM 131.01), trichomonal urethritis (ICD-9-CM 131.02), other urogenital trichomoniasis (ICD-9-CM 131.09), trichomoniasis of other specified sites (ICD-9-CM 131.8) and unspecified trichomoniasis (ICD-9-CM 131.9). Detailed information of the ICD-9-CM codes used in this study is provided in Additional file 1: Table S1.

Study design and population

The patients newly diagnosed with trichomoniasis were selected from the LHID 2000 from 1st January 2000 to 31st December 2013. The following criteria were excluded: (i) patients with trichomoniasis before the index date; (ii) patients with psychiatric disorders before tracking; (iii) patients younger than 18 years of age; and (iv) gender is male or unknown. Ultimately, a total of 9373 subjects with trichomoniasis were included in the study group. The non-trichomoniasis control group (37,492 individuals) was established by matching the age and index year with a 4-fold ratio to the study group.

Covariates

We examined the sociodemographic factors in the study and control groups, including age, monthly income, season, place of residence, urbanization level and hospital level. The patients were classified into three groups based on age: 18–44 years; 45–64 years; and ≥ 65 years. The monthly income in New Taiwan Dollars (NTD) was divided into three groups: <18,000; 18,000–34,999; and ≥35,000. Four seasons (spring, summer, autumn and winter) were considered. The patients living in different areas of Taiwan, including northern, middle, southern, and eastern Taiwan, as well as the outlets islands were compared. The patients were categorized into four urbanization levels from the highest (1) to the lowest (4). Three levels for hospitals where the patients sought medical attention were considered: medical centers; regional hospitals; and local hospitals.

Main outcome measures

All study participants were followed from the index date until the onset of all recorded psychiatric disorders in the NHIRD. The incidences and risk of each individual psychiatric disorder, including depression, anxiety, bipolar disorder, schizophrenia and substance abuse, were compared between the study group and the control group. The incidences and risk for overall and subgroups of psychiatric disorders in the trichomoniasis patients treated with MTZ were compared with the untreated trichomoniasis patients and the non-trichomoniasis group.

Statistical analysis

All statistical analyses were performed using SPSS software v.22.0 (SPSS, Chicago, IL, USA). A Chi-square test was used to analyze the categorical variables. Fisher’s exact test was used to evaluate the differences between the study and control groups. Differences in the risk of psychiatric disorders in the study and control groups were evaluated using the Kaplan-Meier method with a log-rank test and presented as a survival curve. Cox proportional hazards regression analysis was used to determine the risk of psychiatric disorder, and the data were expressed as aHR with a 95% confidence interval (CI).

Results

Demographic characteristics of the study population at the baseline and endpoint

Based on propensity score matching (the ratio of the study population to the control population was 1:4), there were 9373 individuals with trichomoniasis in the study group and 37,492 individuals without trichomoniasis in the control group (Fig. 1). The demographic characteristics of the study and control populations at the baseline are described in Table 1. There was no significant difference in age between the control and study groups (42.06 ± 16.09 vs 42.09 ± 16.71). The percentage of the population whose monthly income less than NTD $18,000 in the study group was significantly higher than the control group (98.13 vs 88.15%; P < 0.001). Compared with the control population, the study population had more medical visits in summer (26.51 vs 23.95%; P < 0.001), with a higher proportion of patients living in eastern Taiwan (14.04 vs 4.35%; P < 0.001). Regarding the medical care system, more patients with trichomoniasis sought medical help in regional hospitals as compared to the non-trichomoniasis group (49.89 vs 29.59%; P < 0.001). The demographic characteristics of the study and control populations at the tracking endpoint are described in Additional file 2: Table S2. Except the difference in age between the study and control groups (45.49 ± 19.64 vs 46.85 ± 17.85; t-test, P < 0.001), all the trends of characteristics between trichomoniasis subjects and non-trichomoniasis subjects were similar to those observed at the baseline.
Fig. 1
Fig. 1

Flowchart of study and control subject’s collection from the Longitudinal Health Insurance Database, a subset of the National Health Insurance Research Database (NHIRD) of Taiwan. The subjects were tracked from 2000 to 2013

Table 1

Demographic characteristics of the study and control populations at the baseline

Characteristic

Total

With

Without

P-valuea

n

%

n

%

n

%

Total

46,865

 

9373

20.00

37,492

80.00

 

Age (years)

42.08 ± 16.59

42.06 ± 16.09

42.09 ± 16.71

0.889

Age group (years)

      

0.999

 18–44

28,350

60.49

5670

60.49

22,680

60.49

 

 45–64

13,615

29.05

2723

29.05

10,892

29.05

 

 ≥ 65

4900

10.46

980

10.46

3920

10.46

 

Insured premium (NT$)

      

<0.001

 < 18,000

42,248

90.15

9198

98.13

33,050

88.15

 

 18,000–34,999

3221

6.87

154

1.64

3067

8.18

 

 ≥ 35,000

1396

2.98

21

0.22

1375

3.67

 

CCI

0.48 ± 1.40

0.61 ± 1.46

0.45 ± 1.39

<0.001

Season

      

<0.001

 Spring (March-May)

12,194

26.02

2380

25.39

9814

26.18

 

 Summer (June-August)

11,466

24.47

2485

26.51

8981

23.95

 

 Autumn (September-November)

11,242

23.99

2212

23.60

9030

24.09

 

 Winter (December-February)

11,963

25.53

2296

24.50

9667

25.78

 

Location

      

<0.001

 Northern Taiwan

18,550

39.58

3241

34.58

15,309

40.83

 

 Middle Taiwan

13,405

28.60

2478

26.44

10,927

29.14

 

 Southern Taiwan

11,774

25.12

2331

24.87

9443

25.19

 

 Eastern Taiwan

2947

6.29

1316

14.04

1631

4.35

 

 Outlets islands

189

0.40

7

0.07

182

0.49

 

Urbanization level

      

<0.001

 1 (The highest)

16,142

34.44

2345

25.02

13,797

36.80

 

 2

20,160

43.02

4746

50.63

15,414

41.11

 

 3

3815

8.14

630

6.72

3185

8.50

 

 4 (The lowest)

6748

14.40

1652

17.63

5096

13.59

 

Level of care

      

<0.001

 Hospital center

14,329

30.58

2863

30.55

11,466

30.58

 

 Regional hospital

15,771

33.65

4676

49.89

11,095

29.59

 

 Local hospital

16,765

35.77

1834

19.57

14,931

39.82

 

aChi-square/Fisher’s exact test on categorical variables and t-test on continuous variables

Abbreviation: CCI, Charlson comorbidity index

Association of trichomoniasis with psychiatric disorders

The incidences of psychiatric disorders were higher for study subjects with trichomoniasis (875 subjects, 9.34%) than control subjects (1988 subjects, 5.3%) (P < 0.001) (Table 2). Additionally, Kaplan-Meier analysis for the cumulative risk of psychiatric disorders during 14 years of follow-up showed a statistical difference in the study group compared with the control group (log-rank P < 0.001), and this difference began from the first year of tracking (Fig. 2). The medium duration from the diagnosis of T. vaginalis infection to the onset of overall psychiatric disorder was 2.17 years. Additionally, the medium duration from the diagnosis of T. vaginalis infection to the onset of individual psychiatric disorder ranged between 0.79–2.34 years (Additional file 3: Table S3). Furthermore, the incidences for the subgroups of the psychiatric disorders were significantly higher in the subjects with trichomoniasis than in the control group, including depression (3.96 vs 2.17%; P < 0.001), anxiety (3.14 vs 1.47%; P < 0.001), bipolar disorder (0.45 vs 0.28%; P = 0.011), schizophrenia (0.97 vs 0.39%; P < 0.001), substance abuse (0.9 vs 0.24%; P < 0.001) and other psychiatric disorders (0.82 vs 0.15%; P < 0.001). The risk of psychiatric disorders in subjects with trichomoniasis was analyzed by Cox regression and presented as adjusted hazard ratio (aHR), with reference to the non-trichomoniasis group (Table 3). The trichomoniasis patients showed a higher risk of overall psychiatric disorders, with an aHR of 1.644 (95% CI: 1.514–1.766; P < 0.001).
Table 2

Incidence of psychiatric disorders in the trichomoniasis patients compared with the control group

Variable

Total

With

Without

P-valuea

n

%

n

%

n

%

Total

46,865

 

9,373

20.00

37,492

80.00

 

Psychiatric disorders

      

<0.001

 Without

44,002

93.89

8498

90.66

35,504

94.70

 

 With

2863

6.11

875

9.34

1988

5.30

 

Depression

      

<0.001

 Without

45,682

97.48

9002

96.04

36,680

97.83

 

 With

1183

2.52

371

3.96

812

2.17

 

Anxiety

      

<0.001

 Without

46,018

98.19

9079

96.86

36,939

98.53

 

 With

847

1.81

294

3.14

553

1.47

 

Bipolar disorders

      

0.011

 Without

46,718

99.69

9331

99.55

37,387

99.72

 

 With

147

0.31

42

0.45

105

0.28

 

PTSD/ASD

      

0.375

 Without

46,816

99.90

9366

99.93

37,450

99.89

 

 With

49

0.10

7

0.07

42

0.11

 

Schizophrenia

      

<0.001

 Without

46,627

99.49

9282

99.03

37,345

99.61

 

 With

238

0.51

91

0.97

147

0.39

 

Substance abuse

      

<0.001

 Without

46,690

99.63

9289

99.10

37,401

99.76

 

 With

175

0.37

84

0.90

91

0.24

 

Other psychiatric disorders

      

<0.001

 Without

46,732

99.72

9296

99.18

37,436

99.85

 

 With

133

0.28

77

0.82

56

0.15

 

aChi-square/Fisher’s exact test on categorical variables and t-test on continuous variables

Abbreviation: PTSD, post-traumatic stress disorder; ASD, acute stress disorder

Fig. 2
Fig. 2

Kaplan-Meier curves for cumulative risk of psychiatric disorders stratified by trichomoniasis with the log-rank test. The numbers of psychiatric disorders in the patients with trichomoniasis and the non-trichomoniasis group are shown during the 14 years of follow-up

Table 3

Risk of psychiatric disorders in the trichomoniasis subjects identified by using Cox regression

Variable

Adjusted HR

95% CI

P-value

Without trichomoniasis

Reference

  

With trichomoniasis

1.644

1.514–1.766

<0.001

Abbreviations: Adjusted HR, adjusted hazard ratio (adjusted for the variables listed in Table 1); CI, confidence interval

Risk of psychiatric disorders in the trichomoniasis group stratified by covariates

The risk of psychiatric disorders in the trichomoniasis group stratified by variables was further evaluated (Table 4). Except for level of medical care, almost all study subjects kept the higher risk of developing psychiatric disorders irrespective of being stratified by independent variables. Specifically, the trichomoniasis patients stratified by the different age groups revealed that the subjects aged 45–64 years had the highest risk (aHR = 2.637; P < 0.001) compared with the non-trichomoniasis control. Additionally, study subjects which had a monthly income of less than NTD $18,000 (aHR = 1.669; P < 0.001) were associated with a higher risk of psychiatric disorders. Furthermore, patients with the lowest urbanization level (level 4) (aHR = 3.814; P < 0.001) had a markedly increased risk of psychiatric disorders.
Table 4

Risk of psychiatric disorders in the trichomoniasis subjects stratified by variables using Cox regression

Stratified

With vs without trichomoniasis

Adjusted HR

95% CI

P-value

Total

1.644

1.514–1.766

<0.001

Age group (years)

 18–44

1.155

1.017–1.312

0.027

 45–64

2.637

2.325–2.991

<0.001

 ≥ 65

0.923

0.696–1.224

0.577

Insured premium (NT$)

 < 18,000

1.669

1.536–1.813

<0.001

 18,000–34,999

0.000

 

0.937

 ≥ 35,000

0.000

 

0.986

Season

 Spring

1.551

1.307–1.841

<0.001

 Summer

2.309

2.010–2.651

<0.001

 Autumn

1.110

0.906–1.360

0.314

 Winter

1.428

1.195–1.706

<0.001

Urbanization level

 1 (the highest)

1.803

1.596–2.037

<0.001

 2

1.428

1.209–1.688

<0.001

 3

1.291

1.074–1.552

0.007

 4 (the lowest)

3.814

2.752–5.285

<0.001

Level of care

 Hospital center

1.479

1.315–1.664

<0.001

 Regional hospital

1.594

1.354–1.877

<0.001

 Local hospital

2.011

1.693–2.389

<0.001

Abbreviations: Adjusted HR, adjusted hazard ratio (adjusted for the variables listed in Table 1); CI, confidence interval; NT$, New Taiwan Dollars

Reduced risk for the subgroups of psychiatric disorders in the trichomoniasis subjects following MTZ treatment

The risk of the main subgroups of psychiatric disorders in trichomoniasis patients was examined (Table 5). Compared with the non-trichomoniasis group, trichomoniasis subjects had a higher risk of substance abuse (aHR = 2.794; 95% CI: 2.035–3.834; P < 0.001), anxiety (aHR = 2.011; 95% CI: 1.738–2.327; P < 0.001), schizophrenia (aHR = 1.981; 95% CI: 1.495–2.624; P < 0.001), bipolar disorders (aHR = 1.784; 95% CI: 1.241–2.565; P < 0.001) and depression (aHR = 1.675; 95% CI: 1.474–1.904; P < 0.001). There was no statistical significance in the risk of post-traumatic stress disorder or acute stress disorder (PTSD/ASD) and other psychiatric disorders between the trichomoniasis and non-trichomoniasis groups.
Table 5

Risk of psychiatric disorders subgroup in the trichomoniasis patients treated with MTZ identified by using Cox regression

Psychiatric disorder subgroup

Trichomoniasis and metronidazole (MTZ)

Competing risk in the model

Population

Event

Adjusted HR

95% CI

P

Adjusted HR

95% CI

P

Adjusted HR

95% CI

P

Overall

Without trichomoniasis

37,492

198

Ref.

  

Ref.

     

With trichomoniasis

9373

875

1.644

1.514–1.766

<0.001

      

 With trichomoniasis, without MTZ

6433

630

   

1.732

1.577–1.902

<0.001

Ref.

  

 With trichomoniasis, with MTZ

2940

245

   

1.458

1.271–1.672

<0.001

0.876

0.739–1.039

0.128

Depression

Without trichomoniasis

37,492

812

Ref.

  

Ref.

     

 With trichomoniasis

9373

371

1.675

1.474–1.904

<0.001

      

 With trichomoniasis, without MTZ

6433

266

   

1.865

1.613–2.156

<0.001

Ref.

  

With trichomoniasis, with MTZ

2940

105

   

1.335

1.083–1.647

0.007

0.639

0.493–0.829

0.001

Anxiety

Without trichomoniasis

37,492

553

Ref.

  

Ref.

     

With trichomoniasis

9373

294

2.011

1.738–2.327

<0.001

      

 With trichomoniasis, without MTZ

6433

231

   

2.120

1.807–2.486

<0.001

Ref.

  

 With trichomoniasis, with MTZ

2940

63

   

1.701

1.301–2.222

<0.001

0.948

0.692–1.300

0.741

Bipolar disorder

Without trichomoniasis

37,492

105

Ref.

  

Ref.

     

With trichomoniasis

9373

42

1.784

1.241–2.565

0.002

      

 With trichomoniasis, without MTZ

6433

35

   

2.219

1.497–3.287

<0.001

Ref.

  

 With trichomoniasis, with MTZ

2940

7

   

0.908

0.418–1.972

0.807

0.481

0.207–1.118

0.089

PTSD/ASD

Without trichomoniasis

37,492

42

Ref.

  

Ref.

     

With trichomoniasis

9373

7

0.792

0.354–1.772

0.570

      

 With trichomoniasis, without MTZ

6433

7

   

1.015

0.450–2.288

0.972

Ref.

  

 With trichomoniasis, with MTZ

2940

0

   

0.0001

0.963

0.0001

0.971

Schizophrenia

Without trichomoniasis

37,492

147

Ref.

  

Ref.

     

With trichomoniasis

9373

91

1.981

1.495–2.624

<0.001

      

 With trichomoniasis, without MTZ

6433

70

   

2.315

1.699–3.156

<0.001

Ref.

  

 With trichomoniasis, with MTZ

2940

21

   

1.352

0.838–2.180

0.216

0.690

0.385–1.237

0.212

Substance abuse

Without trichomoniasis

37,492

91

Ref.

  

Ref.

     

With trichomoniasis

9373

84

2.794

2.035–3.834

<0.001

      

 With trichomoniasis, without MTZ

6433

56

   

2.97

2.073–4.256

<0.001

Ref.

  

 With trichomoniasis, with MTZ

2940

28

   

2.516

1.615–3.919

<0.001

0.978

0.428–2.686

0.057

Other psychiatric disorders

Without trichomoniasis

37,492

56

Ref.

  

Ref.

     

With trichomoniasis

9373

77

1.098

0.872–1.211

0.184

      

 With trichomoniasis, without MTZ

6433

49

   

1.012

0.642–1.19

0.872

Ref.

  

 With trichomoniasis, with MTZ

2940

28

   

1.584

1.104–1.984

0.001

1.971

1.169–3.322

0.011

Abbreviations: MTZ, metronidazole; Adjusted HR, adjusted hazard ratio (adjusted for the variables listed in Table 1); CI, confidence interval; PTSD, post-traumatic stress disorder; ASD, acute stress disorder; Ref., reference

The risk for the subgroups of psychiatric disorders in the trichomoniasis subjects treated with MTZ was examined compared with the non-trichomoniasis group and the trichomoniasis subjects without MTZ treatment (Table 5). The trichomoniasis subjects treated with MTZ had a lower risk of developing bipolar disorder and schizophrenia than the trichomoniasis subjects without MTZ treatment, with aHRs of 0.908 (95% CI: 0.418–1.972; P = 0.807) and 1.352 (95% CI: 0.838–2.180; P = 0.216), respectively, with no statistical difference between the MTZ-treated group and the non-trichomoniasis control. Although MTZ treatment had a lower risk for developing several subgroups of psychiatric disorders with reference to the untreated trichomoniasis subjects, significant reduction was detected for depression only (aHR = 0.639; 95% CI: 0.493–0.829; P = 0.001).

Increased risk of psychiatric disorders in subjects with refractory trichomoniasis

It is estimated that approximately 5–10% of trichomoniasis patients display resistance to drug treatment [23, 24]. We also evaluated the risk for psychiatric disorders in the trichomoniasis subjects who sought medical help more than once (Table 6). Compared with the non-trichomoniasis group, the risk for overall psychiatric disorders in subjects with trichomoniasis was proportional to the number of medical visits. Except for bipolar disorder and PTSD/ASD, refractory trichomoniasis patients (trichomoniasis visits ≥2) had a higher risk for the other psychiatric disorders (P < 0.001) compared with the patients who sought medical help only once.
Table 6

Risk of psychiatric disorders subgroup among study population and trichomoniasis cohort identified by using Cox regression

Psychiatric disorders subgroup

Trichomoniasis visits

Study population

Trichomoniasis cohort

Population

Event

Adjusted HR

95% CI

P

Adjusted HR

95% CI

P

Overall

0 (without trichomoniasis)

37,492

1988

Ref.

     

1 trichomoniasis visit

9051

809

2.560

2.353–2.784

<0.001

Ref.

  

≥ 2 trichomoniasis visits

322

66

7.676

5.953–9.898

<0.001

2.664

2.047–3.467

<0.001

Depression

0

37,492

812

Ref.

     

1

9051

341

2.712

2.381–3.089

<0.001

Ref.

  

≥ 2

322

30

8.306

5.667–12.173

<0.001

2.594

1.741–3.866

<0.001

Anxiety

0

37,492

553

Ref.

     

1

9051

271

2.975

2.562–3.454

<0.001

Ref.

  

≥ 2

322

23

10.674

6.853–16.623

<0.001

3.472

2.199–5.482

<0.001

Bipolar disorder

0

37,492

105

Ref.

     

1

9051

42

2.679

1.854–3.873

<0.001

Ref.

  

≥ 2

322

0

0.000

0.968

<0.0001

0.972

PTSD/ASD

0

37,492

42

Ref.

     

1

9051

7

1.013

0.456–2.298

0.978

Ref.

  

≥ 2

322

0

0.000

0.988

<0.0001

0.989

Schizophrenia

0

37,492

147

Ref.

     

1

9051

84

3.949

2.992–5.212

<0.001

Ref.

  

≥ 2

322

7

12.471

5.739–27.101

<0.001

2.806

1.260–6.247

0.012

Substance abuse

0

37,492

91

Ref.

     

1

9051

80

1.535

1.301–2.011

<0.001

Ref.

  

≥ 2

322

4

3.897

2.049–7.122

<0.001

3.286

1.870–5.864

<0.001

Other psychiatric disorders

0

37,492

56

Ref.

     

1

9051

66

1.862

1.503–2.188

<0.001

Ref.

  

≥ 2

322

11

5.897

3.402–9.864

<0.001

5.642

2.864–7.862

<0.001

Abbreviations: Adjusted HR, adjusted hazard ratio (adjusted for the variables listed in Table 1); CI, confidence interval; PTSD, post-traumatic stress disorder; ASD, acute stress disorder; Ref., reference

Association of trichomoniasis with other sexually transmitted infections

It has been shown that T. vaginalis infection was associated with other sexually transmitted infections (STIs), such as Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum and HIV [2527]. Our data indicated that 3.03% of the subjects with trichomoniasis were co-infected with N. gonorrhoeae or T. pallidum, 0.61% co-infected with N. gonorrhoeae or C. trachomatis, and 0.12% co-infected with T. pallidum or C. trachomatis (Additional file 4: Table S4). Combined analysis revealed that 13.99% of subjects with trichomoniasis were co-infected with one of these three common STIs (N. gonorrhoeae, T. pallidum or C. trachomatis). Additionally, a total of 12 trichomoniasis subjects were infected with HIV, whereas 4 non-trichomoniasis subjects were infected with HIV (Additional file 5: Table S5). Among the trichomoniasis subjects, 5 and 3 subjects were infected with HIV before and after the index date, respectively. For the non-trichomoniasis subjects, 1 and 2 cases were infected with HIV before and after the index date, respectively. All HIV-positive patients were treated.

Discussion

The trichomoniasis subjects enrolled in this study had a higher risk of overall psychiatric disorders, with an aHR of 1.644, as compared with the non-trichomoniasis control. This means that patients with trichomoniasis had a 1.644-fold increased risk for developing psychiatric disorders. The Kaplan-Meier analysis also supported the cumulative risk for psychiatric disorders in the trichomoniasis subjects during 14 years of follow-up (log-rank P < 0.001). More specifically, the trichomoniasis subjects had a significantly increased risk of depression, anxiety, bipolar disorder, schizophrenia and substance abuse. These results highlight the novel role of T. vaginalis in causing psychiatric disorders, and that clinicians should pay more attention to the possible risk resulting from this neglected tropical disease.

Previous studies have reported that some psychiatric disorders are associated with inflammatory diseases, such as periodontitis [28], psoriasis [29] and allergic diseases[30]. The underlying mechanism of this association is possibly due to the release of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-10, tumor necrosis factor alpha, and monocyte chemoattractant protein-1, which have been proved to be involved in the development of depression, anxiety and bipolar disorders. Trichomonas vaginalis infection has been shown to induce IL-8 secretion from primary human monocytes [31] and the symbiotic relationship with Mycoplasma hominis enables induction of an array of inflammatory cytokines in a macrophage cell line [32]. In addition to causing local inflammation, T. vaginalis also induces systemic immune response in infected pregnant women, resulting in higher concentrations of granulocyte-macrophage colony-stimulating factor and C-reactive protein in serum of patients [33]. Further investigation is needed to clarify whether the T. vaginalis-induced immune response plays a role in developing psychiatric disorders.

Another possibility is that a behavioral pathway may link T. vaginalis infection and the risk of psychiatric disorders. For instance, women with T. vaginalis infection might present many vaginal symptoms that may affect their sexual life. Their partners might be annoyed with the diagnoses which can complicate their sexual relationship. Therefore, these problems associated with difficulties in getting cured might increase anxiety and other common mental disorders. Additionally, it has been reported that there is an association between high-risk sexual behaviors and sexually transmitted diseases in patients with psychiatric disorders [34]. Thus, the higher T. vaginalis infection in psychiatric patients may alternatively have resulted from high-risk sexual behaviors of patients during their prodromal stage.

We found that trichomoniasis subjects aged 45–64 years had a higher risk of psychiatric disorders than those aged 18–44 years. Since the maximal follow-up time is 14 years, we proposed that a certain portion of the trichomoniasis population aged 18–44 years may not reach the age of onset for most major psychiatric disorders [35]. Another possible reason for this observation may be due to the menopausal transition, a period late in a woman’s reproductive life before the final menstruation, typically occurring between the ages of 40 and 55 years. Previous studies demonstrated that women with symptomatic menopausal transition may have a higher risk for developing subsequent psychiatric disorders, especially depression [36], anxiety [37] and bipolar disorder [38], thereby enhancing the risk in the trichomoniasis subjects.

Mental disorders contribute to 7% of the global burden of disease as estimated by disability adjusted life years in the world; this is rising, especially in low- and middle-income countries [39]. Low income has been demonstrated to be directly linked with psychiatric disorders [40]. Indeed, we have revealed that the trichomoniasis subjects with a monthly income less than NTD $18,000 were associated with a higher risk of psychiatric disorders.

Although MTZ treatment for the trichomoniasis patients had a lower risk for developing overall psychiatric disorders, the differences between the treated and untreated groups was not statistically significant. Specifically, MTZ treatment was remarkably associated with a decreased risk of bipolar disorder and schizophrenia, suggesting that T. vaginalis infection is closely related with these two psychiatric disorders. Additionally, MTZ treatment was associated with a lower risk for developing depression as compared with the untreated group. Based on these findings, it is likely that trichomoniasis may directly or indirectly involve the process of development for specific psychiatric disorders. Furthermore, increasing reports of failures in the treatment of trichomoniasis and the rising prevalence of MTZ-resistant T. vaginalis isolates have occurred [23, 41, 42]. Hence, the differences in treatment outcomes of patients due to drug resistance may also influence the risk for developing psychiatric disorders. Indeed, our further analysis of the trichomoniasis subjects who sought medical help more than once (≥ 2 times) had a higher risk for psychiatric disorders, which is likely caused by drug resistance. Our data revealed that 68.6% patients with trichomoniasis were not treated. A recent study in Belgium demonstrated that 58.1% of women repeatedly positive for T. vaginalis infection had received no treatment; this was attributed to low awareness, poor attention, and failure of contact tracing of physicians [43].

One of the major strengths of this study is its large-scale population-based nationwide design. Additionally, the long-term monitoring from 2000 to 2013 made the analysis more reliable. However, the study has several limitations. First, the diagnoses were made using ICD-9 codes recorded in the NHIRD, but this database does not contain all types of data, such as laboratory parameters and genetic factors, which may help to postulate the mechanisms mediating the development of psychiatric disorders in patients with trichomoniasis. Secondly, although men were not included in the study, they potentially transmit the infection to women through sexual behavior and affect the treatment outcomes for women. Hence, sexual partners have to be treated to enhance the treatment efficiency. Thirdly, T. vaginalis infection is largely neglected because of ineffective screening protocols and a lack of public health attention [44]. The exact number of patients with trichomoniasis must be higher than those who seek medical attention, and thereby the cases of psychiatric disorders resulted from T. vaginalis infection must be underestimated.

Conclusions

To our knowledge, we provide the first evidence that T. vaginalis infection is associated with the risk of overall psychiatric disorders. The potential role of trichomoniasis in the devolvement of psychiatric disorders will highlight its clinical importance and public health impact. Clinicians should pay more attention to this neglected pathogen, which not only results in urogenital symptoms, but also leads to psychiatric disorders, especially in patients with refractory trichomoniasis.

Abbreviations

aHR: 

adjusted hazard ratio

CI: 

confidence interval

HR: 

hazard ratio

HIV: 

human immunodeficiency virus

IL: 

interleukin

LHID 2000: 

Longitudinal Health Insurance Database 2000

MTZ: 

metronidazole

NHI: 

National Health Insurance

NHIRD: 

National Health Insurance Research Database

NTD: 

New Taiwan Dollars

PTSD: 

post-traumatic stress disorder

ASD: 

acute stress disorder

Declarations

Acknowledgements

We would like to thank the National Defense Medical Center team for support.

Funding

This work was supported by the Ministry of Science and Technology, Taiwan (MOST 107-2320-B-016-008-MY3) to KYH, Tri-Service General Hospital Songshan Branch, Taiwan (TSGHSB-C107-07) to HAL, and Tri-Service General Hospital, Taiwan (TSGH-C107-004; TSGH-C108-003) to WCC.

Availability of data and materials

Data supporting the conclusions of this article are included within the article and its additional files. The datasets used and/or analyzed during the present study will be made available by the corresponding author upon reasonable request.

Authors’ contributions

HCL, KYH, WCC and TSC conceived the idea and wrote the first draft manuscript. HAL and RMC contributed to the manuscript. CHC and CHT contributed to statistical analyses. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
(2)
Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
(3)
Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei, Taiwan
(4)
School of Public Health, National Defense Medical Center, Taipei, Taiwan
(5)
Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan
(6)
Division of Infection, Department of Medicine, Tri-Service General Hospital SongShan Branch, Taipei, Taiwan
(7)
Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
(8)
Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
(9)
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
(10)
Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan

References

  1. WHO. Global incidence and prevalence of selected curable sexually transmitted infection. Geneva: World Health Organization; 2012.Google Scholar
  2. Gratrix J, Plitt S, Turnbull L, Smyczek P, Brandley J, Scarrott R, et al. Trichomonas vaginalis prevalence and correlates in women and men attending STI clinics in western Canada. Sex Transm Dis. 2017;44:627–9.View ArticleGoogle Scholar
  3. Leitsch D. Recent advances in the Trichomonas vaginalis field. F1000Res. 2016;5:162.View ArticleGoogle Scholar
  4. Kissinger P. Trichomonas vaginalis: a review of epidemiologic, clinical and treatment issues. BMC Infect Dis. 2015;15:307.View ArticleGoogle Scholar
  5. Mukanyangezi MF, Sengpiel V, Manzi O, Tobin G, Rulisa S, Bienvenu E, et al. Screening for human papillomavirus, cervical cytological abnormalities and associated risk factors in HIV-positive and HIV-negative women in Rwanda. HIV Med. 2018;19:152–66.View ArticleGoogle Scholar
  6. Hobbs MM, Sena AC. Modern diagnosis of Trichomonas vaginalis infection. Sex Transm Infect. 2013;89:434–8.View ArticleGoogle Scholar
  7. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64:1–137.View ArticleGoogle Scholar
  8. Meites E. Trichomoniasis: the “neglected” sexually transmitted disease. Infect Dis Clin North Am. 2013;27:755–64.View ArticleGoogle Scholar
  9. Javanbakht M, Stirland A, Stahlman S, Smith LV, Chien M, Torres R, et al. Prevalence and factors associated with Trichomonas vaginalis infection among high-risk women in Los Angeles. Sex Transm Dis. 2013;40:804–7.View ArticleGoogle Scholar
  10. Chang PC, Hsu YC, Hsieh ML, Huang ST, Huang HC, Chen Y. A pilot study on Trichomonas vaginalis in women with recurrent urinary tract infections. Biomed J. 2016;39:289–94.View ArticleGoogle Scholar
  11. Stein DJ, Phillips KA, Bolton D, Fulford KW, Sadler JZ, Kendler KS. What is a mental/psychiatric disorder? From DSM-IV to DSM-V. Psychol Med. 2010;40:1759–65.View ArticleGoogle Scholar
  12. Vigo DV, Kestel D, Pendakur K, Thornicroft G, Atun R. Disease burden and government spending on mental, neurological, and substance use disorders, and self-harm: cross-sectional, ecological study of health system response in the Americas. Lancet Public Health. 2018;4:e89–96.View ArticleGoogle Scholar
  13. Coughlin SS. Anxiety and depression: linkages with viral diseases. Public Health Rev. 2012;34:92.PubMedPubMed CentralGoogle Scholar
  14. Fekadu A, Shibre T, Cleare AJ. Toxoplasmosis as a cause for behaviour disorders - overview of evidence and mechanisms. Folia Parasitol (Praha). 2010;57:105–13.View ArticleGoogle Scholar
  15. Idro R, Kakooza-Mwesige A, Asea B, Ssebyala K, Bangirana P, Opoka RO, et al. Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort. Malar J. 2016;15:184.View ArticleGoogle Scholar
  16. Prasad KM, Watson AM, Dickerson FB, Yolken RH, Nimgaonkar VL. Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia. Schizophr Bull. 2012;38:1137–48.View ArticleGoogle Scholar
  17. Xiao J, Prandovszky E, Kannan G, Pletnikov MV, Dickerson F, Severance EG, et al. Toxoplasma gondii: biological parameters of the connection to schizophrenia. Schizophr Bull. 2018;44:983–92.View ArticleGoogle Scholar
  18. Fuglewicz AJ, Piotrowski P, Stodolak A. Relationship between toxoplasmosis and schizophrenia: a review. Adv Clin Exp Med. 2017;26:1031–6.View ArticleGoogle Scholar
  19. Brown AS. Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev Neurobiol. 2012;72:1272–6.View ArticleGoogle Scholar
  20. Khandaker GM, Zimbron J, Lewis G, Jones PB. Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol Med. 2013;43:239–57.View ArticleGoogle Scholar
  21. Wu TY, Majeed A, Kuo KN. An overview of the healthcare system in Taiwan. London J Prim Care (Abingdon). 2010;3:115–9.View ArticleGoogle Scholar
  22. American Hospital Association, American Medical Record Association, Health Care Financing Administration, National Center for Health Statistics. ICD-9-CM coding and reporting official guidelines. J Am Med Rec Assoc. 1990;61(Suppl.):1–17.Google Scholar
  23. Schmid G, Narcisi E, Mosure D, Secor WE, Higgins J, Moreno H. Prevalence of metronidazole-resistant Trichomonas vaginalis in a gynecology clinic. J Reprod Med. 2001;46:545–9.PubMedGoogle Scholar
  24. Crowell AL, Sanders-Lewis KA, Secor WE. In vitro metronidazole and tinidazole activities against metronidazole-resistant strains of Trichomonas vaginalis. Antimicrob Agents Chemother. 2003;47:1407–9.View ArticleGoogle Scholar
  25. Ginocchio CC, Chapin K, Smith JS, Aslanzadeh J, Snook J, Hill CS, et al. Prevalence of Trichomonas vaginalis and coinfection with Chlamydia trachomatis and Neisseria gonorrhoeae in the United States as determined by the Aptima Trichomonas vaginalis nucleic acid amplification assay. J Clin Microbiol. 2012;50:2601–8.View ArticleGoogle Scholar
  26. Abbai NS, Wand H, Ramjee G. Sexually transmitted infections in women participating in a biomedical intervention trial in Durban: prevalence, coinfections, and risk factors. J Sex Transm Dis. 2013;2013:358402.PubMedPubMed CentralGoogle Scholar
  27. Davis A, Dasgupta A, Goddard-Eckrich D, El-Bassel N. Trichomonas vaginalis and human immunodeficiency virus coinfection among women under community supervision: a call for expanded T. vaginalis screening. Sex Transm Dis. 2016;43:617–22.View ArticleGoogle Scholar
  28. Sperr M, Kundi M, Tursic V, Bristela M, Moritz A, Andrukhov O, et al. Prevalence of comorbidities in periodontitis patients compared to the general Austrian population. J Periodontol. 2017. https://doi.org/10.1902/jop.2017.170333.View ArticlePubMedGoogle Scholar
  29. Pompili M, Innamorati M, Forte A, Erbuto D, Lamis DA, Narcisi A, et al. Psychiatric comorbidity and suicidal ideation in psoriasis, melanoma and allergic disorders. Int J Psychiatry Clin Pract. 2017;21:209–14.View ArticleGoogle Scholar
  30. Tzeng NS, Chang HA, Chung CH, Kao YC, Chang CC, Yeh HW, et al. Increased risk of psychiatric disorders in allergic diseases: a nationwide, population-based, cohort study. Front Psychiatry. 2018;9:133.View ArticleGoogle Scholar
  31. Shaio MF, Lin PR, Liu JY, Yang KD. Generation of interleukin-8 from human monocytes in response to Trichomonas vaginalis stimulation. Infect Immun. 1995;63:3864–70.PubMedPubMed CentralGoogle Scholar
  32. Fiori PL, Diaz N, Cocco AR, Rappelli P, Dessi D. Association of Trichomonas vaginalis with its symbiont Mycoplasma hominis synergistically upregulates the in vitro proinflammatory response of human monocytes. Sex Transm Infect. 2013;89:449–54.View ArticleGoogle Scholar
  33. Anderson BL, Cosentino LA, Simhan HN, Hillier SL. Systemic immune response to Trichomonas vaginalis infection during pregnancy. Sex Transm Dis. 2007;34:392–6.PubMedGoogle Scholar
  34. King C, Feldman J, Waithaka Y, Aban I, Hu J, Zhang S, et al. Sexual risk behaviors and sexually transmitted infection prevalence in an outpatient psychiatry clinic. Sex Transm Dis. 2008;35:877–82.View ArticleGoogle Scholar
  35. Yin H, Xu G, Tian H, Yang G, Wardenaar KJ, Schoevers RA. The prevalence, age-of-onset and the correlates of DSM-IV psychiatric disorders in the Tianjin Mental Health Survey (TJMHS). Psychol Med. 2018;48:473–87.View ArticleGoogle Scholar
  36. Chen MH, Su TP, Li CT, Chang WH, Chen TJ, Bai YM. Symptomatic menopausal transition increases the risk of new-onset depressive disorder in later life: a nationwide prospective cohort study in Taiwan. PLoS One. 2013;8:e59899.View ArticleGoogle Scholar
  37. Bryant C, Judd FK, Hickey M. Anxiety during the menopausal transition: a systematic review. J Affect Disord. 2012;139:141–8.View ArticleGoogle Scholar
  38. Hu LY, Shen CC, Hung JH, Chen PM, Wen CH, Chiang YY, et al. Risk of psychiatric disorders following symptomatic menopausal transition: a nationwide population-based retrospective cohort study. Medicine (Baltimore). 2016;95:e2800.View ArticleGoogle Scholar
  39. Mokdad AH, Forouzanfar MH, Daoud F, Mokdad AA, El Bcheraoui C, Moradi-Lakeh M, et al. Global burden of diseases, injuries, and risk factors for young people’s health during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2016;387:2383–401.View ArticleGoogle Scholar
  40. Caron J, Fleury MJ, Perreault M, Crocker A, Tremblay J, Tousignant M, et al. Prevalence of psychological distress and mental disorders, and use of mental health services in the epidemiological catchment area of Montreal South-West. BMC Psychiatry. 2012;12:183.View ArticleGoogle Scholar
  41. Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent RP, Thom EA, et al. Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med. 2001;345:487–93.View ArticleGoogle Scholar
  42. Schwebke JR, Barrientes FJ. Prevalence of Trichomonas vaginalis isolates with resistance to metronidazole and tinidazole. Antimicrob Agents Chemother. 2006;50:4209–10.View ArticleGoogle Scholar
  43. Donders GGG, Ruban K, Depuydt C, Bellen G, Vanden Broeck D, Jonckheere J, et al. Treatment attitudes for Belgian women with persistent Trichomonas vaginalis infection in the VlaResT study. Clin Infect Dis. 2018. https://doi.org/10.1093/cid/ciy736.View ArticlePubMedGoogle Scholar
  44. Roth AM, Williams JA, Ly R, Curd K, Brooks D, Arno J, et al. Changing sexually transmitted infection screening protocol will result in improved case finding for Trichomonas vaginalis among high-risk female populations. Sex Transm Dis. 2011;38:398–400.View ArticleGoogle Scholar

Copyright

© The Author(s) 2019

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Please note that comments may be removed without notice if they are flagged by another user or do not comply with our community guidelines.

Advertisement