Abstract

Background

The purpose of this retrospective study was to determine the effect of surgical operation, age at surgery, sex hormones, and anesthesia modality on the risk of dementia in both sexes.

Methods

Data of females aged between 30 and 70 years old who were diagnosed with dysmenorrhea and underwent hysterectomy/myomectomy or without surgery, and males with benign prostate hyperplasia (BPH) with or without transurethral resection of the prostate (TURP) were identified from the National Health Insurance Research Database 2000–2016. The effect of age at surgery, surgery type, and anesthesia modality on dementia risk was assessed using Cox regression analyses.

Results

Among the 855,893 subjects, 10,242 developed dementia. Surgery at older age increased dementia risk in both sexes. Among females, hysterectomy/myomectomy was not significantly associated with dementia risk , although myomectomy was associated with a lower risk for dementia than hysterectomy. In males, TURP significantly increased the risk of dementia.

Conclusion

Men with BPH and women with dysmenorrhea who were older at surgery have a higher risk of dementia. Regardless of the anesthetic method, surgery increased the risk of dementia in men. Among the data of women, although the surgery factor was not significantly associated with dementia risk, women with myomectomy had a lower risk of dementia than the ones with hysterectomy. These findings together contributed to risk stratification for each sex in such surgical settings.

Keywords

anesthesia, dementia, hysterectomy, myomectomy, transurethral resection of the prostate (TURP)

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Introduction

Males and females exhibited different risks of the occurrence of dementia although not fully understood. Women were more prone to have mental declines than men before having dementia diagnosis. More women than men were diagnosed with Alzheimer’s disease (AD), and this may not be solely attributable to increased longevity. From previous studies, sex steroid hormones were the potential central modulators that underlie such risk discrepancy. ¹ In the last decades, some research suggested that surgical menopause (also, oophorectomy) was independently associated with greater subsequent dementia risk or cognitive impairments. ^2,3 However, other research suggested that hysterectomies during midlife were also associated with greater subsequent dementia risk or cognitive impairments. ⁴ It might be explained by shortened reproductive span as well as reduced cumulative exposure to estrogen. In our cross-sectional study conducted in 2019, we examined the cognitive dysfunction after operation in perimenopausal women and found that the duration of menopause was independently associated with impaired postoperative cognition. ⁵ In another study by our research team, a 14-year longitudinal risk assessment of dementia after hysterectomies was performed, and it was found that not only age at hysterectomy but also the modality of anesthesia significantly correlates with dementia risk. Specifically, general anesthesia (GA) was associated with higher dementia risk as compared with spinal anesthesia (SA), along with a greater impact observed in younger females. ⁶ The results of the above-cited study further joined the recent debates in the medical literature on whether exposure to GA increased the incidence of dementia. ^7-9 Nevertheless, it was indicated that age at surgery, cumulative exposure to female sex hormones, and anesthesia modality in gynecological surgery all had an impact on short-term and long-term cognition, and it further warranted the need for investigating their potential interactions.

Benign prostate hyperplasia (BPH) was common in elderly men, occurring in 15% to 60% of men aged more than 40 years and increasing markedly with age. ^10,11 Current therapies can be divided into conservative or surgical interventions, of which transurethral resection of the prostate (TURP) has long been considered the historical gold standard for the surgical treatment of BPH and has been recognized as the second most commonly performed operation in the United States previously. ^12,13 Despite the fact that medical treatment for BPH has been questioned for its potential adverse effects on individual mental disorders, including dementia and depression ^14,15 , no prior study has reported any association between TURP and subsequent psychiatric problems. Consequently, we deemed that it would be informative to include males with BPH for the sake of assessing the relationships between anesthesia modality and the risk of dementia accompanying women undergoing hysterectomies.

Therefore, we aimed to investigate the potential interaction between procedures, age at surgery, sex hormones, and modality of anesthesia on the risk of dementia in both sexes. We retrospectively compared the females who received hysterectomy versus myomectomy, a procedure without removal of the uterus, for the incidence of dementia at follow-up. We also assessed the impact of TURP and the anesthesia modality on the risk of dementia in males. The influence of age at such surgeries on dementia risk was evaluated among men and women. The analyses were conducted at a population level, using Taiwan’s nationally representative insurance database.

Methods

Study Design and Data Source

The detailed study design is depicted in Supplementary Figure S1. This was an observational, retrospective cohort study using the data of Taiwan’s National Health Insurance Research Database (NHIRD) from 2000 to 2016. In this database, we excluded females aged between 30 and 70 years old who were diagnosed with dysmenorrhea, and males aged between 30 and 70 years old who were diagnosed with BPH with or without TURP. Females and males with missing data of the main study variables or duplicated surgical records were excluded from the primary cohort. Patients with a history of dementia, Parkinson’s disease, cancer, stroke, or brain surgery before the date of the first diagnosis of dysmenorrhea or BPH were also excluded. Information of age at surgery, type of surgery including myomectomy or hysterectomy in females, and modality of anesthesia (i.e., GA, SA, and epidural anesthesia [EA]) in both males and females were also extracted and included in the subsequent analyses (Supplementary Figure S1).

Ethical Statement

The data were obtained from the Health and Welfare Database of the Ministry of Health and Welfare Collaboration Center of Health Information Application. This study was approved by the Research Ethics Review Committee of the Far Eastern Hospital (No:106113-E). The requirement for informed consent was waived since this study was a secondary analysis of a public database in which all patients’ personal information was anonymized. The data files used for analysis followed those used in our previous study and described therein. ⁵

Study Variables

The primary endpoint of the present analysis was the risk of incident dementia at follow-up. The diseases and procedures in the analyses were identified according to the ninth (ICD-9-CM) and tenth editions (ICD-10-CM) of the International Classification of Diseases from the outpatient and inpatient list files of the database. The codes utilized are listed below:

Dementia:

• Other cerebral degenerations: ICD-9-CM: 331; ICD-10-CM: G300/G301/G308/G309/G311

• Senile and presenile organic psychotic conditions: ICD-9-CM: 290; ICD-10-CM: F0390

• Dementia in conditions classified elsewhere: ICD-9-CM: 294.1; ICD-10-CM: F0280/F0281

Only cases with inpatient visits and two or more outpatient visits with the above diagnostic codes were included, and those with dementia diagnosed within three months after hysterectomy/myomectomy or TURP have been excluded. We have also excluded patients with a medical history as described below (only ICD-9-CM before 2011 in Taiwan):

• Cancer: ICD-9-CM:140-208

• Parkinsonism: ICD-9-CM: 332;

• Stroke: ICD-9-CM: 430-434

• Brain operations: ICD-9 procedure codes 01-04

Type of Surgery

The following surgical procedures were further identified by procedure claim codes listed below:

• Hysterectomy: 80403B, 80404C, 80421B, 80416B

• Myomectomy: 80402C, 80420C, 80425C

• TURP: 79406B, 79413B, 79414B, 79415B, N20002

Modality of Anesthesia

We distinguished only two ways of anesthesia using the following codes:

• GA: 96020C

• Regional anesthesia, including SA: 96007C, or EA: 96005C

Comorbidities

The Charlson comorbidity index (CCI), which accounts for 17 diseases, was used for patient characteristics analysis. ^16,17

Statistical Analysis

Categorical data were presented as n (%) and compared using the chi-square test or Fisher’s exact test. Cox regression analyses were used to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of the risk for developing dementia after hysterectomy, myomectomy, or TURP. The assumption of proportional hazards was checked. A two-sided P -value of < 0.05 was regarded as statistically significant. Data management and statistical analyses were conducted using SAS version 9.4 software (SAS Institute, Inc. Cary, NC, USA).

Results

A total of 855,893 male and female subjects aged between 30 and 70 years old were included between the years 2000 and 2016 in the database, of which 10,242 (1.2%) developed dementia at follow-up. Supplementary Table S1 shows the baseline characteristics of the entire study cohort with and without dementia. As compared with female subjects, a greater proportion of males had developed dementia (2.28% vs. 0.60%, P < 0.001). Subjects who had not received surgeries had a larger proportion of dementia than those who had (1.28% vs. 0.99%, P < 0.001). A larger proportion of dementia was observed in the subjects who had undergone SA or EA than those who had received GA (3.01% vs. 0.61%, P < 0.001). The subjects with a CCI score > 2 had a greater proportion of dementia as compared to those with a CCI score ≤ 2 (8.70% vs. 0.98%, P < 0.001). Significant differences in the ratio of dementia were observed in most of the comorbidities, except for MI, peripheral vascular disease, and peptic ulcer disease (Supplementary Table S1).

Supplementary Table S2 shows the baseline characteristics of the study cohort with and without dementia, stratified by gender. For females, the proportion of dementia was greater in patients who had received surgery than those who had not (0.63% vs. 0.57%, P = 0.01). A higher frequency of dementia was observed after hysterectomy than myomectomy. (0.76% vs. 0.12%, P < 0.001). For males, a greater proportion of dementia was observed in those who had received TURP than those who had not (7.43% vs. 2.05%, P < 0.001). With regard to the modality of anesthesia, in both males and females, a higher proportion of dementia was observed among those who received SA or EA as compared with GA (0.88% vs. 0.59% in females; 7.49% vs. 6.35% in males, both P < 0.001). A greater proportion of dementia was observed in both females and males who had CCI scores > 2 as compared to CCI ≤ 2 (0.07% vs. 0.00% in females, 0.09% vs. 0.02% in males, both P < 0.001). As for comorbidities, both in females and males, significantly higher proportions of dementia were found in those who had hypertension, hyperlipidemia, depression, cerebrovascular accident, diabetes, diabetes with chronic complication, hemiplegia or paraplegia, or renal disease, as compared with those who had not (all P < 0.01) (Supplementary Table S2).

Table 1 shows the frequencies and risks of dementia by gender and surgical status at different ages. Both in males and females, as age increases, the HRs for dementia also rise. A substantial increase in the risk can be observed in females around 50 years old (HR = 59.96 in 56–60 years old; 18.22 in 51–55 years old). For males, this situation can be observed around 56 years of age (HR = 18.12 in 56–60 years old; 6.27 in 51–55 years old) (Table 1). The risk of dementia by gender at a different age is depicted in Figure 1.

Table 2 shows the impact of surgery, age at surgery, and anesthesia on the risk for dementia. For all females with dysmenorrhea, surgical treatment with hysterectomy or myomectomy was not significantly associated with the risk for dementia (HR, 0.97; 95% CI, 0.90–1.04; P = 0.38). According to the above result, we suggested that surgery itself is not the main cause of dementia. However, females who received surgery later than 50 years old had 26.09 times higher risk of dementia than those who received surgery at an age younger than 50 years old. After stratifying all females into two subgroups (< 50 y/o and > 50 y/o),
surgery became significantly associated with increased risk for dementia in < 50 y/o subgroup (HR, 1.63; 95% CI, 1.41–1.88; P < 0.001) but not in > 50 y/o subgroup (HR, 0.83; 95% CI, 0.77–0.90; P < 0.001). Among females who had undergone surgery, those who had undergone myomectomy had a significantly lower risk of developing dementia than those who had undergone hysterectomy (HR, 0.48; 95% CI, 0.37–0.63; P < 0.001). The higher risk was observed in females who received surgery later than 50 years old (HR, 16.74; 95% CI, 14.88–18.83; P < 0.001). If stratifying all females who had undergone surgery into two subgroups (< 50 y/o and > 50 y/o), myomectomy is significantly associated with decreased risk for dementia in both subgroups (< 50 y/o: HR, 0.49; 95% CI, 0.35–0.69; P < 0.001; > 50 y/o: HR, 0.46; 95% CI, 0.29–0.73; P < 0.001).