Sociodemographic factors and uncomplicated pyelonephritis in women aged 15-50 years: a nationwide Swedish cohort register study (1997-2018)

Open AccessPublished:August 08, 2021DOI:https://doi.org/10.1016/j.ijid.2021.08.009

      Highlights

      • This study presents novel risk factors associated with pyelonephritis in women.
      • Nationwide primary healthcare data were used in the analyses.
      • Low socioeconomic status (SES) was associated with increased risk.
      • Non-Western origin was associated with increased risk, after adjusting for SES.
      • Certain groups of women might disproportionately suffer from this severe infection.

      Abstract

      Objective: To study the relationship between sociodemographic factors and pyelonephritis.
      Methods: A nationwide open cohort study consisting of 2,052,873 women (76.2% Swedish-born) aged 15-50 years was conducted (1997-2018). The outcome was the first event of acute uncomplicated pyelonephritis diagnosed in primary healthcare settings in relation to the sociodemographic factors. Cox regression models were used in the analyses.
      Results: The study identified 40,724 cases. In the fully adjusted model, women from non-Western countries had a higher risk of pyelonephritis compared to Swedish-born women. Women from Latin America/the Caribbean had the highest risk (Hazard ratio = 1.60; 95% CI 1.49-1.72), followed by Eastern Europe (HR = 1.26; 95% CI 1.21-1.32) and the Middle East/North Africa (HR = 1.25; 95% CI 1.19-1.30). Low education, low income, urban living, and young age were also associated with higher risks of pyelonephritis.
      Conclusion: This study presents novel risk factors associated with pyelonephritis. Women from non-Western countries and with low socioeconomic status might disproportionately suffer from this serious infection. This might be due to biological predispositions and the fact that immigrant women do not acquire the same level of health or might receive less healthcare compared to native women, even in the presence of universal healthcare.

      Keywords

      Introduction

      Acute uncomplicated upper urinary tract infection (UTI) or uncomplicated pyelonephritis often ascends from the lower urinary tract and may occur in otherwise healthy women (
      • Belyayeva M
      • Jeong JM.
      Acute Pyelonephritis.
      ;
      • Nicolle LE.
      Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis.
      ). The majority of women are managed in outpatient settings and treated with oral antibiotics (
      • Belyayeva M
      • Jeong JM.
      Acute Pyelonephritis.
      ;
      • Czaja CA
      • Scholes D
      • Hooton TM
      • Stamm WE.
      Population-based epidemiologic analysis of acute pyelonephritis.
      ;
      • Gupta K
      • Hooton TM
      • Naber KG
      • Wullt B
      • Colgan R
      • Miller LG
      • et al.
      International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
      ;
      • Ki M
      • Park T
      • Choi B
      • Foxman B.
      The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
      ). If treated properly the infection mostly has an uncomplicated course, but can sometimes lead to hospitalisation, serious complications or, more rarely, death (
      • Belyayeva M
      • Jeong JM.
      Acute Pyelonephritis.
      ;
      • Ki M
      • Park T
      • Choi B
      • Foxman B.
      The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
      ;
      • Nicolle LE.
      Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis.
      ;
      • Nicolle LE
      • Friesen D
      • Harding GK
      • Roos LL.
      Hospitalization for acute pyelonephritis in Manitoba, Canada, during the period from 1989 to 1992; impact of diabetes, pregnancy, and aboriginal origin.
      ).
      Established risk factors for uncomplicated pyelonephritis are similar to those of acute uncomplicated lower UTI or uncomplicated cystitis, and include recent sexual intercourse, urinary incontinence and cystitis (
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Gupta K
      • Stapleton AE
      • Stamm WE.
      Risk factors associated with acute pyelonephritis in healthy women.
      ). It has also been suggested that sociodemographic factors are associated with pyelonephritis, although prior research is sparse and it is believed that it not been performed on a nationwide basis among women with access to universal healthcare (
      • Ki M
      • Park T
      • Choi B
      • Foxman B.
      The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
      ;
      • Nicolle LE
      • Friesen D
      • Harding GK
      • Roos LL.
      Hospitalization for acute pyelonephritis in Manitoba, Canada, during the period from 1989 to 1992; impact of diabetes, pregnancy, and aboriginal origin.
      ;
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Gupta K
      • Stapleton AE
      • Stamm WE.
      Risk factors associated with acute pyelonephritis in healthy women.
      ). It has recently been shown that sociodemographic factors are associated with uncomplicated cystitis (
      • Jansåker F
      • Li X
      • Sundquist K.
      Sociodemographic factors and uncomplicated cystitis in women aged 15–50 years: a nationwide Swedish cohort registry study (1997–2018).
      ). The current study aimed to use nationwide population-based datasets, including extensive information on sociodemographic factors, to study uncomplicated pyelonephritis. Access to nationwide primary healthcare data was a particular strength because most cases of uncomplicated pyelonephritis occur in primary healthcare settings (
      • Czaja CA
      • Scholes D
      • Hooton TM
      • Stamm WE.
      Population-based epidemiologic analysis of acute pyelonephritis.
      ;
      • Ki M
      • Park T
      • Choi B
      • Foxman B.
      The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
      ).
      Sweden has a universal tax-financed healthcare system with the goal to provide healthcare on equal terms to the entire population, irrespective of sociodemographic factors. This study aimed to investigate whether there is a relationship between a comprehensive set of sociodemographic factors and uncomplicated pyelonephritis in women aged 15-50 years with access to Swedish universal healthcare and diagnosed in primary healthcare settings.

      Methods

       Study design and setting

      The study was designed as an open cohort study. The study population consisted of 2,052,873 females aged 15-50 years during the study period from 01 January 1997 to 31 December 2018. The STROBE statement checklist for cohort studies was considered when conducting the study and writing the manuscript (
      • von Elm E
      • Altman DG
      • Egger M
      • Pocock SJ
      • Gotzsche PC
      • Vandenbroucke JP
      • et al.
      The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
      ). This research was conducted at the Center for Primary Health Care Research, Lund University, Region Skåne, Malmö, Sweden.

       Ascertainment of the outcome variable

      The first incident of acute uncomplicated pyelonephritis, hereafter “uncomplicated pyelonephritis”, was identified in the Swedish Primary Health Care Register during the study period. Each woman could only be included once. Pyelonephritis was classified with the diagnostic-codes N10 or N12 according to the 10th revision of the International Classification of Diseases (ICD). Both of these codes have been used in primary healthcare for acute pyelonephritis in Sweden and do not include chronic pyelonephritis (N11). This approach is also similar to other population-based studies on acute pyelonephritis (
      • Czaja CA
      • Scholes D
      • Hooton TM
      • Stamm WE.
      Population-based epidemiologic analysis of acute pyelonephritis.
      ;
      • Ki M
      • Park T
      • Choi B
      • Foxman B.
      The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
      ). Ongoing pregnancy or a history of comorbidities not aligned with the diagnosis of uncomplicated pyelonephritis were not included in the definition of the outcome (
      • Belyayeva M
      • Jeong JM.
      Acute Pyelonephritis.
      ;
      • Nicolle LE.
      Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis.
      ). The following diagnoses were considered as history of comorbidities and women with these conditions within two years prior to the event were excluded: human immunodeficiency virus infection and related diseases; non-male urological neoplasms; other immunodeficiency disorders; diabetes mellitus type 1 and 2; paraplegic syndromes; chronic nephritic syndromes; hereditary or acquired nephropathy; chronic pyelonephritis; hydronephrosis; other serious kidney diseases; kidney failure; urinary tract stone diseases; neurological bladder dysfunction; congenital diseases of the kidney, bladder or urinary tract (ICD-10: B20-24, C64-68, D41, D80-89, E10-11, M623, N03, N07, N11, N13-23, N25-29, N32, Q60-64). A redeemed prescription on anti-neoplastic and/or immunomodulating agents or corticosteroids for systemic use within six months prior to the event (Anatomic Therapeutic Chemical classification system code: ATC code: L or H02) were not included in the definition of the outcome.

       Predictor variables

      Ages were grouped into 15-24, 25-34, 35-44, or 45-50 years. Socioeconomic status was defined by individual education and family income. Educational level was classified into three different categories based on the duration of school years attended: compulsory schooling or less (≤ 9 years); short or partially completed high school education (10-11 years); or completed high school education or university or college education (≥ 12 years). For those in the youngest age group, 15-17 years, the highest educational level of the parents was used. Family income was categorised into four groups based on a weighted average income in each family: low (lowest income quartile of the study population), middle-low, middle-high and high (highest quartile). Region of residence was categorized into three groups: large cities (urban living), Southern Sweden and Northern Sweden. Country of origin was categorised as being born in any of the following countries/regions: Sweden; Eastern European countries; Western countries; the Middle East/North Africa (MENA); Africa (excluding North Africa); Asia (excluding the Middle East) and Oceania; or Latin America and the Caribbean. The geographical proximity, cultural and/or economic similarities between countries defined this categorisation that was based on the definitions used in a previous study (
      • Jansåker F
      • Li X
      • Sundquist K.
      Sociodemographic factors and uncomplicated cystitis in women aged 15–50 years: a nationwide Swedish cohort registry study (1997–2018).
      ).

       Data sources

      The study used nationwide healthcare and population-based registers. The register used to identify the outcome was the Swedish Primary Health Care Register, which includes almost nationwide data on clinical diagnoses from primary healthcare consultations in Sweden. The coverage of the data in this register varied over time and region but was based on data from 21 of a total of 22 administrative regions in Sweden. The time periods differed depending on the time of digitalisation of the patient records in a certain region. In 2015, the register contained 72% of the population living in Sweden (
      • Sundquist J
      • Ohlsson H
      • Sundquist K
      • Kendler KS.
      Common adult psychiatric disorders in Swedish primary care where most mental health patients are treated.
      ), and 87% of the population was included at the end of the present study (
      • Jansåker F
      • Li X
      • Sundquist K.
      Sociodemographic factors and uncomplicated cystitis in women aged 15–50 years: a nationwide Swedish cohort registry study (1997–2018).
      ). Other registers used were: the Medical Birth Register, which includes data on, for example, pregnancies in Sweden; the Hospital Discharge Register and the Out-Patient Register, which include hospital discharge diagnoses and diagnoses from outpatient specialist care; the Swedish Prescribed Drug Register, which contains the specific ATC codes on redeemed medical drug prescriptions; and the Cause of Death Register. The Total Population Register was used to collect data on emigration, country of origin, income, education, and other sociodemographic data. The population register is nearly 100% complete for the entire national population (
      • Ludvigsson JF
      • Almqvist C
      • Bonamy AK
      • Ljung R
      • Michaelsson K
      • Neovius M
      • et al.
      Registers of the Swedish total population and their use in medical research.
      ). All linkages between the individual-level clinical and population registry data were performed using a pseudonymised version of the unique 10-digit personal identification number assigned to each person in Sweden for their lifetime upon birth or permanent immigration to Sweden.

       Statistical analysis

      Descriptive statistics (population size and number of first events of uncomplicated pyelonephritis) were calculated in each category of the different variables. To assess the association between the predictor variables and the outcome, Cox regression models were used to estimate Hazard ratios (HR) and 95% confidence intervals (CI) during the study period. The study period started on 01 January 1997 and person‐years were calculated until an outcome event, death, emigration, or end of the study period (31 December 2018). Three models were used: Model 1 was a univariate model for each variable; Model 2 adjusted only for age; and Model 3 adjusted for all predictor variables. To examine that the strength of the associations did not change over time, proportionality assumptions were checked by plotting the incidence rates over time and calculating Schoenfeld (partial) residuals – these assumptions were fulfilled. Incidence rates (per 1000 person-years) of the outcome were calculated for each separate predictor variable. A two-tailed p-value of < 0.05 was used to determine statistical significance. The analyses did not exclude observations with missing values (range 1.1% to 4.0%) – education (2.0%), income (4.0%), region of residence (1.5%), and country of origin (1.1%) – they were instead included in the category labelled “unknown”. A sensitivity analysis was performed including parities as a categorical variable. SAS software version 9.4 was used for all statistical analyses.

       Ethical consideration

      This study was approved by the Regional Ethical Review Board in Lund (Dnr 2012/795 and 2019/0378).

       Role of funding source

      The funding sources of the study had no role in the study design, the collection, analysis, and interpretation of data, the writing of the report, or in the decision to submit the paper for publication.

      Results

      The study population consisted of 2,052,873 women aged 15-50 years during the study period 1997-2018. The number of outcome events of uncomplicated pyelonephritis during the study period was 40,724 (2.0% of the study population), corresponding to an incidence per 1000 person-years of 1.74 (95% CI 1.73-1.76). Table 1 describes the characteristics of the study population and distribution of the number of events regarding age group, education level, family income, region of residence and country of birth. Of the total number of events, one-third (33.8%) occurred in the youngest age group (aged 15-24 years) and 76.3% occurred in Swedish-born women.
      Table 1Characteristics of study population and number of first events of uncomplicated pyelonephritis in women aged 15-50 years (1997-2018).
      Total populationEvents
      N%N%
      Age groups (years)
      15-24586,98928.613,75533.8
      25-34592,93328.910,34725.4
      35-44556,69027.110,27425.2
      45-50316,26115.4634815.6
      Educational level
      ≤ 9295,24014.4785619.3
      10-11424,12620.710,05124.7
      ≥ 121,291,94062.922,37754.9
      Unknown41,5672.04401.1
      Family income
      Low492,38924.011,17327.4
      Middle-low492,43724.010,63126.1
      Middle-high492,50824.0960523.6
      High493,54824.0765918.8
      Unknown81,9914.016564.1
      Region of residence
      Large cities1,258,00361.327,21866.8
      Southern Sweden518,85125.3887121.8
      Northern Sweden245,75212.0439810.8
      Unknown30,2671.52370.6
      Country of origin
      Sweden1,563,87476.231,06876.3
      Eastern Europe113,1465.524075.9
      Western countries94,1314.614283.5
      Middle East/North Africa (MENA)116,2235.724566.0
      Africa (excluding North Africa)38,4261.96601.6
      Asia (excluding Middle East) and Oceania76,7763.714673.6
      Latin America and the Caribbean27,3751.37811.9
      Unknown22,9221.14571.1
      All2,052,873100.040,724100.0
      Table 2 shows that the incidence rate (IR) per 1000 person-years of outcome events was highest in the youngest age group and in those women with a low education, low income, living in large cities and/or originating from non-Western countries (especially Latin America/the Caribbean, followed by MENA countries). The IR declined in the intermediate age groups and increased again in the oldest age group, indicating a biphasic age distribution.
      Table 2Incidence rate (per 1000 person-years) of first event uncomplicated pyelonephritis in women aged 15-50 years (1997-2018).
      Incidence rate, per 1000 person-years
      IR95% CI
      Age groups (years)
      15-242.132.092.16
      25-341.551.521.58
      35-441.571.541.60
      45-501.721.681.76
      Educational level
      ≤ 92.222.172.27
      10-111.861.821.90
      ≥ 121.571.551.59
      Unknown3.072.783.35
      Family income
      Low2.011.972.05
      Middle-low1.721.681.75
      Middle-high1.641.611.67
      High1.501.461.53
      Unknown2.592.472.72
      Region of residence
      Large cities1.781.761.80
      Southern Sweden1.711.671.74
      Northern Sweden1.571.521.62
      Unknown5.514.816.21
      Country of origin
      Sweden1.661.641.68
      Eastern Europe2.132.042.21
      Western countries1.641.551.72
      Middle East/North Africa (MENA)2.222.132.30
      Africa (excluding North Africa)2.001.852.15
      Asia (excluding Middle East) and Oceania2.031.922.13
      Latin America and the Caribbean2.702.512.89
      Unknown2.322.112.54
      All1.741.731.76
      Table 3 presents the associations between the individual sociodemographic variables and the outcome. In Model 1, the univariate analysis showed that those in the youngest age group had a higher risk of uncomplicated pyelonephritis compared to the oldest age group, while the two intermediate age groups had somewhat lower risks. Low education, low family income, living in large cities, and/or being born in non-Western countries were associated with a higher risk of uncomplicated pyelonephritis compared to their corresponding reference group. For example, the HRs for those with the lowest education and income were 1.43 (95% CI 1.39-1.47), and 1.35 (95% CI 1.31-1.39), respectively. For women originating from non-Western countries, all HRs were significantly higher compared to Swedish-born women. For example, women from Latin American/the Caribbean and originating from MENA had HRs of 1.61 (95% CI 1.50-1.73) and 1.32 (95% CI 1.27-1.37), respectively, compared to Swedish-born women. In Model 2, the age-adjusted model, the HRs were slightly altered compared to Model 1 and all significant results remained. In Model 3, adjusted for all covariates, the significant results also remained more or less unaltered but were generally somewhat attenuated. The HRs for age remained practically unaltered in this model. Low socioeconomic status remained associated with increased risk of uncomplicated pyelonephritis compared to the highest socioeconomic status, especially for education. Women with the lowest education and income level had HRs of 1.31 (95% CI 1.27-1.34) and 1.14 (95% CI 1.10-1.17), respectively, compared to the corresponding highest socioeconomic group. The variable region of residence remained almost unchanged in all models, with somewhat lower risks of uncomplicated pyelonephritis in women living outside the large cities. For example, the HR was 0.88 (95% CI 0.85-0.90) for women residing in Northern Sweden. For country of origin, women from MENA, Eastern Europe, and Latin America/the Caribbean had the highest risks of uncomplicated pyelonephritis compared to Swedish-born women, with HRs of 1.25 (95% CI 1.19-1.30), 1.26 (95% CI 1.21-1.32), and 1.60 (95% CI 1.49-1.72), respectively.
      Table 3Association of individual sociodemographic variables and first event uncomplicated pyelonephritis in women aged 15-50 years (1997-2018).
      Model 1Model 2Model 3
      CovariatesHR95% CIP-valueHR95% CIP-valueHR95% CIP-value
      Age (ref. age 45-50 years)
      15-241.231.201.27< 0.00011.231.201.27< 0.00011.211.171.25< 0.0001
      25-340.890.870.92< 0.00010.890.870.92< 0.00010.910.880.93< 0.0001
      35-440.910.890.94< 0.00010.910.890.94< 0.00010.910.880.93< 0.0001
      Educational level (ref. ≥ 12 years)
      ≤ 91.431.391.47< 0.00011.371.331.40< 0.00011.311.271.34< 0.0001
      10-111.201.181.23< 0.00011.241.211.27< 0.00011.241.211.27< 0.0001
      Unknown1.441.311.58< 0.00011.301.181.43< 0.00010.860.750.980.0269
      Family income (ref. High)
      Low1.351.311.39< 0.00011.291.251.33< 0.00011.141.101.17< 0.0001
      Middle-low1.171.131.20< 0.00011.141.111.17< 0.00011.071.041.10< 0.0001
      Middle-high1.111.081.15< 0.00011.091.051.12< 0.00011.051.021.080.0014
      Unknown1.621.541.71< 0.00011.381.311.46< 0.00011.221.151.29< 0.0001
      Region of residence (ref. Large cities)
      Southern Sweden0.940.920.96< 0.00010.920.900.94< 0.00010.930.910.95< 0.0001
      Northern Sweden0.870.850.90< 0.00010.860.830.88< 0.00010.880.850.90< 0.0001
      Unknown1.411.241.60< 0.00011.421.251.61< 0.00011.461.211.760.0001
      Country of origin (ref. Born in Sweden)
      Eastern Europe1.271.221.33< 0.00011.311.251.36< 0.00011.261.211.32< 0.0001
      Western countries0.950.901.000.07161.000.951.060.91730.980.931.040.5528
      Middle East/North Africa (MENA)1.321.271.37< 0.00011.341.281.39< 0.00011.251.191.30< 0.0001
      Africa (excluding North Africa)1.181.091.27< 0.00011.201.111.29< 0.00011.111.021.200.0113
      Asia (excluding Middle East) and Oceania1.201.141.27< 0.00011.251.191.32< 0.00011.171.111.24< 0.0001
      Latin America and the Caribbean1.611.501.73< 0.00011.661.541.78< 0.00011.601.491.72< 0.0001
      Unknown1.361.241.49< 0.00011.391.271.53< 0.00011.341.221.48< 0.0001
      Model 1: Univariate model; Model 2: age adjusted model; Model 3: Fully adjusted.
      Supplementary Table S1 includes the multivariate models with addition of parities as a categorical variable. The two categories with the highest number of parities yielded higher risks. However, the number of parities did not change the associations to any great extent; the HRs in Model 3 (Table 3) remained more or less unchanged.

      Discussion

      The main findings of this nationwide cohort of 2,052,873 women were that women with low socioeconomic status and those originating from non-Western countries had higher risks of uncomplicated pyelonephritis compared to women with high socioeconomic status and Swedish origin, respectively. Urban living and young age were also associated with higher risks compared to their corresponding reference group. These findings are suggestive of an unequal distribution of this serious infection in women.
      Women from MENA, Eastern Europe, and Latin America/the Caribbean had, respectively, a 25%, 26%, and 60% higher risk of uncomplicated pyelonephritis compared to Swedish-born women. It is believed that no other studies have used nationwide population-based data to examine the relationship between country of origin and pyelonephritis. It is believed that two previous studies have examined such a relationship: a population-based study from Canada found that Native American women were overrepresented among hospitalisations due to pyelonephritis, which was validated in data from two acute care institutions (
      • Nicolle LE
      • Friesen D
      • Harding GK
      • Roos LL.
      Hospitalization for acute pyelonephritis in Manitoba, Canada, during the period from 1989 to 1992; impact of diabetes, pregnancy, and aboriginal origin.
      ); and a case-control study from USA found no ethnical disparities in women with pyelonephritis compared to the control group, although there were some indications that ethnical minorities were overrepresented in the relatively small group being hospitalised due to the infection (
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Gupta K
      • Stapleton AE
      • Stamm WE.
      Risk factors associated with acute pyelonephritis in healthy women.
      ). Even if these studies were considerably smaller than the current study and of different design, the indications were in line with the current findings, and it cannot be ruled out that an ethnic predisposition for pyelonephritis might exist. However, possible mechanisms behind these associations have not have been thoroughly examined. One potential explanation could be that a high proportion of immigrant women live in large cities and under poor socioeconomic circumstances, which are factors associated with increased risks of both pyelonephritis, as shown in this study, and cystitis (
      • Jansåker F
      • Li X
      • Sundquist K.
      Sociodemographic factors and uncomplicated cystitis in women aged 15–50 years: a nationwide Swedish cohort registry study (1997–2018).
      ). Medical aid (for low-income families) has also been found to be associated with an increased risk of recurrent pyelonephritis in South Korea (
      • Ki M
      • Park T
      • Choi B
      • Foxman B.
      The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
      ), but these women also appeared to have a lower annual incidence of pyelonephritis (when diagnosed in outpatient clinics) compared to women with health insurance. Low socioeconomic status also seemed to occur to a larger extent in non-pregnant women with pyelonephritis (n = 242) compared to the control group (n = 546) in USA, but with no strong nor significant association (
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Gupta K
      • Stapleton AE
      • Stamm WE.
      Risk factors associated with acute pyelonephritis in healthy women.
      ).
      Nevertheless, when adjusting for socioeconomic and other covariates, this study found that there were still significantly higher risks of being diagnosed with uncomplicated pyelonephritis among women originating from non-Western countries. Thus, it is possible that other explanations behind the findings might exist. For example, a genetic basis (i.e., innate immune deficiency) linked to pyelonephritis has been found in Sweden (
      • Lundstedt AC
      • McCarthy S
      • Gustafsson MC
      • Godaly G
      • Jodal U
      • Karpman D
      • et al.
      A genetic basis of susceptibility to acute pyelonephritis.
      ). Furthermore, ethnic differences of the human vaginal microbiome might be an explanation for the increased risk of UTI, as certain vaginal microbiomes associated with UTI (
      • Gupta K
      • Stapleton AE
      • Hooton TM
      • Roberts PL
      • Fennell CL
      • Stamm WE.
      Inverse association of H2O2-producing lactobacilli and vaginal Escherichia coli colonization in women with recurrent urinary tract infections.
      ;
      • Stapleton AE
      • Au-Yeung M
      • Hooton TM
      • Fredricks DN
      • Roberts PL
      • Czaja CA
      • et al.
      Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection.
      ) and other genitourinary infections (
      • Dareng EO
      • Ma B
      • Adebamowo SN
      • Famooto A
      • Ravel J
      • Pharoah PP
      • et al.
      Vaginal microbiota diversity and paucity of Lactobacillus species are associated with persistent hrHPV infection in HIV negative but not in HIV positive women.
      ;
      • Ravel J
      • Gajer P
      • Abdo Z
      • Schneider GM
      • Koenig SS
      • McCulle SL
      • et al.
      Vaginal microbiome of reproductive-age women.
      ) might be overrepresented in certain ethnic groups of women (
      • Ravel J
      • Gajer P
      • Abdo Z
      • Schneider GM
      • Koenig SS
      • McCulle SL
      • et al.
      Vaginal microbiome of reproductive-age women.
      ). For example, women of African and Hispanic origin (living in USA) seem to have a higher pH and a lower proportion of the generally considered “healthy” Lactobacillus spp. in their vaginal flora compared to Asian and Caucasian women (
      • Ravel J
      • Gajer P
      • Abdo Z
      • Schneider GM
      • Koenig SS
      • McCulle SL
      • et al.
      Vaginal microbiome of reproductive-age women.
      ). Lactobacillus spp. is generally considered to be protective against UTI due to the low pH (caused by the production of lactic acid), combined with bacteriocins and hydrogen peroxide, which is considered to protect the vaginal flora from colonization and growth by unwanted pathogens such as Escherichia coli (
      • Gupta K
      • Stapleton AE
      • Hooton TM
      • Roberts PL
      • Fennell CL
      • Stamm WE.
      Inverse association of H2O2-producing lactobacilli and vaginal Escherichia coli colonization in women with recurrent urinary tract infections.
      ;
      • Stapleton AE
      • Au-Yeung M
      • Hooton TM
      • Fredricks DN
      • Roberts PL
      • Czaja CA
      • et al.
      Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection.
      ) – the causative agent of the vast majority of uncomplicated cystitis and uncomplicated pyelonephritis (
      • Nicolle LE.
      Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis.
      ). Therefore, it is quite possible that a genetic or biological vulnerability at a group level could be present, which could partly explain the association between country of origin and uncomplicated pyelonephritis, and other forms of urogenital infections. Further research on this and other possible causal mechanisms is needed. For example, concerning possible genetic predisposition, it would be of interest to examine whether the associations between country of origin and uncomplicated pyelonephritis remain in the second-generation of women born in Sweden to foreign-born parents.
      Even if universal tax-financed healthcare systems aspire to provide healthcare on equal terms to the entire population, irrespective of sociodemographic factors, health inequalities still exist. Hitherto, sociodemographic disparities have been found to be associated with several medical conditions and healthcare outcomes (
      • Carlsson AC
      • Li X
      • Holzmann MJ
      • Arnlov J
      • Wandell P
      • Gasevic D
      • et al.
      Neighborhood socioeconomic status at the age of 40 years and ischemic stroke before the age of 50 years: A nationwide cohort study from Sweden.
      ;
      • Carlsson AC
      • Li X
      • Holzmann MJ
      • Wandell P
      • Gasevic D
      • Sundquist J
      • et al.
      Neighbourhood socioeconomic status and coronary heart disease in individuals between 40 and 50 years.
      ;
      • Mezuk B
      • Chaikiat A
      • Li X
      • Sundquist J
      • Kendler KS
      • Sundquist K.
      Depression, neighborhood deprivation and risk of type 2 diabetes.
      ;
      • Wandell P
      • Carlsson AC
      • Gasevic D
      • Holzmann MJ
      • Arnlov J
      • Sundquist J
      • et al.
      Socioeconomic factors and mortality in patients with atrial fibrillation-a cohort study in Swedish primary care.
      ). It has recently been shown that these health inequalities include cystitis (
      • Jansåker F
      • Li X
      • Sundquist K.
      Sociodemographic factors and uncomplicated cystitis in women aged 15–50 years: a nationwide Swedish cohort registry study (1997–2018).
      ) and it is worrisome that it seems to also be the case for the more serious UTI, pyelonephritis. It is possible that women belonging to certain ethnic groups, women of low socioeconomic status, and those living in larger cities could have a higher degree of comorbidities and other risk factors, which might affect their risk of UTI. These may include factors associated with UTI (e.g., urinary incontinency, sexual intercourse, a new partner, use of spermicides, family history) (
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Gupta K
      • Stapleton AE
      • Stamm WE.
      Risk factors associated with acute pyelonephritis in healthy women.
      ;
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Stapleton AE
      • Gupta K
      • Stamm WE.
      Risk factors for recurrent urinary tract infection in young women.
      ) or risk factors such as being overweight (associated with urinary incontinency) or urban living (associated with sexual behaviour) (
      • Chaparro MP
      • Koupil I.
      The impact of parental educational trajectories on their adult offspring's overweight/obesity status: a study of three generations of Swedish men and women.
      ;
      • Herlitz C
      • Ramstedt K.
      Assessment of sexual behavior, sexual attitudes, and sexual risk in Sweden (1989-2003).
      ;
      • Schreiber Pedersen L
      • Lose G
      • Hoybye MT
      • Elsner S
      • Waldmann A
      • Rudnicki M.
      Prevalence of urinary incontinence among women and analysis of potential risk factors in Germany and Denmark.
      ). In addition, cystitis seems to have similar risk factors and is in itself a risk factor for pyelonephritis (
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Gupta K
      • Stapleton AE
      • Stamm WE.
      Risk factors associated with acute pyelonephritis in healthy women.
      ). Healthcare workers could bear this in mind when they are consulted by patients with sociodemographic vulnerabilities. For example, Sweden has a high proportion of immigrants from around the globe, who are granted equal access to the universal healthcare system. However, it seems that some of these groups, especially those of non-Western origin, may have poorer health than the Swedish-born population, which might predispose them to severe infections such as pyelonephritis. It is also warranted to investigate if an unequal distribution of this potentially severe infection might exist in other countries, in order to plan for a more equal delivery of healthcare (
      • Das P
      • Aujla M
      • Grac E
      Racial and ethnic equality-time for concrete action.
      ). More specifically for pyelonephritis, providing equal treatment of potential risk factors (
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Gupta K
      • Stapleton AE
      • Stamm WE.
      Risk factors associated with acute pyelonephritis in healthy women.
      ) may lower the seemingly higher incidence of this serious infection in certain groups of women.
      The most important limitation of the present study was that it may not reflect the “true” incidence of uncomplicated pyelonephritis, since a register study of this calibre cannot take into account if the patients were correctly diagnosed (e.g., symptoms and microbiological data were unavailable). However, the incidence rate (IR) per 1000 person-years of 1.74 (95% CI 1.73-1.76) found in the present study was similar to the estimated IR of outpatients (1.2-1.3 per 1000 person-years) in a study from the USA involving a few thousand patients, which (in line with the current study) did not include recurrent infections (
      • Czaja CA
      • Scholes D
      • Hooton TM
      • Stamm WE.
      Population-based epidemiologic analysis of acute pyelonephritis.
      ). It is important to be aware of that the IRs may vary between population-based nationwide studies, explained by given differences of design (
      • Ki M
      • Park T
      • Choi B
      • Foxman B.
      The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
      ). In the end, the intention was to examine differences between sociodemographic groups among those cases of uncomplicated pyelonephritis diagnosed in primary healthcare rather than assessing the “true” incidence, which is unfeasible in nationwide datasets. Although this potential bias is most likely non-differential, it is possible that it may differ somewhat between different groups. In addition, the incidence ratio between uncomplicated cystitis (
      • Jansåker F
      • Li X
      • Sundquist K.
      Sociodemographic factors and uncomplicated cystitis in women aged 15–50 years: a nationwide Swedish cohort registry study (1997–2018).
      ) and uncomplicated pyelonephritis in the current study population (17:1) is of similar magnitude compared to previously described estimated incidence ratios between these two infections (18-29:1) (
      • Nicolle LE.
      Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis.
      ). Furthermore, this study did not have access to data on age of sexual debut and sexual behaviour that could represent risk factors for uncomplicated pyelonephritis (
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Gupta K
      • Stapleton AE
      • Stamm WE.
      Risk factors associated with acute pyelonephritis in healthy women.
      ). Finally, although Swedish patients have access to certified translators, there were no data on the quality of the different translators in the different regions, which could have an impact on the healthcare-seeking behaviour of women with poor language skills.
      The major strength of this study was that it involved several nationwide data registries (
      • Ludvigsson JF
      • Almqvist C
      • Bonamy AK
      • Ljung R
      • Michaelsson K
      • Neovius M
      • et al.
      Registers of the Swedish total population and their use in medical research.
      ), which this research group are highly familiar with (
      • Carlsson AC
      • Li X
      • Holzmann MJ
      • Arnlov J
      • Wandell P
      • Gasevic D
      • et al.
      Neighborhood socioeconomic status at the age of 40 years and ischemic stroke before the age of 50 years: A nationwide cohort study from Sweden.
      ;
      • Carlsson AC
      • Li X
      • Holzmann MJ
      • Wandell P
      • Gasevic D
      • Sundquist J
      • et al.
      Neighbourhood socioeconomic status and coronary heart disease in individuals between 40 and 50 years.
      ;
      • Jansåker F
      • Li X
      • Sundquist K.
      Sociodemographic factors and uncomplicated cystitis in women aged 15–50 years: a nationwide Swedish cohort registry study (1997–2018).
      ;
      • Mezuk B
      • Chaikiat A
      • Li X
      • Sundquist J
      • Kendler KS
      • Sundquist K.
      Depression, neighborhood deprivation and risk of type 2 diabetes.
      ;
      • Wandell P
      • Carlsson AC
      • Gasevic D
      • Holzmann MJ
      • Arnlov J
      • Sundquist J
      • et al.
      Socioeconomic factors and mortality in patients with atrial fibrillation-a cohort study in Swedish primary care.
      ). In addition, this group had access to primary healthcare data, which is quite unique compared to previous epidemiological studies on pyelonephritis (
      • Czaja CA
      • Scholes D
      • Hooton TM
      • Stamm WE.
      Population-based epidemiologic analysis of acute pyelonephritis.
      ;
      • Ki M
      • Park T
      • Choi B
      • Foxman B.
      The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
      ;
      • Nicolle LE
      • Friesen D
      • Harding GK
      • Roos LL.
      Hospitalization for acute pyelonephritis in Manitoba, Canada, during the period from 1989 to 1992; impact of diabetes, pregnancy, and aboriginal origin.
      ;
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Gupta K
      • Stapleton AE
      • Stamm WE.
      Risk factors associated with acute pyelonephritis in healthy women.
      ). Except for age and income (
      • Ki M
      • Park T
      • Choi B
      • Foxman B.
      The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
      ), no other sociodemographic variables seem to have been previously examined on a nationwide basis. Moreover, the age distribution in this study revealed that the infection might have a biphasic pattern: the IR was highest in the youngest age group, declined in the intermediate age groups, and increased again in the oldest age group. A similar phenomenon was found in both a small population-based study in the USA (
      • Czaja CA
      • Scholes D
      • Hooton TM
      • Stamm WE.
      Population-based epidemiologic analysis of acute pyelonephritis.
      ) and in a large nationwide study in South Korea (
      • Ki M
      • Park T
      • Choi B
      • Foxman B.
      The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
      ). The finding of increased risks of pyelonephritis in non-pregnant women with multiple parities strengthens the consistency between these results and those from previous studies, in regard to age and parities (
      • Nicolle LE
      • Friesen D
      • Harding GK
      • Roos LL.
      Hospitalization for acute pyelonephritis in Manitoba, Canada, during the period from 1989 to 1992; impact of diabetes, pregnancy, and aboriginal origin.
      ;
      • Scholes D
      • Hooton TM
      • Roberts PL
      • Gupta K
      • Stapleton AE
      • Stamm WE.
      Risk factors associated with acute pyelonephritis in healthy women.
      ). This supports that the current data sources were robust and representative. Finally, is it believed that this nationwide open cohort study involved previously unprecedented analyses of the relationship between highly comprehensive sociodemographic factors and acute uncomplicated pyelonephritis in otherwise healthy women.
      In conclusion, the findings of increased risks of uncomplicated pyelonephritis in women with low socioeconomic status and those originating from non-Western countries represent important information. These findings provide new knowledge on this common and serious bacterial infection among otherwise healthy women and suggest that women with low socioeconomic status and immigrant women from around the globe might disproportionately suffer from this infection, even when they live in a country with universal healthcare. More studies on potential causal mechanisms behind the sociodemographic disparities described are warranted.

      Contributors

      All authors approved the final version of the manuscript. Concept: FJ. Development of idea and design: all authors. Access, acquisition, and analysis of data: KS and XL. Statistical analysis and tables: XL supported by KS and FJ. Interpretation of data: FJ supported by KS and XL. Literature search and drafting of manuscript: FJ supported by KS and XL. Critical revision of the manuscript for intellectual content: KS and XL. The authors attest that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

      Data sharing statement

      This study made use of several national registers and, owing to ethical and legal concerns, data cannot be made openly available. Further information regarding the health registries is available from the Swedish National Board of Health and Welfare: https://www.socialstyrelsen.se/en/statistics-and-data/registers/.

      Declaration of interest

      The authors have nothing to disclose.

      Acknowledgments

      This work was supported by research funding granted to Filip Jansåker from the Primary Health Care Management in Region Skåne and ALF funding (both Region Skåne, Sweden), and the Swedish Society of Medicine. It was also funded by grants provided to Kristina Sundquist from the Swedish Research Council and ALF funding. We thank Patrick Reilly and Rebecca Nelsson Jansåker for language edits and review services.

      Appendix. Supplementary materials

      References

        • Belyayeva M
        • Jeong JM.
        Acute Pyelonephritis.
        StatPearls, Treasure IslandFL2021
        • Carlsson AC
        • Li X
        • Holzmann MJ
        • Arnlov J
        • Wandell P
        • Gasevic D
        • et al.
        Neighborhood socioeconomic status at the age of 40 years and ischemic stroke before the age of 50 years: A nationwide cohort study from Sweden.
        Int J Stroke. 2017; 12: 815-826
        • Carlsson AC
        • Li X
        • Holzmann MJ
        • Wandell P
        • Gasevic D
        • Sundquist J
        • et al.
        Neighbourhood socioeconomic status and coronary heart disease in individuals between 40 and 50 years.
        Heart. 2016; 102: 775-782
        • Chaparro MP
        • Koupil I.
        The impact of parental educational trajectories on their adult offspring's overweight/obesity status: a study of three generations of Swedish men and women.
        Soc Sci Med. 2014; 120: 199-207
        • Czaja CA
        • Scholes D
        • Hooton TM
        • Stamm WE.
        Population-based epidemiologic analysis of acute pyelonephritis.
        Clin Infect Dis. 2007; 45: 273-280
        • Dareng EO
        • Ma B
        • Adebamowo SN
        • Famooto A
        • Ravel J
        • Pharoah PP
        • et al.
        Vaginal microbiota diversity and paucity of Lactobacillus species are associated with persistent hrHPV infection in HIV negative but not in HIV positive women.
        Sci Rep. 2020; 10: 19095
        • Das P
        • Aujla M
        • Grac E
        Racial and ethnic equality-time for concrete action.
        Lancet. 2020; 396: 1055-1056
        • Gupta K
        • Hooton TM
        • Naber KG
        • Wullt B
        • Colgan R
        • Miller LG
        • et al.
        International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
        Clin Infect Dis. 2011; 52: e103-e120
        • Gupta K
        • Stapleton AE
        • Hooton TM
        • Roberts PL
        • Fennell CL
        • Stamm WE.
        Inverse association of H2O2-producing lactobacilli and vaginal Escherichia coli colonization in women with recurrent urinary tract infections.
        J Infect Dis. 1998; 178: 446-450
        • Herlitz C
        • Ramstedt K.
        Assessment of sexual behavior, sexual attitudes, and sexual risk in Sweden (1989-2003).
        Arch Sex Behav. 2005; 34: 219-229
        • Jansåker F
        • Li X
        • Sundquist K.
        Sociodemographic factors and uncomplicated cystitis in women aged 15–50 years: a nationwide Swedish cohort registry study (1997–2018).
        The Lancet Regional Health - Europe. 2021; 4100108
        • Ki M
        • Park T
        • Choi B
        • Foxman B.
        The epidemiology of acute pyelonephritis in South Korea, 1997-1999.
        Am J Epidemiol. 2004; 160: 985-993
        • Ludvigsson JF
        • Almqvist C
        • Bonamy AK
        • Ljung R
        • Michaelsson K
        • Neovius M
        • et al.
        Registers of the Swedish total population and their use in medical research.
        Eur J Epidemiol. 2016; 31: 125-136
        • Lundstedt AC
        • McCarthy S
        • Gustafsson MC
        • Godaly G
        • Jodal U
        • Karpman D
        • et al.
        A genetic basis of susceptibility to acute pyelonephritis.
        PLoS One. 2007; 2: e825
        • Mezuk B
        • Chaikiat A
        • Li X
        • Sundquist J
        • Kendler KS
        • Sundquist K.
        Depression, neighborhood deprivation and risk of type 2 diabetes.
        Health Place. 2013; 23: 63-69
        • Nicolle LE.
        Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis.
        Urol Clin North Am. 2008; 35 (v): 1-12
        • Nicolle LE
        • Friesen D
        • Harding GK
        • Roos LL.
        Hospitalization for acute pyelonephritis in Manitoba, Canada, during the period from 1989 to 1992; impact of diabetes, pregnancy, and aboriginal origin.
        Clin Infect Dis. 1996; 22: 1051-1056
        • Ravel J
        • Gajer P
        • Abdo Z
        • Schneider GM
        • Koenig SS
        • McCulle SL
        • et al.
        Vaginal microbiome of reproductive-age women.
        Proc Natl Acad Sci U S A. 2011; 108 (Suppl): 4680-4687
        • Scholes D
        • Hooton TM
        • Roberts PL
        • Gupta K
        • Stapleton AE
        • Stamm WE.
        Risk factors associated with acute pyelonephritis in healthy women.
        Ann Intern Med. 2005; 142: 20-27
        • Scholes D
        • Hooton TM
        • Roberts PL
        • Stapleton AE
        • Gupta K
        • Stamm WE.
        Risk factors for recurrent urinary tract infection in young women.
        J Infect Dis. 2000; 182: 1177-1182
        • Schreiber Pedersen L
        • Lose G
        • Hoybye MT
        • Elsner S
        • Waldmann A
        • Rudnicki M.
        Prevalence of urinary incontinence among women and analysis of potential risk factors in Germany and Denmark.
        Acta Obstet Gynecol Scand. 2017; 96: 939-948
        • Stapleton AE
        • Au-Yeung M
        • Hooton TM
        • Fredricks DN
        • Roberts PL
        • Czaja CA
        • et al.
        Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection.
        Clin Infect Dis. 2011; 52: 1212-1217
        • Sundquist J
        • Ohlsson H
        • Sundquist K
        • Kendler KS.
        Common adult psychiatric disorders in Swedish primary care where most mental health patients are treated.
        BMC Psychiatry. 2017; 17: 235
        • von Elm E
        • Altman DG
        • Egger M
        • Pocock SJ
        • Gotzsche PC
        • Vandenbroucke JP
        • et al.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        Lancet. 2007; 370: 1453-1457
        • Wandell P
        • Carlsson AC
        • Gasevic D
        • Holzmann MJ
        • Arnlov J
        • Sundquist J
        • et al.
        Socioeconomic factors and mortality in patients with atrial fibrillation-a cohort study in Swedish primary care.
        Eur J Public Health. 2018; 28: 1103-1109