Gestational Diabetes Mellitus and the risk for urinary tract infections: A case-control study

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Data may be preliminary. 5 January 2025 V1 Latest version Share on Gestational Diabetes Mellitus and the risk for urinary tract infections: A case-control study Authors : Maya Fishbein Sela , Nimrod Truzman , Daniel Noy , Avi Peretz , Maya Azrad , Enav Yefet , and Yuri Perlitz [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173607923.30117928/v1 806 views 162 downloads Contents Abstract ABSTRACT Methods Results Discussion Contribution to Authorship Supplementary Material References Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective : This study aimed to determine whether gestational diabetes mellitus (GDM) increases the risk of urinary tract infections (UTIs), including pyelonephritis, which can affect preterm birth rates and maternal morbidity. Design : A retrospective case-control study. Setting : The study was performed at Tzafon Medical Center, focusing on data collected from 2010 to 2021. Population or Sample : The study included 912 pregnant women who underwent urine culture testing during hospitalization, divided into 449 with positive urine cultures (UTI group) and 463 with negative cultures (control group). Methods : Women were grouped based on urine culture results, matched for age and year of testing. The primary exposure was the GDM rate in each group. Main Outcome Measures : The main outcomes were the incidence of GDM in women with UTIs versus those without and the association of multiple gestations, renal diseases, and thrombophilia with UTI occurrence. Results : GDM rates were 5% in both groups (23/449 in the UTI group and 22/463 in the control group; p = 0.80). Significant associations were found between UTIs and multiple gestations, renal diseases, and thrombophilia. Conclusions : GDM does not increase the risk of UTIs during pregnancy. Further prospective studies are recommended to confirm these findings. Gestational Diabetes Mellitus and the risk for urinary tract infections: A case-control study Maya Fishbein Sela 1 *, Nimrod Truzman 1 *, Daniel Noy 1 , Avi Peretz 1,3 , Maya Azrad 3 , Enav Yefet 1,2,& and Yuri Perlitz 1,2,& 1 Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel 2 Department of Obstetrics and Gynecology, Tzafon Medical Center, Poriya, Israel 3 Clinical Microbiology Laboratory, Tzafon Medical Center, Poriya, Israel * Equal contribution & Senior authors that contributed equally [email protected] ; [email protected] ; [email protected] ; [email protected] ; [email protected] ; [email protected] ; [email protected] . Corresponding author: Dr. Yuri Perlitz, Department of OB&GYN Tzafon Medical Center, MPO Lower Galillee, Israel. Zip 1520800. Tel:+972-4-6652529. Mail: [email protected] Running title: Urinary tract infection in women with gestational diabetes. ABSTRACT Objective : This study aimed to determine whether gestational diabetes mellitus (GDM) increases the risk of urinary tract infections (UTIs), including pyelonephritis, which can affect preterm birth rates and maternal morbidity. Design : A retrospective case-control study. Setting : The study was performed at Tzafon Medical Center, focusing on data collected from 2010 to 2021\RL. Population or Sample : The study included 912 pregnant women who underwent urine culture testing during hospitalization, divided into 449 with positive urine cultures (UTI group) and 463 with negative cultures (control group). Methods : Women were grouped based on urine culture results, matched for age and year of testing. The primary exposure was the GDM rate in each group. Main Outcome Measures : The main outcomes were the incidence of GDM in women with UTIs versus those without and the association of multiple gestations, renal diseases, and thrombophilia with UTI occurrence. Results : GDM rates were 5% in both groups (23/449 in the UTI group and 22/463 in the control group; p = 0.80). Significant associations were found between UTIs and multiple gestations, renal diseases, and thrombophilia. Conclusions : GDM does not increase the risk of UTIs during pregnancy. Further prospective studies are recommended to confirm these findings. Funding: No. Keywords : Gestational Diabetes (GDM); Urinary tract infection (UTI); Asymptomatic bacteriuria (ASB); Pregnancy; Diabetes Mellitus (DM). Main text Funding No funding accepted for this manuscript. Introduction Gestational diabetes mellitus (GDM) is associated with maternal and neonatal unfavorable outcomes such as fetal macrosomia, intrauterine fetal death, metabolic abnormalities, and increased risk of future diabetes mellitus (DM) 1 . During pregnancy there are several physiological changes concerning the mother and the fetus, such as increased insulin demand and gluconeogenesis in the mother and increased glucose demand in the fetus. Failure in insulin synthesis with high rate of gluconeogenesis by the maternal liver increases the overall glucose blood concentration of the pregnant woman leading to GDM 2 . The clinical approach to control GDM involves life-style modifications (e.g. diet, physical activity and weight-control) and strict follow-up of blood glucose concentrations. Most women will be able to control glucose levels by life-style modification while some will need medications as well 2 . Urinary tract infection (UTI) is the most common bacterial infection in both men and women but is more common in women. Approximately half of the women experience UTI at least once in their lifetime, and a quarter of women who have had UTI, experience recurrent infections. Risk factors associated with community-acquired UTI are age, history of UTI, sexual activity, diabetes, and obesity. The most common pathogen is Escherichia Coli ( E.Coli ) which is responsible for about 80% of cases 3–5 . The infection may involve any part of the urinary tract and symptoms may vary or may be absent at all in case of asymptomatic bacteriuria 6 (ASB). UTI is a common complication during pregnancy, especially during the third trimester 7 . During pregnancy the urinary tract undergoes anatomical and physiological changes including increased renal length and glomerular filtration rate (GFR) and decreased ureter peristalsis. Mechanical narrowing of the urinary tract occurs due to the growing uterus, as well as the deviation of the urinary bladder forward and upward. These anatomical and physiological changes increase the transition from cystitis or ASB to pyelonephritis 8 . Therefore, screening and treatment of ASB during pregnancy became standard of care in many countries 8,9 . The association between GDM and increased risk for infections was demonstrated previously 10 . With regards to the urinary tract system, the association between GDM and UTI is less clear. Previous studies that assessed the association between GDM and UTI had various study designs, differences in GDM definition and conflicting results 10 . In the present study we further investigated the association between UTI and GDM. Methods Study design and setting This population-based case control study was conducted at the department of obstetrics and gynecology at Tzafon Medical Center, a university affiliated hospital in Poriya, Israel. The study was authorized by the local review board at Tzafon Medical Center (approval 84 - 21 - POR). Study population included pregnant women who were hospitalized between 2010 and 2021, in the department of obstetrics and gynecology at Tzafon Medical Center of whom urinary culture was obtained. Women were excluded if urine culture was not obtained, if they had pre-GDM or if GDM status was not evaluated during pregnancy. GDM was assessed routinely from the 24 gestational week or earlier if risk factors coexist (e.g. previous GDM). In those cases GDM assessment was repeated between 24 and 28 gestational week if the initial evaluation was negative. Diagnosis of GDM was established if the 50 g glucose challenge test was at least 200 mg/dl or if the 100g oral glucose tolerance test had two abnormal values according to the Carpenter and Coustan criteria 11 . Urine culture Urine samples were collected from midstream urine or through urinary catheters, into sterile containers. Samples were seeded either on CHROMOSTREAK Urine Culture Device (UCD) at the obstetrics and gynecology department (Novamed, Jerusalem, Israel) or on CHROMagar orientation medium (BD Diadnostics, Sparks, MD) at the clinical microbiology laboratory. The UCD use two culture media: MacConkey agar which is a selective medium for gram negative bacteria, and CHROMagar orientation agar, a non-selective medium that enables early recognition of bacteria by colony color (blue for E. coli and pink for Klebsiella spp., etc.). Urinary samples that were not seeded on this UCD, were seeded on CHROMagar orientation agar plates (BD Diagnostics) with a calibrated 1 μL disposable loop. Urine cultures were incubated at defined according to the American Society of Microbiology guidelines 12 . Final bacterial identification was performed using the matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) technology (Bruker Daltonics, Bremen, Germany). Study groups Women were divided into a research group of women with at least one positive urine culture according to the microbiology laboratory database (UTI group) and a matched control group of women with negative cultures in all the available cultures during pregnancy. The control group was matched to the UTI group with respect to age-groups (up to 20, 21-29, 30-35, 36-39, 40 years old and above) and the year urine culture was obtained (2010-2013, 2014-2017 and 2018-2021). Data collection and outcomes The primary explanatory variable was the rate of GDM in each group. Additional data that was collected was the type of GDM; indication for obtaining urine culture; type of infection (ASB, cystitis, pyelonephritis); responsible pathogen; the week of pregnancy in which UTI was detected, and maternal and neonatal complications. Data regarding the study outcomes and variables, urine culture and pregnancy, delivery, and neonatal characteristics were collected retrospectively from medical records of the obstetrics and gynecology department as well as from the microbiology laboratory database. Statistical analysis The rate of GDM is ranging from 0.6 to 15% 13,14 . Assuming that the rates of GDM with and without UTI were 10% versus 5%, respectively, the sample size required was 868 women (5% 2-sided alpha, 80% power). The associations between categorical variables were analyzed using Chi-square test or Fisher exact test. For continuous data, differences were assessed via the t-test or Mann–Whitney U test. Statistical analyses were carried out with SAS version 9.4 (SAS Institute, Cary, NC, USA). Significance was set at a p value of less than 0.05. Results General Features We collected data on 932 pregnant women, of whom, 466 women had UTI and a matched control of 466 women without UTI with respect to their age group and the year urine culture was obtained. Out of those, 17 women in the UTI group and 3 in the control group were excluded due to urine culture contamination and missing of pregnancy follow-up documentation. All together, we evaluated 912 pregnant women, of whom 449 were diagnosed with UTI and 463 were diagnosed without UTI. The indications for performing urine culture are presented in figure 1. \RL Urinary tract infection characteristics are summarized in Table 1. Most cases were classified as asymptomatic bacteriuria (62%). The most common pathogens detected in the positive cultures were E.coli (36%), followed by Enterococcus species (34%) and Streptococcus agalactiae (14%). (Table 2). Among the E.coli isolates, 153 (94%) were sensitive to gentamicin, 152 (94%) were sensitive to nitrofurantoin, 126 (78%) were sensitive to cefuroxime, and 8 (5%) were Extended Spectrum Beta-Lactamase (ESBL) positive. All Enterococcus species were sensitive to vancomycin. Association between GDM and UTI The rate of GDM was similar in the UTI and control groups (23 (5%) women versus 22 (5%) women, respectively; P=0.80). In all the cases of GDM with positive culture the culture was obtained after the 20th gestational week. In sub analysis of women with pyelonephritis (n = 50) the prevalence of GDM was not different than the control group (1 (2%) versus 22 (5%), respectively; P = 0.72). Association between UTI and maternal characteristics The rates of various maternal characteristics in the UTI and control groups are presented in table 3. Parity, gravidity, renal disease, thrombophilia and multiple gestations were associated with increased risk for UTI during pregnancy. Association between UTI, delivery, and neonatal outcomees We assessed delivery and neonatal outcomes in the UTI and control groups (Table 4). All the outcomes that were assessed were not statistically or clinically significant between the groups (Table 4). Discussion Main findings In the present study we aimed to examine the association between GDM and UTI. We found that GDM was not associated with UTI as the prevalence of GDM in women with and without UTI during pregnancy was 5%. Risk factors for UTI were renal disease, thrombophilia, gravidity, parity and multiple gestations. Finally, delivery and neonatal outcomes were similar in women with and without UTI during pregnancy. Other studies findings in the literature Four studies investigated the association between GDM and UTI; three indicated that GDM may be associated with an increased incidence of UTI 15–17 , while the fourth study did not find an association between the two 18 . A recent meta-analysis that analyzed the rate of infections during pregnancy in women with GDM was conducted 10 . The risk for infections during pregnancy was higher in women with GDM compared with women without GDM (pooled OR 1.3 a 95% CI 1.2 to 1.5). For UTI the meta-analysis that analyzed those 4 studies 15–18 , showed a significant association with GDM (pooled OR 1.2 a 95% CI 1.1 to 1.3). Egger’s test showed no significant publication bias (p = 0.39). It should be noted that those studies were highly heterogeneous with regard to their study design (case control, cross-sectional study, prospective cohort study and retrospective cohort study) and area of origin (United States of America, Bangladesh, United Arab Emirates and South Korea), and GDM diagnosis criteria. In addition, they had several methodological limitations: UTI diagnosis method was described only in one study 18 . Only in one study the control group was matched to the research group by age and parity 16 . Type of UTI was reported only in one study 18 . Indications for assessing UTI were not provided. Importantly, the data of those studies was from 1997-2012 when protocols for glycemic control were probably less strict and oral hypoglycemic agents were less available, thus, affecting treatment compliance. In contrast, the current study has several advantages; the data used for this study is more updated ranging from 2010 to 2021; all UTI diagnoses were based on urine cultures from the same microbiology laboratory of the medical center that used the same protocol; indications for assessing UTI were analyzed and also the type of UTI. And finally, matching was done as well as collecting data regarding other demographic characteristics. The rate of UTI in the current study did not differ between women with and without GDM. This observation is in contract with previous studies from the literature 10 . Possible explanations for the difference from the existing literature may be the case control design with matching of the age and year urine culture was obtained, that probably decreased the risk for confounders. Another explanation is by addressing a later period with better modalities and treatments for glycemic control. Our study suggests an association between UTI and other risk factors, among them, multiple gestations, renal diseases and thrombophilia. Multiple gestation was demonstrated previously to be associated with increased risk for UTI 19 as well as urinary tract abnormalities 20 . The association between UTI and thrombophilia is not clear. One study that focused on the most common pathogens that caused UTI requiring hospitalization found that out of 23 women who necessitated hospitalization before term due to UTI, 4 suffered from DM (17%) and 3 from thrombophilia (13%) 21 . But it is not clear what the rate of thrombophilia in the investigated population was. Therefore, the hypothesis that thrombophilia is associated with a higher risk to develop UTI during pregnancy should be investigated further in future studies. Strengths and limitations of the current study The strengths of this study are large sample size with matched control, systematic culture indications and laboratory diagnosis, clear definition for GDM diagnosis and real time computerized data collection. The limitations of our study are its retrospective design, and that data was collected from medical records of the medical center, which may miss community data regarding diagnosis and treatment of UTI. Conclusions GDM was not associated with increased risk for UTI. Future prospective studies are needed to strengthen our results. Disclosure of Interests All authors declare no conflicts of interest related to this study. No specific funding was received for this work. Contribution to Authorship MFS, NT, EY an YP conceived the study. MFS, NT and DN collected the data and contributed to the data analysis. MFS an EY drafted the manuscript. All authors were involved in the critical discussion and approved the final article prior to publication. Supplementary Material File (bjog figure 1.docx) Download 37.78 KB File (bjog tables.docx) Download 23.12 KB References 1. 1. Coustan DR. Gestational diabetes mellitus. Clin Chem. 2013;59(9):1310–21. Google Scholar 2. 2. Lende M, Rijhsinghani A. Gestational diabetes: Overview with emphasis on medical management. Int J Environ Res Public Health. 2020;17(24):1–12. Google Scholar 3. 3. Z T, FM W. Global epidemiology of urinary tract infections. Curr Opin Infect Dis [Internet]. 2016 [cited 2021 Jul 15];29(1):73–9. Available from: https:// .ncbi.nlm.nih.gov/26694621/ Google Scholar 4. 4. McLellan LK, Hunstad DA. Urinary Tract Infection: Pathogenesis and Outlook. Trends Mol Med. 2016;22(11):946–57. Google Scholar 5. 5. Chu CM, Lowder JL. Diagnosis and treatment of urinary tract infections across age groups. Am J Obstet Gynecol. 2018;219(1):40–51. Google Scholar 6. 6. Foxman B, Manning SD, Tallman P, Bauer R, Zhang L, Koopman JS, et al. Uropathogenic Escherichia coli are more likely than commensal E. coli to be shared between heterosexual sex partners. Am J Epidemiol. 2002 Dec 15;156(12):1133–40. Google Scholar 7. 7. Wait RB. Urinary tract infection during pregnancy. Asymptomatic bacteriuria, acute cystitis, and acute pyelonephritis. Postgrad Med. 1984;75(8):153–7, 161. Google Scholar 8. 8. AP G, AJ S. Urinary Tract Infection and Bacteriuria in Pregnancy. Urol Clin North Am [Internet]. 2015 Nov 1 [cited 2021 Aug 2];42(4):547–60. Available from: https:// .ncbi.nlm.nih.gov/26475951/ Google Scholar 9. 9. NL R, M S, DT D, C K, F K, F M, et al. Uropathogenic Escherichia coli isolates from pregnant women in different countries. J Clin Microbiol [Internet]. 2012 Nov [cited 2021 Jul 16];50(11):3569–74. Available from: https:// .ncbi.nlm.nih.gov/22915606/ Google Scholar 10. 10. Yefet E, Bejerano A, Iskander R, Zilberman Kimhi T, Nachum Z. The Association between Gestational Diabetes Mellitus and Infections in Pregnancy—Systematic Review and Meta-Analysis. Microorganisms. 2023 Jul 31;11(8):1956. Google Scholar 11. 11. Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol [Internet]. 1982 Dec 1 [cited 2024 Jan 14];144(7):768–73. Available from: http://www.ajog.org/article/0002937882903490/fulltext Google Scholar 12. 12. Garcia, L.S., and H.D. Isenberg. c2010. Clinical Microbiology Procedures Handbook, 3rd ed. ASM Press, Washington, DC. Google Scholar 13. 13. Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the Prevalence of Preexisting Diabetes and Gestational Diabetes Mellitus Among a Racially/Ethnically Diverse Population of Pregnant Women, 1999–2005. Diabetes Care. 2008 May 1;31(5):899–904. Google Scholar 14. 14. DeSisto CL, Kim SY, Sharma AJ. Prevalence Estimates of Gestational Diabetes Mellitus in the United States, Pregnancy Risk Assessment Monitoring System (PRAMS), 2007–2010. Prev Chronic Dis. 2014 Jun 19;11:130415. Google Scholar 15. 15. Schneeberger C, Erwich JJHM, Heuvel ER van den, Mol BWJ, Ott A, Geerlings SE. Asymptomatic bacteriuria and urinary tract infection in pregnant women with and without diabetes: Cohort study. European Journal of Obstetrics and Gynecology and Reproductive Biology [Internet]. 2018 Mar 1 [cited 2021 Sep 28];222:176–81. Available from: http://www.ejog.org/article/S0301211517305523/fulltext Google Scholar 16. 16. Mannan M, Rahman M, Ara I, Afroz H. Prevalence and Pregnancy Outcome of Gestational Diabetes Mellitus Among Bangladeshi Urban Pregnant Women. J Med. 2012 Nov 26;13(2):147–51. Google Scholar 17. 17. Khatun N, Latif SA, Uddin MM. Pregnancy associated complications of mothers with gestational diabetes mellitus. Mymensingh Med J. 2005 Jul;14(2):196–8. Google Scholar 18. 18. Rizk DE, Mustafa N, Thomas L. The prevalence of urinary tract infections in patients with gestational diabetes mellitus. Int Urogynecol J Pelvic Floor Dysfunct. 2001;12:317–21. Google Scholar 19. 19. Conde-Agudelo A, Belizán JM, Lindmark G. Maternal morbidity and mortality associated with multiple gestations. Obstetrics and gynecology. 2000 Jun;95(6 Pt 1):899–904. Google Scholar 20. 20. Matuszkiewicz-Rowińska J, Małyszko J, Wieliczko M. State of the art paper Urinary tract infections in pregnancy: old and new unresolved diagnostic and therapeutic problems. Archives of Medical Science. 2015;1:67–77. Google Scholar 21. 21. Beksac AT, Orgul G, Tanacan A, Uckan H, Sancak B, Portakal O, et al. Uropathogens and Gestational Outcomes of Urinary Tract Infections in Pregnancies that Necessitate Hospitalization. Curr Urol. 2019 Oct;13(2):70–3. 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Keywords diabetes in pregnancy genitourinary medicine maternal medicine Authors Affiliations Maya Fishbein Sela Bar-Ilan University The Azrieli Faculty of Medicine View all articles by this author Nimrod Truzman Bar-Ilan University The Azrieli Faculty of Medicine View all articles by this author Daniel Noy Bar-Ilan University The Azrieli Faculty of Medicine View all articles by this author Avi Peretz Bar-Ilan University The Azrieli Faculty of Medicine View all articles by this author Maya Azrad Tzafon Medical Center View all articles by this author Enav Yefet Bar-Ilan University The Azrieli Faculty of Medicine View all articles by this author Yuri Perlitz [email protected] Bar-Ilan University The Azrieli Faculty of Medicine View all articles by this author Metrics & Citations Metrics Article Usage 806 views 162 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Maya Fishbein Sela, Nimrod Truzman, Daniel Noy, et al. 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