Skip to main content

Recurrent UTI in Women

Recurrent urinary tract infection (rUTI) in women is defined as ≥2 UTIs in 6 months or ≥3 UTIs in 12 months (with at least one culture-confirmed episode), affecting nearly 25% of women who experience an initial UTI.[1][2] The 2025 AUA / CUA / SUFU guideline update represents a paradigm shift toward non-antibiotic prevention strategies, microbiome-centered care, and antimicrobial stewardship.[3][4]

Part I: Epidemiology​

Over 50% of adult women experience at least one UTI in their lifetime.[5][1] Among those with a first UTI, approximately 27–44% will experience recurrence within 12 months.[2] The annual healthcare burden is enormous — in 2019, more than 400 million individuals globally had UTIs, and more than 200,000 died of UTI-related complications.[6]

Microbiology. Escherichia coli causes approximately 75–80% of recurrent UTIs. Other common organisms include Enterococcus faecalis, Proteus mirabilis, Klebsiella species, and Staphylococcus saprophyticus, particularly in patients with risk factors for complicated UTI.[5][7]

Part II: Pathophysiology — evolving understanding​

A. Traditional model — fecal-perineal-urethral ascent​

The classic model holds that uropathogenic bacteria from the gastrointestinal tract colonize the periurethral area, ascend the urethra, and cause cystitis. This model explains the association with sexual intercourse, spermicide use, and anatomic factors.[8][4]

B. Intracellular bacterial communities (IBCs) and quiescent intracellular reservoirs (QIRs)​

A critical advance in understanding rUTI pathogenesis is the discovery that UPEC can invade urothelial cells and form intracellular bacterial communities:[9][10][11]

  1. IBCs — UPEC binds to and invades superficial umbrella cells via type 1 pili, then replicates intracellularly to form biofilm-like communities. IBCs are transient and occur primarily during acute infection.[9]
  2. QIRs — after IBC dispersal, bacteria penetrate into deeper, immature urothelial layers where they enter a quiescent, non-replicating state. These QIRs are protected from antibiotics and immune surveillance.[9][12][11]
  3. Reactivation — as immature host cells differentiate and migrate toward the bladder lumen, dormant bacteria can reactivate and seed recurrent infection — potentially weeks to months after the initial episode.[12][11]

Rosen et al. (2007) confirmed this pathway in humans — IBCs were found in 18% (14/80) of urine specimens from women with acute cystitis, and filamentous bacteria (a hallmark of IBC dispersal) were found in 41%.[10] Approximately 35% of clinical UPEC isolates demonstrate quorum-dependent quiescence in vitro.[13]

C. The urinary microbiome paradigm​

Updated models recognize that the bladder harbors a complex microbiome, and interactions between the urinary and vaginal environments and immune mechanisms at the bladder mucosal surface influence infection susceptibility. Postmenopausal women experience microbiome shifts (loss of protective Lactobacillus species) that increase vulnerability to recurrent infections.[4]

Part III: Risk factors​

PopulationRisk factors
PremenopausalSexual intercourse ≥3× / week, spermicide use, new / multiple sex partners, UTI before age 15, history of UTI in first-degree female relative
PostmenopausalVaginal atrophy / hypoestrogenism, urinary incontinence, cystocele, elevated postvoid residual, prior UTI history
GeneticBlood-group antigen non-secretor phenotype, P1 phenotype, lower CXCR1 (IL-8 receptor) expression, family history of UTI in first-degree female relatives
Not establishedPrecoital / postcoital voiding patterns, wiping patterns, daily beverage consumption, tampon use, douching, hot tub use, type of underwear, BMI
[1][2][3]

Part IV: Diagnosis​

The 2025 AUA / CUA / SUFU guideline update emphasizes several key diagnostic principles:[3][1][14]

Urine culture. At least one symptomatic episode should be verified by urine culture to confirm the diagnosis and guide treatment. A clean-catch or catheterized specimen typically reveals ≥10⁵ CFU/mL, though lower counts (≥10² CFU/mL) may be significant in symptomatic women.[5][2]

Urinalysis. The 2025 update highlights the value of a negative urinalysis in ruling out UTI — a paradigm shift away from microbial detection toward reliance on clinician judgment when weighing individual risks and benefits of antibiosis.[3]

Distinguishing relapse vs. reinfection:[5]

  • Reinfection (>90% of cases) — different organism, or same organism >2 weeks after treatment; originates from outside the urinary tract.
  • Relapse / persistence — same organism within 2 weeks; suggests occult source (calculi, diverticula, foreign body) requiring further evaluation.

Part V: Role of imaging and cystoscopy​

The ACR Appropriateness Criteria (updated 2026) and AUA guidelines are consistent:[5][15][16]

Uncomplicated rUTI (no risk factors) — imaging is usually not appropriate. Cystoscopy has a negative predictive value of 93% for normal findings in women without risk factors, and routine use yields few abnormalities that alter management.[5][16]

Complicated rUTI or red flags — imaging should be considered when:[5][15]

  • Rapid recurrence within 2 weeks (relapse / persistence).
  • Nonresponse to conventional therapy.
  • Hematuria persisting after infection resolution.
  • Known risk factors (calculi, prior surgery, anatomic abnormalities, pneumaturia, fecaluria).
  • CT urography (CTU) or MR urography (MRU) are usually appropriate; ultrasound is a reasonable screening tool.[15]

Flowmetry and postvoid residual (PVR) — more clinically useful than cystoscopy. Abnormalities were identified in 134 / 593 patients and altered treatment (e.g., pelvic-floor training, referral) more frequently than cystoscopy findings.[16]

Part VI: Treatment of acute episodes​

Treatment of an acute rUTI episode follows the same principles as sporadic uncomplicated cystitis:[1][2][17]

First-line agents (per IDSA / AUA guidelines):

  • Nitrofurantoin monohydrate / macrocrystals 100 mg BID × 5 days.
  • Trimethoprim-sulfamethoxazole (TMP-SMX) 160/800 mg BID × 3 days (if local resistance <20%).
  • Fosfomycin 3 g single dose.[2][17][18]

Part VII: Prevention — non-antibiotic strategies​

The 2025 AUA / CUA / SUFU update and multiple guidelines now emphasize non-antibiotic prevention as the preferred first approach before resorting to suppressive antibiotics.[3][19][4]

A. Vaginal estrogen (postmenopausal women) — first-line​

The AUA / CUA / SUFU guideline issues a Moderate Recommendation that peri- and postmenopausal women with rUTI should receive vaginal estrogen therapy to reduce future UTIs, if no contraindication exists.[14]

  • Raz and Stamm (1993) — landmark NEJM placebo-controlled trial of intravaginal estriol; cumulative protection from UTI markedly higher in the estrogen group than placebo, establishing topical estrogen as a foundational rUTI-prevention strategy in postmenopausal women.[22]
  • Meta-analysis of 5 RCTs (1,936 patients) — vaginal estrogen reduced rUTIs by 58% (RR 0.42; 95% CI 0.30–0.59) compared with placebo. Oral estrogen showed no benefit (RR 1.11; 95% CI 0.92–1.35).[20]
  • Tan-Kim et al. (2023) — in 5,638 women prescribed vaginal estrogen for rUTI, UTI frequency decreased by 51.9% (from 3.9 to 1.8 episodes / year; p<0.001).[21]

Formulations. Vaginal estrogen cream (conjugated estrogens 0.5 g 2× / week), estradiol vaginal ring (Estring, replaced every 3 months), or estradiol vaginal tablet (10 mcg 2× / week).[23]

B. Methenamine hippurate​

Methenamine hippurate (1 g BID) works by converting to formaldehyde in acidic urine, acting as a urinary antiseptic without promoting antibiotic resistance.[24][14]

  • ALTAR trial (Harding et al., 2022; n = 240) — multicenter RCT demonstrated methenamine hippurate non-inferior to daily low-dose antibiotics for rUTI prevention (1.38 vs. 0.89 episodes / person-year; absolute difference 0.49, within the predefined non-inferiority margin of 1 UTI / person-year). Antibiotic resistance in E. coli was higher in the antibiotic group (72% vs. 56%; p = 0.05).[24][25]
  • ImpresU trial (Heltveit-Olsen et al., 2025; n = 289 women ≥70 years) — methenamine hippurate reduced antibiotic treatments for UTI by 25% during the 6-month treatment period (IRR 0.75; 95% CI 0.57–1.0; p = 0.049). After discontinuation, the methenamine group had a higher UTI incidence (IRR 1.7; p<0.05).[26]
  • Emerging concern. Hodgkinson et al. (2026) identified formaldehyde-resistant E. coli in 5.8% of ALTAR-derived isolates, mediated by non-functional frmR variants — methenamine has its own resistance risks.[27]

C. Cranberry products​

A network meta-analysis of 50 RCTs (10,495 subjects) found cranberry products reduced UTI incidence by 28% (RR 0.72; 95% CI 0.60–0.87) compared with placebo.[28] The WikiGuidelines consensus (2024) provides a clear recommendation supporting cranberry for rUTI prevention in women, children, and individuals susceptible to UTIs after interventions.[29] Cranberry is less effective than antibiotic prophylaxis, and optimal dosing remains undefined.[2]

D. D-mannose​

D-mannose, a monosaccharide that inhibits bacterial adherence to uroepithelial cells by binding type 1 fimbriae, showed the strongest effect in the network meta-analysis (RR 0.34; 95% CI 0.21–0.56).[28]

However, the MERIT RCT (Hayward et al., 2024; JAMA Intern Med) — the first large, placebo-controlled trial — found that D-mannose 2 g daily for 6 months did not significantly reduce UTI recurrence vs. placebo in a primary-care population. The authors concluded that the evidence does not support recommending D-mannose for rUTI prevention.[6]

E. Probiotics​

Lactobacillus-containing probiotics reduced UTI incidence by 31% (RR 0.69; 95% CI 0.50–0.94) in the network meta-analysis.[28] The AUGS recommends Lactobacillus-containing probiotics as a non-antibiotic alternative, particularly in combination with vaginal estrogen in postmenopausal women.[23]

F. Behavioral modifications​

  • Adequate hydration (one RCT showed increased water intake by 1.5 L / day reduced UTI episodes by ~50%).
  • Urge-initiated voiding and postcoital voiding.
  • Avoidance of spermicidal contraceptives.[5][19]

G. Immunoprophylaxis​

  • OM-89 (Uro-Vaxom) — oral immunostimulant containing E. coli extracts; supported by some European guidelines.[30][31]
  • MV140 — sublingual vaccine containing inactivated uropathogens; promising in reducing rUTI rates in observational studies.[31]

Part VIII: Prevention — antibiotic prophylaxis​

When non-antibiotic strategies fail, antibiotic prophylaxis remains effective and is supported by the AUA / CUA / SUFU as a Conditional Recommendation (Grade B).[14]

Continuous prophylaxis (for infections unrelated to intercourse)[17][2]​

  • Nitrofurantoin 50–100 mg daily at bedtime.
  • TMP-SMX 40/200 mg (half-strength tablet) daily or 3× / week.
  • Trimethoprim 100 mg daily.
  • Fosfomycin 3 g every 10 days.

Continuous prophylaxis reduces recurrences by ~95% (from 2–3 to 0.1–0.2 episodes / patient-year). Typically initiated for a 6-month trial but has been safely continued for 2–5 years without emergence of resistant organisms.[17]

  • TMP-SMX 40/200 mg or 80/400 mg single dose after intercourse.
  • Nitrofurantoin 50–100 mg single dose after intercourse.
  • Ciprofloxacin 125 mg single dose after intercourse.

Postcoital prophylaxis achieves similar recurrence reduction as continuous prophylaxis with lower total antibiotic exposure.[17]

Caveats​

  • Benefits of antibiotic prophylaxis are confined to the usage period — recurrence rates return to baseline after discontinuation.[29]
  • Prophylaxis should not be initiated until eradication of active infection is confirmed by a negative urine culture 1–2 weeks after treatment.[17]
  • Fluoroquinolones should be avoided for prophylaxis given resistance concerns and adverse-effect profile.

Part IX: Special populations​

Postmenopausal women — represent the largest affected group. Management hierarchy:[19][14][21]

  1. Vaginal estrogen (first-line).
  2. Non-antibiotic supplements (methenamine, cranberry).
  3. Antibiotic prophylaxis (if above measures fail).

Women with anatomic / functional abnormalities — cystocele, elevated PVR, urethral diverticula, or mesh erosion require targeted evaluation and treatment of the underlying condition.[5][32]

Antibiotic-resistant infections — multidisciplinary management involving infectious-disease specialists is recommended. Intravesical therapies (antibiotic and non-antibiotic) offer localized treatment with reduced systemic-resistance risk.[31]

Part X: Emerging therapies​

A. Bacteriophage therapy​

The ELIMINATE trial (Kim et al., 2024) — first interventional study of a genetically enhanced bacteriophage cocktail (LBP-EC01, a CRISPR-Cas3-enhanced 6-phage cocktail) — demonstrated a favorable safety profile in uncomplicated UTIs caused by E. coli. Part 2 is testing a combined intraurethral + intravenous phage regimen with concurrent TMP-SMX.[7]

Joshi et al. (2026) showed that lytic phage ΦHP3 reduced UPEC adhesion and invasion of vaginal and bladder epithelial cells in vitro, and daily intravaginal phage administration significantly reduced vaginal UPEC burden in humanized-microbiota mice.[33]

B. UTI vaccines​

Multiple vaccine platforms are under investigation:[31]

  • MV140 (Uromune) — sublingual vaccine containing inactivated E. coli, Klebsiella, Proteus, and Enterococcus; observational data show significant reduction in rUTI rates.
  • OM-89 (Uro-Vaxom) — oral E. coli extract; the most studied immunoprophylactic agent, with some European guidelines recommending its use.

The network meta-analysis found vaccines reduced UTI incidence by 35% (RR 0.65; 95% CI 0.52–0.82).[28]

C. Fecal microbiota transplantation (FMT)​

Initial findings suggest FMT may interrupt the rUTI cycle by restoring a healthy gut microbiome and reducing intestinal colonization with uropathogenic organisms, though clinical data remain preliminary.[34]

D. Intravesical therapies​

Intravesical glycosaminoglycan (GAG) layer replenishment (hyaluronic acid ± chondroitin sulfate) aims to restore the protective bladder lining. Some evidence supports reduced UTI recurrence, though data quality is limited.[19][31]

Part XI: Management algorithm​

Based on the 2025 AUA / CUA / SUFU update and multisociety consensus:[3][1][23][19]

  1. Confirm the diagnosis — at least one culture-proven symptomatic UTI; rule out other causes of LUTS.
  2. Treat the acute episode — short-course antibiotics (nitrofurantoin, TMP-SMX, or fosfomycin).
  3. Identify and modify risk factors — spermicide avoidance, behavioral modifications, adequate hydration.
  4. Non-antibiotic prevention first:
    • Postmenopausal — vaginal estrogen (first-line) ± methenamine hippurate ± cranberry.
    • Premenopausal — behavioral modifications, cranberry, consider methenamine hippurate.
  5. Antibiotic prophylaxis (if non-antibiotic strategies fail):
    • Intercourse-related — postcoital single-dose prophylaxis.
    • Non-intercourse-related — continuous low-dose daily prophylaxis (6-month trial).
    • Self-start therapy for infrequent episodes (≤2 / year).
  6. Further evaluation (if refractory):
    • Flowmetry and PVR measurement.
    • Imaging (CTU / MRU) if complicated features present.
    • Cystoscopy only if red flags (hematuria, suspected structural abnormality).
    • Multidisciplinary referral (urology, infectious disease, urogynecology).

Part XII: Key paradigm shifts (2025 update)​

The 2025 AUA / CUA / SUFU guideline update and contemporary reviews highlight several important shifts:[3][4]

  • From pathogen eradication to microbiome support — emphasis on enhancing the protective urinary and vaginal microbiome rather than solely eliminating pathogens.
  • From routine antibiotics to non-antibiotic first — vaginal estrogen, methenamine hippurate, and cranberry products are now prioritized before antibiotic prophylaxis.
  • From microbial detection to clinical judgment — a negative urinalysis has increasing value in ruling out UTI; treatment decisions should weigh individual risks and benefits rather than relying solely on culture results.
  • From routine cystoscopy to selective evaluation — cystoscopy and imaging are reserved for complicated presentations, not routine rUTI.
  • Antimicrobial stewardship — recognition that repetitive antibiotic use causes "collateral damage" — rising resistance, microbiome disruption, and adverse effects — driving the search for alternatives.

Cross-references​

References​

1. Advani SD, Thaden JT, Perez R, et al. "State-of-the-art review: recurrent uncomplicated urinary tract infections in women." Clin Infect Dis. 2025;80(3):e31–e42. doi:10.1093/cid/ciae653

2. Arnold JJ, Hehn LE, Klein DA. "Common questions about recurrent urinary tract infections in women." Am Fam Physician. 2016;93(7):560–569.

3. Ackerman AL, Bradley M, D'Anci KE, et al. "Updates to recurrent uncomplicated urinary tract infections in women: AUA / CUA / SUFU guideline (2025)." J Urol. 2025. doi:10.1097/JU.0000000000004723

4. Siddiqui NY, Bradley MS. "Updates in clinical management of recurrent urinary tract infections." Obstet Gynecol. 2025. doi:10.1097/AOG.0000000000006060

5. Venkatesan AM, Oto A, Allen BC, et al. "ACR Appropriateness Criteria® recurrent lower urinary tract infections in females." J Am Coll Radiol. 2020;17(11S):S487–S496. doi:10.1016/j.jacr.2020.09.003

6. Hayward G, Mort S, Hay AD, et al. "D-mannose for prevention of recurrent urinary tract infection among women: a randomized clinical trial." JAMA Intern Med. 2024;184(6):619–628. doi:10.1001/jamainternmed.2024.0264

7. Kim P, Sanchez AM, Penke TJR, et al. "Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial." Lancet Infect Dis. 2024;24(12):1319–1332. doi:10.1016/S1473-3099(24)00424-9

8. Hooton TM. "Uncomplicated urinary tract infection." N Engl J Med. 2012;366(11):1028–1037. doi:10.1056/NEJMcp1104429

9. Hannan TJ, Totsika M, Mansfield KJ, et al. "Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection." FEMS Microbiol Rev. 2012;36(3):616–648. doi:10.1111/j.1574-6976.2012.00339.x

10. Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ. "Detection of intracellular bacterial communities in human urinary tract infection." PLoS Med. 2007;4(12):e329. doi:10.1371/journal.pmed.0040329

11. Sharma K, Thacker VV, Dhar N, et al. "Early invasion of the bladder wall by solitary bacteria protects UPEC from antibiotics and neutrophil swarms in an organoid model." Cell Rep. 2021;36(3):109351. doi:10.1016/j.celrep.2021.109351

12. Blango MG, Ott EM, Erman A, Veranic P, Mulvey MA. "Forced resurgence and targeting of intracellular uropathogenic Escherichia coli reservoirs." PLoS One. 2014;9(3):e93327. doi:10.1371/journal.pone.0093327

13. DiBiasio EC, Ranson HJ, Johnson JR, et al. "Peptidoglycan sensing prevents quiescence and promotes quorum-independent colony growth of uropathogenic Escherichia coli." J Bacteriol. 2020;202(20):e00157-20. doi:10.1128/JB.00157-20

14. Anger JT, Bixler BR, Holmes RS, et al. "Updates to recurrent uncomplicated urinary tract infections in women: AUA / CUA / SUFU guideline." J Urol. 2022;208(3):536–541. doi:10.1097/JU.0000000000002860

15. Expert Panel on Urological Imaging, Ward RD, Allen BC, et al. "ACR Appropriateness Criteria® recurrent lower urinary tract infections in females: update 2026." J Am Coll Radiol. 2026. doi:10.1016/j.jacr.2026.03.006

16. Pat JJ, Steffens MG, Witte LPW, Marcelissen TAT, Blanker MH. "Comparison of the diagnostic yield of routine versus indicated flowmetry, ultrasound and cystoscopy in women with recurrent urinary tract infections." Int Urogynecol J. 2022;33(8):2283–2289. doi:10.1007/s00192-021-04871-2

17. Fihn SD. "Acute uncomplicated urinary tract infection in women." N Engl J Med. 2003;349(3):259–266. doi:10.1056/NEJMcp030027

18. Stamm WE, Hooton TM. "Management of urinary tract infections in adults." N Engl J Med. 1993;329(18):1328–1334. doi:10.1056/NEJM199310283291808

19. Steinman MA. "Alternative treatments to selected medications in the 2023 American Geriatrics Society Beers Criteria®." J Am Geriatr Soc. 2025;73(9):2657–2677. doi:10.1111/jgs.19500

20. Chen YY, Su TH, Lau HH. "Estrogen for the prevention of recurrent urinary tract infections in postmenopausal women: a meta-analysis of randomized controlled trials." Int Urogynecol J. 2021;32(1):17–25. doi:10.1007/s00192-020-04397-z

21. Tan-Kim J, Shah NM, Do D, Menefee SA. "Efficacy of vaginal estrogen for recurrent urinary tract infection prevention in hypoestrogenic women." Am J Obstet Gynecol. 2023;229(2):143.e1–143.e9. doi:10.1016/j.ajog.2023.05.002

22. Raz R, Stamm WE. "A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections." N Engl J Med. 1993;329(11):753–756. doi:10.1056/NEJM199309093291102

23. Smith AL, Brown J, Wyman JF, et al. "Treatment and prevention of recurrent lower urinary tract infections in women: a rapid review with practice recommendations." J Urol. 2018;200(6):1174–1191. doi:10.1016/j.juro.2018.04.088

24. Harding C, Mossop H, Homer T, et al. "Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open-label, randomised, non-inferiority trial." BMJ. 2022;376:e068229. doi:10.1136/bmj-2021-0068229

25. Harding C, Chadwick T, Homer T, et al. "Methenamine hippurate compared with antibiotic prophylaxis to prevent recurrent urinary tract infections in women: the ALTAR non-inferiority RCT." Health Technol Assess. 2022;26(23):1–172. doi:10.3310/QOIZ6538

26. Heltveit-Olsen SR, Arnljots ES, Sundvall PD, et al. "Methenamine hippurate as prophylaxis for recurrent urinary tract infections in older women — a triple-blind, randomised, placebo-controlled, phase IV trial (ImpresU)." Clin Microbiol Infect. 2025. doi:10.1016/j.cmi.2025.07.006

27. Hodgkinson NC, Al-Rubaye T, Reed TCP, et al. "Implications for methenamine hippurate use in recurrent urinary tract infection management: formaldehyde resistance and altered urinary composition." PLoS Pathog. 2026;22(3):e1014081. doi:10.1371/journal.ppat.1014081

28. Han Z, Yi X, Li J, Liao D, Ai J. "Nonantibiotic prophylaxis for urinary tract infections: a network meta-analysis of randomized controlled trials." Infection. 2025;53(2):535–546. doi:10.1007/s15010-024-02357-z

29. Nelson Z, Aslan AT, Beahm NP, et al. "Guidelines for the prevention, diagnosis, and management of urinary tract infections in pediatrics and adults: a WikiGuidelines Group consensus statement." JAMA Netw Open. 2024;7(11):e2444495. doi:10.1001/jamanetworkopen.2024.44495

30. Kwok M, McGeorge S, Mayer-Coverdale J, et al. "Guideline of guidelines: management of recurrent urinary tract infections in women." BJU Int. 2022;130(Suppl 3):11–22. doi:10.1111/bju.15756

31. Sze C, Attia S, Zimmern P. "Effective risk-reduction strategies and pharmacological treatment for uncomplicated recurrent urinary tract infections." Expert Opin Pharmacother. 2025. doi:10.1080/14656566.2025.2584405

32. Nosseir SB, Lind LR, Winkler HA. "Recurrent uncomplicated urinary tract infections in women: a review." J Womens Health (Larchmt). 2012;21(3):347–354. doi:10.1089/jwh.2011.3056

33. Joshi B, Zulk JJ, Serchejian C, et al. "Bacteriophage-mediated reduction of uropathogenic E. coli from the urogenital epithelium." Infect Immun. 2026;94(4):e0054325. doi:10.1128/iai.00543-25

34. Zare M, Vehreschild MJGT, Wagenlehner F. "Management of uncomplicated recurrent urinary tract infections." BJU Int. 2022;129(6):668–678. doi:10.1111/bju.15630