Urinary tract infections are the most common bacterial infection in women, with over 50% of women experiencing at least one UTI during their lifetime. The significant financial and social burden imposed by UTIs is compounded when infections become recurrent, a condition defined as three or more culture-positive episodes in one year, or two or more episodes within six months. The vast majority of these infections originate from uropathogenic bacteria, primarily Escherichia coli (UPEC), which ascend from the gastrointestinal tract.

Postmenopausal women face a heightened risk profile, with approximately 10% requiring treatment for a UTI annually, and 5% of those developing a recurrence within the subsequent year. This increased vulnerability is intricately linked to the hormonal changes of menopause, which necessitate the consideration of alternative preventative strategies due to rising rates of antibiotic resistance and the associated comorbidities of repetitive antibiotic use.

The biological driver behind rUTI susceptibility in menopausal women is the development of GSM, a chronic condition characterized by symptoms resulting from estrogen deficiency, including vaginal dryness, dyspareunia, dysuria, urgency, and recurrent urinary tract infections. GSM affects approximately 50% of postmenopausal women.

The mechanism underlying rUTI susceptibility involves a degenerative shift in the vaginal flora triggered by the lack of estrogen. This hormonal deficiency leads to a significant decrease in protective Lactobacillus species and a consequential increase in vaginal pH. This shift creates an environment favorable for the colonization and proliferation of uropathogens, diminishing the body’s natural defense mechanisms. The focus of non-hormonal treatments like the CO₂ laser is thus centered on reversing this atrophic state and restoring the healthy, acidic vaginal microenvironment.

The rationale for using the CO₂ laser rests on its capacity to induce regenerative changes in the atrophic vaginal and urethral tissues, thereby reversing the physiological hallmarks of GSM that predispose women to rUTI.

Fractional CO₂ laser technology operates through dual effects: photothermal action and biostimulation. The laser precisely ablates superficial layers of tissue while concentrating thermal energy in small strips of the tissue[8]. This controlled thermal injury stimulates the deeper layers, initiating a healing response that includes the regeneration of collagen and elastin fibers (neocollagenesis and elastogenesis)[8, 9]. The photothermal effect is reported to penetrate the vagina to a depth of approximately 0.5 millimeters[9].

This biostimulant effect is crucial because it aims to restore key vaginal functions that are impaired by estrogen deficiency, including mucosal secretion, elasticity, lubrication, and thickness of the vaginal epithelium[8, 9]. Clinically, the observed improvement in GSM symptoms, particularly those related to urinary function, is theorized to result from the restoration of atrophy in the urethral and bladder mucosa[10]. Objective evidence of tissue health improvement is often measured using the Vaginal Health Index Score (VHIS), which studies show significantly increases following laser therapy[11, 12, 13].

The most compelling biological explanation for the laser's potential effectiveness in preventing rUTI is its restorative effect on the urogenital microbiome. The fundamental hypothesis guiding ongoing research suggests that the physical regeneration of the vaginal mucosa creates an environment that facilitates the return of a protective microbial community, specifically decreasing the presence of uropathogens (such as UPEC) and increasing protective Lactobacillus species.

Data from published studies substantiate this microbial shift. Research focusing on postmenopausal women treated with fractional CO₂ laser therapy documented a substantial and statistically significant increase in Lactobacillus prevalence, which rose from 30% initially to 79% after the final treatment session[15]. Critically, this shift was accompanied by the biological re-acidification of the vaginal environment, with the mean vaginal pH decreasing from 5.5 ± 0.8 at baseline to 4.7 ± 0.5 post-treatment (p < 0.001)[15].

This microbiological evidence provides a strong foundation for understanding the clinical outcomes. The improvement in epithelial thickness, coupled with the reduction in pH and the repopulation of Lactobacillus, collectively establishes a powerful physiological barrier and competitive environment that directly inhibits the colonization and growth of uropathogens. Thus, the CO₂ laser functions as a mucosal regeneration therapy that restores the premenopausal protective state without requiring exogenous hormones, making it mechanistically suitable for patients with hormonal contraindications[4].

Clinical outcomes reported in the literature demonstrate that CO₂ laser therapy provides measurable benefits in reducing rUTI recurrence rates and improving associated urinary symptoms.

While short-term results are promising, the durability of the therapeutic effect requires careful consideration. The analysis of subjective distress, measured by the UDI-6, indicated a strong initial response at 3 months, but this significant reduction was not maintained at the 6-month follow-up (MD = -3.034, 95% CI (-7.357, 1.259), p = 0.169)[11].

This temporal observation suggests a complex pattern of recovery and potential decline in symptomatic relief. While objective markers of tissue regeneration, such as the VHIS, continued to show significant improvement at 12 months (MD = 1.553, p = 0.027), and scores related to urinary incontinence (ICIQ-UI SF) were also maintained at 12 months, the general measure of urogenital distress (UDI-6) decreased in significance by six months[11]. This divergence implies that while the structural regeneration and improvement in structural support mechanisms may be long-lasting, the more transient anti-inflammatory or neural effects that relieve overall distress may dissipate faster, potentially indicating a need for maintenance treatments to sustain optimal patient satisfaction beyond the initial treatment course[4, 17].

The synthesis of these quantitative measures is presented below.

Despite positive outcomes reported in prospective cohort studies regarding rUTI reduction and symptom relief, a rigorous critical evaluation of the randomized controlled trial (RCT) literature raises serious questions about the comparative efficacy of the CO₂ laser against control groups.

The conclusion of a systematic review of RCTs found that, overall, there is no statistically significant evidence that the fractional microablative CO₂ lasers are superior to a sham procedure or topical estrogen for the treatment of GSM. This finding is paramount for establishing the true value of the technology.

In trials comparing the laser to a sham procedure (which mimics the essential steps while omitting the energy delivery), three out of five RCTs analyzed showed no statistically significant results compared to the sham group across follow-up periods ranging from 12 weeks to 12 months. Conversely, only two RCTs demonstrated statistically significant benefits for the laser group over the sham. Furthermore, when comparing laser treatment to the established gold standard, topical estrogen, two studies found neither treatment option to be statistically superior to the other (suggesting potential non-inferiority, but not superiority).

The inconsistency between strong efficacy observed in non-randomized studies and the weak showing in sham-controlled RCTs suggests that the observed benefits in small studies may be significantly influenced by a substantial placebo effect, or the contextual benefits associated with a structured, multi-session intervention[2]. If the CO₂ laser is not demonstrably superior to a sham device in most high-quality studies, its broad utility may be limited until further definitive evidence emerges.

The current body of evidence is substantially weakened by pervasive methodological deficiencies across many of the published trials. One primary limitation is the fundamental lack of statistical power. Many trials did not perform necessary power calculations, resulting in consistently small sample sizes. The consequence of underpowered trials is an increased susceptibility to Type II errors—the failure to detect a true difference between the laser and control groups, thereby potentially masking real clinical efficacy.

This methodological gap directly impacts the interpretation of clinical guidelines. The uncertainty regarding comparative efficacy is exacerbated by short follow-up durations, often limited to between three and twelve months, which are insufficient to reliably assess long-term durability, maintenance needs, or sustained prevention of rUTI. Longer follow-up periods, ideally one year or more, are essential for evaluating the sustained regenerative and preventative effects necessary for chronic conditions like rUTI. Further methodological weaknesses include unclear reporting on critical elements such as allocation concealment and whether intention-to-treat or per-protocol analyses were utilized, which further compromises the internal validity and replicability of the findings.

Evaluating the safety profile of the fractional CO₂ laser is crucial for its adoption, especially considering that the treatment is applied to a population already susceptible to genitourinary infections.

Fractional CO₂ laser treatment is generally reported as safe and well-tolerated in studies focusing on GSM[13, 17]. Patients typically report low levels of procedure-related pain; the maximal mean pain score recorded during one study was only 3.1 ± 3.2, primarily associated with probe movement[17].

Mild-to-moderate adverse events (AEs) reported following the procedure are usually transient, including temporary increases in vaginal discharge and mild pain lasting one to two days[12]. These effects resolve quickly, and reports indicate that no patients discontinued treatment due to these mild AEs[12, 17]. Furthermore, a systematic review on CO₂ laser compared to sham found no serious adverse effects reported across the included trials, though the certainty of this evidence is limited by the short duration of follow-up (3 to 12 months)[5].

Clinical guidelines from major professional societies maintain a cautious stance on the broad use of CO₂ laser therapy for GSM symptoms, including rUTI. The American Urogynecologic Society (AUGS) noted a lack of sufficient evidence, resulting in insufficient consensus on many statements related to vaginal energy-based devices (EBDs).

The joint clinical guidelines from the American Urological Association (AUA) and other bodies explicitly recommend local low-dose vaginal estrogen to reduce the risk for future urinary tract infections in patients with GSM and rUTI (Moderate Recommendation; Evidence Level: Grade B)[5]. The Royal College of Obstetricians and Gynaecologists (RCOG) also endorses vaginal estrogens as the gold standard, reiterating the concerns raised by the U.S. Food and Drug Administration (FDA) regarding the adverse effects of EBDs. The FDA issued a public warning that, while lasers are approved for various surgical applications, they are not approved for specific gynecologic indications like GSM or rUTI.

Despite the methodological uncertainties and the lack of demonstrated superiority over sham, the CO₂ laser fulfills a critical role as a non-hormonal treatment option for high-risk populations. The key clinical niche for this therapy lies in the management of GSM and rUTI in patients for whom estrogen is medically contraindicated or actively avoided, particularly breast cancer survivors.

For patients who face reluctance or contraindications concerning vaginal hormone replacement due to endocrine therapy or fear of cancer recurrence, the CO₂ laser provides a regenerative mechanism to restore vaginal tissue health and microbiome balance without systemic or local hormone exposure. Research focused on breast cancer survivors has shown sustained improvement in sexual function and GSM symptoms up to two years post-treatment, without serious adverse effects[23]. Therefore, the CO₂ laser is not poised to replace topical estrogen as the first-line defense but rather acts as a vital, second-line therapeutic modality designed to address the specific needs of hormone-restricted patients.