Relaxin is an insulin-like hormone that has physiological targets in organs that are important for insulin action (e.g., the pancreas, the liver and muscle).[1] It is widely known  in  clinical practice and academic field that higher levels of relaxin are  a risk factor for pelvic dysfunction (PD) such as urinary incontinence (UI).[2] Although this mechanistic explanation is reasonable, clinical research on relaxin concentration dosage and UI assessment is limited and inconclusive, thus, its impact on PFM function is not yet known. The primary aim is to investigate relaxin concentration between GDM and non-GDM during pregnancy according to UI status.

This was a cross-sectional study approved by the Institutional Ethical Committee (Protocol Number CAAE 82225617.0.0000.5411). All subjects met the following inclusion criteria: pregnant women period between 24 to 40 weeks of gestation; singleton pregnancy; 18–40 years of age; had not received PFM training or any musculoskeletal PFM treatment before or during pregnancy. The participants were allocated in GDM group if they presented fasting glycemic levels ≥92 mg/dL or 1 hour ≥180 mg/dL or 2 hours ≥153 mg/dL. In addition, participants who had lower levels composed the Non-GDM group. To compose the subgroups according to urinary incontinence status, ICIQ-SF and ISI questionnaires were applied on the same day as relaxin dosage.[3] So, we composed 4 different groups: non-gestational diabetes mellitus continent group (non-GDM-C), non-gestational diabetes mellitus incontinent group (non-GDM-PSUI), gestational diabetes mellitus continent group (GDM-C) and gestational diabetes mellitus incontinent group (GDM-PSUI). The sample size calculation was performed a priori using G*Power. Considering that any other previous research performed the measurement proposed by this study, we considered to the calculations a one-way analysis of variance test, power of 0.80, probability of error α 0.05, effect size of 0.25. According to the study design, it was considered for the calculation four groups (non-GDM-C, non-GDM-PSUI, GDM-C and GDM-PSUI); the estimated sample size required was 180 participants (45 in each group).

282 participants were successfully included in this study, of these, 186 were Non-GDM and were divided according to continence status, 81 were continent and 105 with PSUI; 96 were GDM which divided into 46 continent and 50 with PSUI. The baseline characteristics of 282 participants are summarized on (Table 1). The age of GDM-PSUI was similar to other groups, the pre-gestational BMI was higher compared to the Non-GDM-C and the gestational BMI was higher compared to the Non-GDM-C and GDM-C. The OGTT (fasting; 1 hour and 2 hours), as expected, were different between the Non-GDM and GDM group. The groups were matched for gestational age, maternal weight gain, ethnicity, and previous C-section. The prevalence of PSUI was statistically similar (p=0.485) between the non-GDM (56.5%) and GDM (52.1%) groups. When relaxin-2 concentrations were compared between the non-GDM and GDM groups, excluding the stratification by continence status, the analysis showed similar levels 510.5 (58.7-2563.1) and 437.9 (76.3-3369.7) pg/mL (p=0.216). Tests comparing groups by continence status showed a significant difference (p= <0.001). The GDM-PSUI showed lower relaxin levels than the GDM-C (p=0.027) and Non-GDM-C (p=0.001) groups. In addition, the Non-GDM-PSUI group had lower relaxin levels compared to the Non-GDM-C group (p=0.023) (figure 1).

Our findings showed that the relaxin-2 concentration was associated to the presence of PSUI on GDM and non-GDM groups. Contradicting the literature, the relaxin-2 levels of pregnant with PSUI were lower comparing to pregnant continent. Our main aim was quantifying the relaxin-2 concentrations in the presence to GDM and incontinence, there is no data available considering BMI and maternal age influencing relaxin-2 concentration, but it is important to consider that our groups diverged regarding maternal age and pre-gestational and gestational BMI. These differences should be addressed to the group composition, since in general maternal age and higher BMI are the risk factors of GDM and should be enrolled on the incontinence pathophysiology. DeLancey and Petros highlight the importance of the functional balance between connective tissues and PFM for the continence process. According to hormonal theory, estrogen, progesterone and relaxin-2 are the three most common hormones associated with UI . Relaxin is recognized as an anti-fibrotic hormone. The relaxin’s action facilitates collagen degradation as it promotes changes in its  concentration and remodels the matrix metalloproteinases, gelatinases, collagenases, alpha smooth muscle, in addition to decreasing the gene expression of collagen I and III, and inter-collagen fibril interactions leading to increased collagen fibril sliding and ligament length. Although in clinical practice and even in academic field the concept of higher levels of relaxin leads to pelvic dysfunction, in particular, UI, articles correlating it with the dosage  of relaxin concentrations are scarce, have poor methodological quality and small sample, thus, findings are of limited value  to allow this statement. In our study, we found that pregnant women with PSUI in both the GDM and non-GDM groups, presented lower levels of relaxin in comparison to continent groups, contradicting the higher levels hypothesis. No studies were found comparing non-GDM and GDM groups regarding or not continence status.

Contrasting physiological action on extracellular matrix underlying the subjects of this article, while diabetes leads to a fibrosis process, relaxin, on the other hand leads to anti-fibrotic process. Further studies are needed to investigate the influence over time and determine the strength of the connection between lower levels of relaxin on PFM impairment and fibrosis in GDM population, especially in GDM-PSUI.

Feijóo-Bandín S, Aragón-Herrera A, Rodríguez-Penas D, Portolés M, Roselló-Lletí E, Rivera M, et al. Relaxin-2 in Cardiometabolic Diseases: Mechanisms of Action and Future Perspectives. Front. Physiol. [Internet]. 2017;8. Available from: http://journal.frontiersin.org/article/10.3389/fphys.2017.00599/full
Sangsawang B. Risk factors for the development of stress urinary incontinence during pregnancy in primigravidae: A review of the literature. Eur. J. Obstet. Gynecol. Reprod. Biol. [Internet]. 2014;178:27–34. Available from: http://dx.doi.org/10.1016/j.ejogrb.2014.04.010
Tamanini JTN, Dambros M, D’Ancona CAL, Palma PCR, Rodrigues Netto Jr N. Validação para o português do “International Consultation on Incontinence Questionnaire - Short Form” (ICIQ-SF). Rev. Saude Publica [Internet]. 2004;38:438–44. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0034-89102004000300015&lng=pt&nrm=iso&tlng=pt

Continence 2S2 (2022) 100264
DOI: 10.1016/j.cont.2022.100264