By Dr. Sara Naseri, Dr. Ryan Brewster and Professor Paul D. Blumenthal

For decades, glycated hemoglobin A1c (HbA1c) has been the diagnostic and prognostic standard for primary management of diabetes mellitus (DM).¹ It serves as an index of long-term glycemic control and a predictive indicator of preventable micro- and macrovascular complications, making routine monitoring an essential clinical practice.^2,3 To ensure timely therapeutic adjustments, guidelines advise biannual to quarterly HbA1c assessments, depending on the severity of the disease. Unfortunately, adherence to testing recommendations has been shown to be suboptimal.⁴ Furthermore, the reasons for poor compliance are thought to be multifactorial, including logistical challenges and needle anxiety. Compared to men, women may face greater barriers to effective diabetes management, given known sex-based differences in cardiovascular risk factors, medication compliance, and access to treatment.⁵

But what if there were another way to assess Hemoglobin A1C or for that matter, many other health markers that people, and particularly women, may benefit from knowing on a regular basis?  One answer may lie in thinking about menstrual blood not just as a waste product, but rather as a clinical tool and a window into a variety of health or disease states.  Indeed, menstrual blood is a complex fluid comprising whole blood, vaginal secretions, and cells of the uterine and cervical lining. To date, little is known about its characteristics at a molecular level. However, some recent analyses have revealed a profile similar to systemic blood, along with the presence of clinically-relevant indicators of uterine abnormalities.⁶ A recent pilot study, for example, demonstrated high agreement between menstrual and systemic blood for common biomarkers.⁷ HbA1c, among seven other biomarkers, was found to significantly correlate between the two sources. These results suggested that menstrual blood may be a safe, non-invasive, and cost-effective option for diagnostics, screening, and monitoring in women. Other preliminary work indicates that menstrual blood could also be leveraged in screening for HPV and other cancer biomarkers.⁸

To assess this relationship more definitively, we performed a prospective, observational study to characterize the association between HbA1c levels measured in menstrual and systemic blood among diabetic and healthy women of reproductive age who regularly menstruate. The results of this project are now published in the BMJ-SRH.⁹ One of the innovations applied here was the use of the the Q-Pad^TM (Qurasense, Palo Alto USA), a modified menstrual pad containing a paper-based, dried blood spot (DBS) strip. The public might be most familiar with dried blood spots because they are commonly found at crime scenes and are often used to extract DNA and possibly lead to the identity of a perpetrator.  DBS technology has been widely used for inherited metabolic disease screening in newborns and, more recently, in the measurement of numerous blood-based biomarkers, including HbA1c.^10-12 Importantly, the Q-Pad enables convenient (and non-messy!), acquisition  and stabilization of menstrual blood specimens, which can then be sent to a lab for subsequent analysis.

In this project, 172 volunteers provided both menstrual blood and systemic blood specimens for analysis.  And what did we find? Mean HbA1c levels were 6.53% for menstrual blood and 6.50% for systemic blood (Supplemental Table 2). There were no statistically significant differences in mean HbA1c between blood sources among the overall cohort (p=0.471) or among diabetic patients (p=0.272). When examining the data specifically among the diabetic women mean HbA1c levels in menstrual and systemic blood were not significantly different for patients with either type 1 (p=0.561) or type 2 (p=0.356) diabetes. In fact there was a “straight-line” relationship between Menstrual blood HbA1c and systemic blood HbA1c, meaning that in this study, the menstrual blood was really a window into the woman’s health!

Recent advances in self-care and point-of-care (POC) technologies highlight the advantages of more timely and convenient approaches to this kind of preventive screening¹³.  This is particularly important for women, for whom the opportunity costs inherent in family and child-care responsibilities can make scheduling clinical appointments logistically challenging or inconvenient. It is also  important to recognize novel uses of menstrual blood in the context of well-described gender disparities in diabetes management and outcomes⁵. Previous research indicates that women with diabetes experience disproportionately higher rates of cardiovascular complications and have poorer adherence to treatment regimens.^14-18  Based on our results,  menstrual blood-based HbA1c monitoring could carry economic, clinical, and practical value analogous to POC testing.

Importantly, we found that the Q-Pad performed well with respect to sample acquisition, efficiency and processing. The DBS strip embedded in the Q-Pad was reliable for these purposes. With further validation, the Q-Pad has potential utility to facilitate further investigations and downstream clinical applications involving menstrual blood.

Of course, there are limitations to the present study. Menstrual and systemic blood specimens were subject to differential storage and transport conditions. An unbroken cold chain was maintained for serum samples, while the Q-Pad were left at ambient temperatures until processing. Further studies we will determine the possible effect of sample stability. Another limitation was that participants’ demographic information regarding race or ethnicity was not collected, which have shown to be important factors in HbA1c variability.¹⁹ That said, there is little reason to suspect that menstrual or serum specimens themselves would behave differently by race or ethnicity.

In summary, leveraging the novel Q-Pad for self-collection, we found a high degree of concordance between HbA1c levels in menstrual blood and systemic blood in healthy and diabetic women of reproductive age. Future research is needed to establish menstrual blood-specific reference ranges for HbA1C and other biomarkers and more comprehensively assess both the user experience and the cost-effectiveness associated with Q-Pad usage. However, menstrual blood-based testing could become a safe, non-invasive, and potentially cost-effective alternative to conventional serum -based approaches to improve primary diabetes screening and management in women. More broadly, our findings open the possibility of transforming the significance of menstrual blood from a reproductive waste product to a valuable clinical tool with the potential to address sex-specific differences in healthcare access and outcomes and reduce menstrual stigma globally.

References:

1. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes—2018.Diabetes Care 41, S55–S64 (2018).
2. Eberly, L. E., Cohen, J. D., Prineas, R., Yang, L., & Intervention Trial Research group. Impact of incident diabetes and incident nonfatal cardiovascular disease on 18-year mortality: the multiple risk factor intervention trial experience. Diabetes Care 26, 848–854 (2003).
3. Stamler, J., Vaccaro, O., Neaton, J. D. & Wentworth, D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16, 434–444 (1993).
4. Lian, J. & Liang, Y. Diabetes management in the real world and the impact of adherence to guideline recommendations. Curr Med Res Opin 30, 2233–2240 (2014).
5. The Lancet Diabetes & Endocrinology. Sex disparities in diabetes: bridging the gap. The Lancet Diabetes & Endocrinology 5, 839 (2017).
6. Yang, H., Zhou, B., Prinz, M. & Siegel, D. Proteomic Analysis of Menstrual Blood. Molecular & Cellular Proteomics 11, 1024–1035 (2012).
7. S, N., K, L. & Pd, B. Comparative Assessment of Serum versus Menstrual Blood for Diagnostic Purposes: A Pilot Study. Journal of Clinical and Laboratory Medicine 4, (2019).
8. Wong, S. C. C. et al. Human Papillomavirus DNA Detection in Menstrual Blood from Patients with Cervical Intraepithelial Neoplasia and Condyloma Acuminatum. J. Clin. Microbiol. 48, 709–713 (2010).
9. Naseri S, Brewster RCL, Blumenthal PD. Novel use of menstrual blood for monitoring glycaemic control in patients with diabetes: a proof-of-concept study. BMJ Sex Reprod Health. 2021 Nov 10:bmjsrh-2021-201211. doi: 10.1136/bmjsrh-2021-201211. Epub ahead of print. PMID: 34759003.
10. Bhatti, P. et al. Blood spots as an alternative to whole blood collection and the effect of a small monetary incentive to increase participation in genetic association studies. BMC Medical Research Methodology 9, (2009).
11. Mei, J. V., Alexander, J. R., Adam, B. W. & Hannon, W. H. Use of Filter Paper for the Collection and Analysis of Human Whole Blood Specimens. The Journal of Nutrition 131, 1631S-1636S (2001).
12. Parker, S. P. & Cubitt, W. D. The use of the dried blood spot sample in epidemiological studies. Journal of Clinical Pathology 52, 633–639 (1999).
13. Schnell, O., Crocker, J. B. & Weng, J. Impact of HbA1c Testing at Point of Care on Diabetes Management. Journal of Diabetes Science and Technology 11, 611–617 (2017).
14. Rust, G. et al. Point of care testing to improve glycemic control. International Journal of Health Care Quality Assurance 21, 325–335 (2008).
15. Petersen, J. R. et al. Effect of Point-of-Care on Maintenance of Glycemic Control as Measured by A1C. Diabetes Care 30, 713–715 (2007).
16. Raum, E. et al. Medication non-adherence and poor glycaemic control in patients with type 2 diabetes mellitus. Diabetes Research and Clinical Practice 97, 377–384 (2012).
17. Al-Salameh, A., Chanson, P., Bucher, S., Ringa, V. & Becquemont, L. Cardiovascular Disease in Type 2 Diabetes: A Review of Sex-Related Differences in Predisposition and Prevention. Mayo Clinic Proceedings 94, 287–308 (2019).
18. Siddiqui, M., Khan, M. & Carline, T. Gender Differences in Living with Diabetes Mellitus. Mater Sociomed 25, 140 (2013).
19. Herman, W. H. et al. Differences in A1C by Race and Ethnicity Among Patients With Impaired Glucose Tolerance in the Diabetes Prevention Program. Diabetes Care 30, 2453–2457 (2007).

Read more: Novel use of menstrual blood for monitoring glycaemic control in patients with diabetes: a proof-of-concept study

Sara Naseri, MD is a native of Denmark and a graduate of Aarhus University. Her primary focus is on Women’s health and she is the founder of Qvin, a women’s health company focused on non-invasive health monitoring using menstrual blood.