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Unique Biomarkers in Predicting Gestational Diabetes

Is it time to challenge the glucose challenge?

According to the American Diabetes Association, the incidence pregnancy-associated diabetes is on the rise, the majority of cases being gestational diabetes mellitus (GDM), and the remaining cases being mostly pregestational diabetes. It is known that uncontrolled diabetes in pregnancy can lead to spontaneous abortion, fetal malformations, pre-eclampsia, macrosomia, and intrauterine fetal demise, as well as other conditions. Among common testing in early pregnancy, the fasting oral glucose tolerance test and hemoglobin A1C testing have been considered standard. However, both have limitations as OGTT is difficult for some patients to tolerate, and A1C results may be factitious due to the increased erythrocyte turnover during pregnancy. Several investigators have examined alternative biomarkers and their ability to predict GDM in the early phases of pregnancy. The ideal biomarker would have both high sensitivity, identifying women who will not require further intervention, and high specificity, identifying women who will require further treatment or preventive measures.

Insulin resistance is known to rise near the start of the second semester. Non-diabetic mothers are able to produce sufficient insulin to overcome this syndrome, where pre-gestational and GDM patients do not. Two proposed markers of insulin resistance, fasting insulin and sex hormone-binding globulins (SHBG), have been looked at as early predictors of GDM. Studies looking at fasting insulin in the first trimester failed to establish it as an independent predictor for GDM. SHGB is inversely related to insulin resistance, and first trimester SHGB levels were shown to be lower in women who went on to develop GDM. However, a screen based on this association has not been developed.

Inflammatory markers such as C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α) have been linked to obesity and have been used to predict diabetes in non-pregnant subjects. CRP has been linked to high BMI, but has not been shown to be an independent predictor for GDM.  While placental TNF-α potentiates insulin resistance, studies have not shown a connection between TNF-α and GDM.

First trimester elevations in adipokines, proteins released by adipocytes, have been associated with GDM. Adiponectin enhances insulin sensitivity, so decreased levels may be a marker for GDM, while leptin, which acts as a centrally acting appetite suppressant and peripherally promotes insulin effects, has been shown to be elevated in patients who go on to develop GDM. An earlier study has suggested that adiponectin may be a useful tool in improving prediction of risk, however, the strength of evidence for leptin is not as strong.

Placenta-derived markers include follistatin-like-3 (FSTL3), placental growth factor (PLGF), and placental exosomes, have all been looked at as predictor markers for GDM, with FSTL3 having an inverse relationship, and PLGF and exosomes displaying a direct relationship in patients with GDM. However, a lack of standardized tests for FSTL3, discrepancies in predictive ability of PLGF, and the early state of research into placental exosomes render these as unfavorable markers at present.

Other unique biomarkers are currently being investigated. Glycosylated fibronectin has shown promise in one mid-sized study as an independent predictor, and a newer prospective study is currently under way.  Another study looking at (pro)renin receptor levels showed increased levels in women who developed GDM. However, there was significant overlap with levels displayed in women who maintained normal glucose status.

At present, the use of oral glucose tolerance tests and correlation with other present risk factors remains the community standard for detecting the risk of gestational diabetes. Ongoing studies are examining other biomarkers, and new early term tests may be available in the near future.

Practice Pearls:

  • Both the ADA and the American College of Obstetricians and Gynecologists agree that maintenance of normoglycemia in pregnancy is key in reducing maternal and fetal adverse outcomes.
  • Many specific and unique biomarkers have shown promise in early prediction of gestational diabetes, although most have not been conclusively proven to be useful.
  • The adipocyte protein adiponectin has yielded the most favorable results of reported studies, and further trials are warranted to support preliminary findings.  For now, OGGT remains the standard.

References:

American Diabetes Association. 12. Management of Diabetes in Pregnancy. Diabetes Care. 2016;39 Suppl 1:S94-8. doi: 10.2337/dc16-S015. PubMed PMID: 26696688.

Powe CE. Early Pregnancy Biochemical Predictors of Gestational Diabetes Mellitus. Curr Diab Rep. 2017;17(2):12. doi: 10.1007/s11892-017-0834-y. PubMed PMID: 28229385.

 

Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD