CME INDIA Presentation by Dr Awadhesh Kumar Singh and Dr Ritu Singh, Department of Diabetes & Endocrinology, & Department of Gynaecology & Obstetrics, G.D Hospital & Diabetes Institute, Kolkata (India)
(As per publication in Expert Opinion on Pharmacotherapy 2020)
Gestational diabetes and pharmacotherapy is a very hot topic and equally misunderstood. Apart from Insulin, metformin has emerged as a strong contender. Still no clear consensus exists till date. Dr Awadhesh Kumar Singh (DM, Endo) and Dr Ritu Singh explain the evidence-based way ahead.
The Problem
- Gestation diabetes mellitus (GDM) is the most encountered medical condition and the commonest form of Hyperglycemia in Pregnancy (HIP).
- This estimate found GDM accounts for 84% of the HIP cases, while remaining 16% relates to diabetes in pregnancy (DIP), which could be either pre-existing diabetes (type 1 or type 2 diabetes) or overt diabetes diagnosed during index pregnancy.
- HAPO showed that a fasting plasma glucose (FPG) of 100-105 mg/dL (5.6-5.8 mmol/L) had five-fold increase in macrosomia as compared to FPG of <75mg/dl.
- Collectively, untreated GDM has often been associated with short- and long-term adverse consequences in mother and child, as evident from both the HAPO and HAPO Follow Up Study (HAPO-FUS).
Why to treat?
- The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS)- Treatment of GDM significantly reduced the serious perinatal morbidities from 4% to 1%.
- Landon et al showed that treating even milder GDM (abnormal oral glucose-tolerance test [OGTT] but a FPG < 95 mg/dL ) significantly improved maternal and neonatal outcomes as compared to no active treatment.
- United States Preventive Services Task Force [2013]-Meta-analysis found 38% relative risk reduction in pre-eclampsia, 50% risk reduction in macrosomia (birth weight >4Kg) and 58% lesser risk of shoulder dystocia in the active treatment arm as compared to the usual care.
- Moreover, it was also not fully conclusive from this meta-analysis, whether maternal weight or gestational weight gain imparted a higher risk of adverse events compared to GDM in the presence of modestly high glucose level. Indeed, the effect of maternal obesity on fetal growth is overwhelming and in the secondary analysis of the LIMIT (Limiting weight gain in overweight and obese women during pregnancy) study, both the factors were more closely related to the adverse outcomes as compared to GDM alone.
- A secondary analysis from HAPO study challenges these findings since both obesity and GDM were independent predictors of several adverse outcomes. HAPO found a significant risk of macrosomia (odds ratio [OR] 2.19, 95% confidence interval [CI] 1.93-2.47) when GDM was present in the absence of obesity, compared to obesity alone in absence of GDM (OR 1.73, 95% CI 1.50-2.00).
- Incidentally, treatment of GDM also led to a significant decrease in both maternal weight gain as well as BMI in Landon et al study (∆ -2.2 Kg and ∆ -1.0 Kg/m2).
Timing is a game changer?
- Exact timing of treatment in GDM is not yet fully clear.
- A secondary analysis of the study by Landon et al in mild GDM (between 24-31 weeks of gestation) stratified on early vs. late treatment (24-26 weeks vs. 27 weeks vs. 28 weeks vs. 29 weeks vs. ≥30 weeks), found no differences in maternal and perinatal outcomes.
- The long-term follow-up study of Landon et al that evaluated children (n=500) of age 5-10 years found no reduction in childhood obesity or metabolic dysfunction between treated and untreated mothers with mild GDM.
Starting Pharmacotherapy
- Since majority of pregnant women with GDM can achieve euglycemia with the lifestyle modifications (LSM) including medical nutritional therapy (MNT) and exercise, only 20-30% require pharmacotherapy in general.
- Understandably, pharmacotherapy should be initiated once normoglycemia is no longer maintained by LSM.
- However, the optimum glucose threshold at which the benefits of initiating pharmacotherapy clearly outweigh the risk, is still not definitively established. Moreover, there is no clear consensus for the timing of pharmacotherapy initiation in literature.
- n (ADA) and the American College of Obstetricians and Gynecologists (ACOG) recommend initiation of pharmacotherapy (preferably insulin therapy), whenever the following upper limits of desirable glucose level is exceeded· Fasting blood glucose >95 mg/dL (>5.3 mmol/L) · One-hour postprandial blood glucose >140 mg/dL (>7.8 mmol/L) · Two-hour postprandial glucose >120 mg/dL.
- It is also not fully known as to how many abnormal glucose values are required to be exceeded on LSM before initiating pharmacotherapy. It seems reasonable to start with 2-weeks of LSM in GDM, although an initial FPG of >95 mg/dL has been found to require pharmacotherapy eventually.
- Heterogeneity indirectly hints to a lack of universal consensus with regards to the timing of initiating pharmacotherapy in GDM.
- Additional indication of initiating pharmacotherapy has emerged from a few RCTs and their meta-analysis even in absence of marked hyperglycemia. Results suggested that initiation of pharmacotherapy should be done in presence of fetal hyperinsulinemia (indirectly measured by ultrasound having fetal abdominal circumference >75th percentile) even in the absence of marked hyperglycemia. This indication may be of limited value in obese mothers with constitutionally large baby. Moreover, macrosomia is often secondary and later consequence in the history of diabetes. This may be the reason as to why these studies also suggested avoiding active pharmacotherapy in women with GDM having a lower risk.
So, What is the Expert Opinion?
- It is indisputable that the treatment of GDM largely improves the short-term adverse maternal and perinatal outcomes.
- It is still inconclusive whether the benefits extend to the long-term outcomes in mother and offspring
- Unanswered Questions:
1.No validated criteria for the dietary failure exists currently, even though three-fourth of GDM can be well managed on LSM.
2. The current cut-offs and targets for treatment initiation in GDM set by the ADA and the ACOG were extrapolated from women also having pre-existing type 2 diabetes in pregnancy.
- These recommendations were based on the 2007 International Workshop Conference on GDM (era of GDM diagnosis, based on Carpenter and Coustoncriteria), before the results of 2008 HAPO study (era of GDM diagnosis, based on International Association of Diabetes in Pregnancy Study Groups [IADPSG] criteria endorsed by World health Organization [WHO] and International Federation of Obstetrics and Gynecology [FIGO].
- The previous Carpenter and Couston criteria for the diagnosis of GDM upon which these current target cut-offs are based, was primarily stratified on future risk of type 2 diabetes to mother with minimal attention given on perinatal outcomes.
- The current target that represents the upper limit of desirable glycemic levels does not match with the mean glucose value of non-diabetic pregnant mothers. Whether lowering the current cut-off value for initiating treatment in GDM would further reduce the adverse outcomes or not, is currently unknown.
3. Is not yet clearly known as to how many measurements exceeding these thresholds would trigger pharmacological intervention.
- To this end, while some suggested initiating pharmacotherapy for ≥2 elevated values for an interval of two weeks, others waited for more persistent elevations and some advocate insulin initiation when one-third of fasting or postprandial glucose levels exceed the target in a given week.
- Finally, while it sounds reasonable to receive pharmacotherapy to decrease the risk of macrosomia in mothers with large fetal abdominal circumferences (>75th percentile) even with mild or no hyperglycemia, ultrasound guided therapy would likely increase in number of women requiring more insulin treatment and more ante-natal visits, besides the increasing frequency of repeated ultrasound examination and its cost-effectiveness.
CME INDIA Take Home
- Collectively, these findings underline the unmet need to update and standardize the universal criteria for the treatment of GDM including the life-style measures and the initiation of pharmacotherapy.
- What we truly need are- well-designed and well-powered future RCTs that can answer the optimal timing of pharmacotherapy initiation and the long-term consequences of treating women with GDM including the future risk of type 2 diabetes, obesity and metabolic syndrome in them and their offspring.
Further Reading
1. Balsells M, García-Patterson A, Gich I, Corcoy R. Ultrasound-guided compared to conventional treatment in gestational diabetes leads to improved birthweight but more insulin treatment: systematic review and meta-analysis. Acta Obstet Gynecol Scand 2014; 93:144. (• This metanalysis evaluated the outcomes of initiating pharmacotherapy based on ultrasound)
2. Caissutti C, Saccone G, Khalifeh A, et al. Which criteria should be used for starting pharmacologic therapy for management of gestational diabetes in pregnancy? Evidence from randomized controlled trials. The Journal of Maternalfetal & Neonatal Medicine. 2019;32(17):2905-2914. (• This systematic review studied the timings of initiating pharmacotherapy in GDM across 15 RCTs)
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