14th September 2020, Dr Chee L Khoo
Tell me this is not, broadly, what you have in mind when you think about gestational diabetes mellitus (GDM). We know that hyperglycaemia and pregnancy does not mix well. GDM is not quite full-blown diabetes in pregnancy but is nonetheless, associated with risks for the mother and infant and with long-term metabolic consequences in both mother and child. While the traditional oral glucose tolerance test (OGTT) is performed at 24-28-week gestation, some women may develop GDM earlier. Since most women in south west Sydney probably fit into one high-risk group or another, we might as well organise an OGTT pretty much at booking, right? Thus, it is important to diagnosed GDM as early as possible so that we can treat the hyperglycaemia early to prevent the adverse effects of hyperglycaemia. Well, not quite!
Screening – who, when and how
Brocard, in 1898 showed that found the presence of glycosuria 2 hours after the ingestion of 50g of glucose in 50% of pregnant women compared to 11% found in non-pregnant women . Glycosuria was also found to be recurrent in successive pregnancies . Professor William in 1909 showed that if a woman’s urine had between 1 – 3 g /L of sugar, it was most likely to be a physiologic condition, but a higher concentration was suggestive of diabetes, particularly if present in early pregnancy or in the presence of symptoms (2). However, the presence of glycosuria during pregnancy and its role as diagnostic of asymptomatic diabetes was a strongly debated subject at the time.
Since that time, there have been many combinations and permutations of glucose tolerance tests ranging from 50g 1-hour test to 100g 3-hour test with all sorts of differing criteria for the diagnosis. The O’Sullivan and Mahan criteria (1964), became the standard for diabetes detection in pregnancy for decades, although they were originally formulated to predict type 2 diabetes in the future and not to predict maternal and foetal problems in the index pregnancy (3).
Along came the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study in 2002. It was meant to clarify the risk of adverse outcomes associated with different degrees of hyperglycaemia in pregnancy (4). We were hoping for a line in the sand to inform us on what is a safe level of glucose but they found that the associations of maternal glycaemia with perinatal outcomes were continuous with no obvious thresholds at which risks increased.
In women with pre-existing diabetes who become pregnant, very tight glucose control is vital. There is evidence to inform us that tight glycaemic control reduces maternal and offspring mortality and morbidity and improve offspring future metabolic health. Similarly, in women who were diagnosed with GDM at 28-week with an OGTT, tight glucose control also improves morbidity, mortality and future health of the child (5). While some countries do not recommend 75g OGTT except in high risk women, 28-week 75g OGTT is recommended in all women in SWS irrespective of their risks.
Should we test earlier than 28 weeks?
Onset of GDM might occur as early as 16–20 weeks. Some (but not all) of these women with early GDM continue to test positive at 28 weeks with an OGTT.
In women where GDM was diagnosed at 28 weeks, foetal overgrowth is already present when GDM is diagnosed. Foetal overgrowth is also present at 20 weeks in women who have overweight or obesity (6). In India, elevated foetal adiposity has been found before the diagnosis of gestational diabetes in women who did not have prediabetes or type 2 diabetes in early pregnancy (7). It is logical to then advocate for screening women earlier for GDM. In fact, the IADPSG and WHO recommend using the same diagnostic threshold used at 24–28 weeks (ie, fasting plasma glucose ≥5·1 mmol/L) to diagnose GDM at an earlier date (8).
However, many clinicians have not followed this recommendation because of insufficient interventional evidence, clinical capacity, and concerns about increasing medicalisation during pregnancy. Most women (80%) with untreated gestational diabetes do not have adverse pregnancy outcomes.
One of the problems of early screening is that fasting glucose can be physiologically higher at the beginning of pregnancy . Some women who were diagnosed with GDM early may test negative at 28 weeks. The Chinese study report that many women with ‘early GDM’ did not have GDM when the oral glucose tolerance test (OGTT) was repeated at 24–28 weeks . Similarly, in a recent Japanese study, women with early-onset GDM (<20 weeks) diagnosed according to IADPSG criteria were followed up without treatment. A repeat 75 g OGTT during mid-pregnancy (24-28 weeks) were normal in about 50% (10).
Does it matter if we treat all these women from booking?
Does early pregnancy screening and intervention improve cardiometabolic outcomes for the offspring, in the short-term and longer term? We don’t actually know. There is little evidence that treating mild early pregnancy fasting hyperglycaemia reduces adverse outcomes in the short-term.
Are we unnecessarily overtreating early GDM women who turn out not to be GDM at later testing (false positive)? Early GDM treatment may reduce incidence of LGA but could lead to SGA/foetal under-nutrition with an increase neonatal admission rate. What is the optimal glycaemic target early in pregnancy? We don’t know and thus, have to be cautious.
It’s not all harmless
Sweeting et al reported that in women at a high risk of GDM, early-onset GDM was associated
with poor pregnancy outcomes that were more comparable with those of women with type 2 diabetes mellitus (11). The group with the poorest pregnancy outcome were diagnosed before 12 weeks. In the Japanese study, compared with false positive early GDM, true GDM was more frequently associated with adverse pregnancy outcomes.
You can now see why we are in a bit of a pickle because our data is incomplete. The Treatment of BOoking Gestational diabetes Mellitus (TOBOGM) was a randomised controlled trial (RCT) comparing pregnancy outcomes among women with booking gestational diabetes (GDM) receiving immediate or deferred treatment (12). It was conducted at Campbelltown Hospital by Professor David Simmons et al and reported 2 years ago. While it was a small pilot study, the study suggests that early treatment may have benefits and harm. A larger RCT is warranted.
So, what is the protocol for screening for GDM in SWS?
- Universally screen all pregnant women using a 75 g oral glucose tolerance test (OGTT) at 24 to 28 weeks. There is no requirement for a 3-day high carbohydrate diet prior to testing. There is no argument here.
- For women at risk of GDM, offer fasting blood glucose test prior to 12 weeks gestation:
- BMI ≥ 30 kg / m2.
- Ethnic background – Asian, Indian subcontinent, Aboriginal, Torres Strait Islander, Pacific Islander, Maori, Middle Eastern, non-white African.
- Previous GDM, elevated blood glucose, or impaired glucose tolerance.
- Family history of DM (first degree relative with diabetes or sister with GDM).
- A previous baby with macrosomia (birth weight > 4500 g).
- Previous perinatal loss.
- Polycystic Ovary Syndrome (PCOS)
- Taking medication that may cause diabetes, e.g., steroids, antipsychotics, immunosuppressants.
- Maternal age ≥ 40 years.
What diagnostic criteria do we use?
- Fasting BGL ≥ 5.1 to 6.9 mmol/L, or
- 1 hour BGL ≥ 10.0 mmol/L, or
- 2 hour BGL ≥ 8.5 to 11.0 mmol/L
- Overt diabetes in pregnancy (likely pre-existing diabetes, needs
- Fasting BGL ≥ 7.0 mmol/L, or
- 2 hour BGL ≥ 11.1 mmol/L, or
- Random BGL ≥ 11.1 mmol/L with symptoms.
If ≥ 6.1 mmol/L, complete urgent referral to diabetes in pregnancy clinic.
If 5.1 to 6.0 mmol/L, refer woman for 75 g OGTT to be completed prior to 20 weeks.
For all women without early GDM or pre-existing diabetes, offer a repeat 75 g OGTT at 24 to 28 weeks gestation.
- Brocard: La glycosuria de al groaesser. These de Paris; 1898.
- Williams JW: The clinical significance of glycosuria in pregnant women. Am J Med Sci 1909, 137:1–26.
- O’Sullivan J, Mahan C: Criteria for the oral glucose tolerance test in pregnancy. Diabetes 1964, 13:278–285.
HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy
Outcomes. N Engl J Med 2008; 358:1991-2002
- Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477-2486. doi:10.1056/NEJMoa042973
- Sovio U, Murphy HR, Smith GC. Accelerated fetal growth prior to diagnosis of gestational diabetes mellitus: a prospective cohort study of nulliparous women. Diabetes Care 2016; 39: 982–87.
- Venkataraman H, Ram U, Craik S, Arungunasekaran A, Seshadri S, Saravanan P. Increased fetal adiposity prior to diagnosis of gestational diabetes in South Asians: more evidence for the ‘thinfat’ baby. Diabetologia 2017; 60: 399–405.
- Metzger BE, Gabbe SG, Persson B, et al.; International Association of Diabetes and Pregnancy Study Groups Consensus Panel . International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676–682
- Zhu WW, Yang HX, Wei YM, Yan J, Wang ZL, Li XL, Wu HR, Li N, Zhang MH, Liu XH, Zhang H. Evaluation of the value of fasting plasma glucose in the first prenatal visit to diagnose gestational diabetes mellitus in China. Diabetes Care. 2013;36(3):586–90.
- Nakanishi S, Aoki S, Kasai J, et al. High probability of false-positive gestational diabetes mellitus diagnosis during early pregnancy. BMJ Open Diab Res Care 2020;8:e001234. doi:10.1136/bmjdrc-2020-001234
- Sweeting AN, Ross GP, Hyett J, Molyneaux L, Constantino M, Harding AJ, Wong J. Gestational diabetes mellitus in early pregnancy: evidence for poor pregnancy outcomes despite treatment. Diabetes Care. 2016;39(1):75–81.
- Simmons, D., Nema, J., Parton, C. et al. The treatment of booking gestational diabetes mellitus (TOBOGM) pilot randomised controlled trial. BMC Pregnancy Childbirth 18, 151 (2018). https://doi.org/10.1186/s12884-018-1809-y