14th May 2023, Dr Chee L Khoo
TOBOGM is the very first study to see if immediate treatment of early gestational diabetes mellitus (GDM) increases or reduces pregnancy complications among women with GDM diagnosed with OGTT before 20 weeks’ gestation. TOBOGM study results will significantly contribute to the management decisions of pregnant women with early GDM. Campbelltown Hospital was the lead recruiting centre with Professor David Simmons being the chief investigator of this international study. Well, the wait is finally over (8). We need to dissect the TOBOGM findings as what is written in the 300-word abstract doesn’t tell us the whole story.
Why TOBOGM?
Hyperglycaemia during pregnancy in women with pre-existing diabetes is never good news to offspring nor mother. GDM is associated with increased risks of preeclampsia, obstetrical intervention, large-for-gestational-age neonates, shoulder dystocia, birth trauma, and neonatal hypoglycaemia (1). Hyperglycemia and Adverse Pregnancy Outcome (HAPO) tells us that there are positive associations between increasing plasma glucose levels and both adverse maternal and offspring outcomes in a LINEAR fashion (2).
The HAPO study results is based on the diagnosis of GDM performed between 24-28 weeks. We now screen for GDM at 24-28 weeks in the hope that if we can start treating the hyperglycaemia early we could reduce harm to both mother and offspring. What about women who had hyperglycaemia earlier than 24 weeks? There is evidence that hyperglycaemia in these women is associated with accelerated foetal growth before we get to 24 -28 weeks of pregnancy (3). Is the diagnosis and treatment of women at 24-28 weeks gestation a bit late to prevent adverse neonatal outcomes? It would make sense then, to diagnose GDM before the 24-28 week mark and treat the hyperglycaemia before damage to the offspring have occurred. We already have early screening in place for women with high risk factors for GDM. The only problem is the data for benefit in treating these women is lacking. Until now.
What is TOBOGM?
TOBOGM is a randomised, controlled trial to assess pregnancy outcomes after treatment for gestational diabetes had been initiated before 20 weeks’ gestation, as compared with deferred or no treatment that depended on the results of repeat oral glucose-tolerance testing (OGTT) at 24 – 28 weeks’ gestation. Women were recruited from 17 hospitals in Australia, Austria, Sweden and India. Women ≥ 18 years with a singleton pregnancy between 4 weeks’ and 19 weeks 6 days’ gestation and at least one risk factor (previous GDM, BMI >30, >40 years old, first degree relative with diabetes, previous macrosomia, PCOS or non-European ancestry). In other words, these are women who are at higher risk of GDM.
A 2-hour 75-g OGTT was performed before 20 weeks’ gestation. The diagnostic glucose criteria for GDM used were the World Health Organisation 2013 criteria:
- Fasting ≥ 5.1 mmol/L, or
- 1-hour ≥ 10.0 mmol/L, or
- 2-hour ≥ 8.5 mmol/L
before 20 weeks’ gestation. Women were excluded if they had known pre existing diabetes, a fasting glucose ≥6.1 mmol/L or a 2-hour glucose ≥11.1 mmol/L.
Randomisation
Women were randomly assigned in a 1:1 ratio to receive immediate treatment for GDM or deferred or no treatment, depending on whether the results of a repeat OGTT performed at 24 to 28 weeks’ gestation met the diagnostic criteria for GDM. To conceal the trial-group assignment from the women in the control group and the treating health care team, some women without early gestational diabetes (“decoys”) were randomly assigned in a 2:1 ratio to the same trial procedures (immediate treatment or control). The clinic and trial staff and participants were unaware of the OGTT results. See the flow diagram here.
Management
Management included education, dietary advice, and instructions on how to monitor capillary blood glucose levels. Neonates underwent heel-prick blood glucose testing within 1 to 2 hours after birth, and biometric measurements were recorded within 72 hours after birth.
What was TOBOGM looking for?
The primary outcomes are:
- Composite of adverse neonatal outcomes – birth before 37 weeks’ gestation, birth weight of ≥ 4500 g, birth trauma, neonatal respiratory distress
- Pregnancy-related hypertension – composite of preeclampsia, eclampsia, or gestational hypertension
- Neonatal lean body mass
The secondary outcomes are:
- Total gestational weight gain,
- Caesarean delivery, induction of labour, perineal injury
- Quality of life as measured by the EQ-5D18 at 24 – 28 weeks’ gestation
- Maternal hypoglycaemia
- Birth weight, large-for-gestational-age status and small-for-gestational-age status
- Mean upper-arm circumference, sum of neonatal calipers, neonatal fat mass,
- Severe neonatal hypoglycaemia, bed days in a neonatal intensive care unit (ICU) or in a special care unit at sites with no or an insufficient number of separate neonatal ICU beds.
What did they find?
802 women underwent randomisation — 50.6% were assigned to the immediate treatment group and 49.4% to the control group. The initial OGTT was performed at mean of 15.6 weeks’ gestation; OGTT was performed before 14 weeks’ gestation in 23.2% of the participants. On repeat OGTT at 24 to 28 weeks’ gestation, gestational diabetes was diagnosed again in 67.0% of the women in the control group. (In other words, in 33% women in the control group, the OGTT normalised (according to WHO 2013 criteria) by 24-28 weeks).
A greater percentage of women in the immediate treatment group than in the control group received insulin (58.1% vs. 41.4%) or metformin therapy (23.6% vs. 10.4%).
Neonatal outcomes
An adverse neonatal outcome event occurred in 94 of 378 women (24.9%) in the immediate-treatment group and in 113 of 370 women (30.5%) in the control group, for an adjusted mean difference of −5.6 percentage points (p = 0.02); an adjusted relative risk of 0.82. The number needed to treat to prevent one such event of 18.
If we were to dive into the components of the composite neonatal outcome, respiratory distress occurred in 9.8% of infants born to women in the immediate-treatment group and in 17.0% of infants born to women in the control group, for an adjusted difference of −7 percentage points (or 41% reduction). This was the main driver of the between-group difference observed for the first primary outcome. Respiratory distress is known to occur more frequently in infants born to women with GDM but its incidence has not previously been shown to be lower when we treat GDM diagnosed at 24 to 28 weeks’ gestation (4-7).
In exploratory subgroup analyses, it appears that intervention in women with the glycaemia in the higher range and in women who underwent OGTT at <14 weeks had greater benefit for the composite adverse neonatal outcomes compared with intervention in women with lower range hyperglycaemia (fasting 5.1-5.2 mmol/L, 1-hour 10.0 – 10.5 mmol/L, 2-hour 8.5 – 8.9 mmol/L) and among those who underwent OGTT at/after 14 weeks’ gestation.
The mean neonatal lean body mass was 2.86 g in the immediate-treatment group and 2.91 g in the control group (adjusted mean difference, −0.04 g-no significant difference). However, birthweight was significantly reduced by 72g, neonatal fat mass was reduced by 30g and days in neonatal ICU or special care nursery were reduced by 0.8 days (a 40% reduction).
Exploratory sub-analyses also suggested that among those in the lower OGTT glycaemic range (but not the higher range) with early treatment, there is a possibility of an increased risk of small-for-gestational-age infants. Perhaps, they suggest the possibility that treatment may be more likely to benefit women with higher levels of glycaemia at early screening and may be more likely to confer harm among those with lower values.
Maternal outcomes
Pregnancy-related hypertension occurred in 40 of 378 women (10.6%) in the immediate treatment group and in 37 of 372 women (9.9%) in the control group, for an adjusted mean difference of 0.7% which was not significantly different.
Severe perineal injury occurred in 3 of 375 women (0.8%) in the immediate-treatment group and in 13 of 365 women (3.6%) in the control group, for an adjusted mean difference of −2.8 %. This might be explained by the reduced fat mass and birth weight. Maternal gestational weight gain and the percentage of women who underwent caesarean delivery or induction of labour were similar in the two groups. There was an improvement in the quality of life scores with early treatment.
Thus, overall, immediate treatment of gestational diabetes before 20 weeks’ gestation led to a significantly lower incidence (adjusted relative risk -18%) of a composite of adverse neonatal outcomes than no immediate treatment. The main driver for the modest lower incidence of adverse neonatal outcomes was respiratory distress. The NEJM article referred to the reduction as “modest” but I didn’t think 18% reduction is modest. There were also reductions in neonatal fat mass, days in ICU or special care nursery.
While statistically there was no significant difference in neonatal lean mass, exploratory sub-analyses suggest that intervention in women with GDM diagnosed with OGTT at <20 weeks but with glycaemia at the lower range of hyperglycaemia may confer some harm.
There is no difference in primary maternal outcomes but early diagnosis and treatment of GDM before 20 weeks was associated with a significant reduction of severe perineal tear in women (0.8% vas 3.6%) compared with women in the control group.
The findings from TOBOGM have really thrown open when we should be screening women for GDM especially in women who are at higher risk of GDM. By the time we diagnose GDM at 24-28 weeks, many women, especially those at high risk of GDM, may already have GDM and the damage from hyperglycaemia may already have begun. Further, the diagnostic criteria we are currently using to diagnose GDM will need to be re-looked at in light of the TOBOGM findings.
In the meantime, in women who are at higher risk of GDM, early screening is paramount as early diagnosis and treatment can significantly reduce adverse offspring and maternal outcomes.
References:
- ACOG practice bulletin no. 190: gestational diabetes mellitus. Obstet Gynecol 2018; 131(2): e49-e64.
- The HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcomes. N Engl J Med 2008; 358:1991-2002. DOI: 10.1056/NEJMoa0707943
- Immanuel J, Simmons D. Screening and treatment for early-onset gestational diabetes mellitus: a systematic review and meta-analysis. Curr Diab Rep 2017; 17:115.
- Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009; 361: 1339-48.
- Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005; 352: 2477-86.
- Li Y, Wang W, Zhang D. Maternal diabetes mellitus and risk of neonatal respiratory distress syndrome: a meta-analysis. Acta Diabetol 2019; 56: 729-40.
- Harper LM, Jauk V, Longo S, Biggio JR, Szychowski JM, Tita AT. Early gestational diabetes screening in obese women:a randomized controlled trial. Am J Obstet Gynecol 2020; 222(5): 495.e1-495.e8.
- Simmons D, Immanuel J, Hague WM, Teede H, Nolan CJ, Peek MJ, Flack JR, McLean M, Wong V, Hibbert E, Kautzky-Willer A, Harreiter J, Backman H, Gianatti E, Sweeting A, Mohan V, Enticott J, Cheung NW; TOBOGM Research Group. Treatment of Gestational Diabetes Mellitus Diagnosed Early in Pregnancy. N Engl J Med. 2023 May 5. doi: 10.1056/NEJMoa2214956.