By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: Therapy for gestational diabetes diagnosed before 20 weeks of pregnancy was associated with a slightly decreased frequency of a composite of unfavorable neonatal outcomes compared to deferred treatment or no therapy. No significant changes were demonstrated for pregnancy-related hypertension or neonatal lean body mass between the two groups.
SOURCE: Simmons D, Immanuel J, Hague WM, et al. Treatment of gestational diabetes mellitus diagnosed early in pregnancy. N Engl J Med 2023;388:2132-2144.
Globally, it is estimated that approximately 14% to 16.5% of pregnancies are affected by gestational diabetes mellitus (GDM), a condition characterized by impaired glucose tolerance with onset or first recognition during pregnancy.1,2 According to the Centers for Disease Control and Prevention, 2% to 10% of pregnancies in the United States are affected by GDM every year.3 Because of different diagnostic criteria and cut-off thresholds for the diagnosis of GDM, the prevalence rate varies significantly from country to country.4 Additionally, several other factors contribute to the prevalence of GDM, including maternal age, ethnicity, family history of diabetes, pre-pregnancy weight, and lifestyle factors.5
The treatment of GDM diagnosed early in pregnancy can be a subject of controversy, since there are varying opinions on the best approaches to manage this condition.6 The controversy mainly revolves around the optimal treatment targets and the potential risks and benefits of interventions. Early diagnosis and treatment of GDM generally are associated with better maternal, fetal, and neonatal outcomes, including a reduced risk of preeclampsia, shoulder dystocia, fetal macrosomia, and cesarean delivery.7 Early diagnosis and management of GDM also may have positive effects on long-term maternal and infant health, possibly reducing the risk of developing type 2 diabetes and other metabolic conditions later in life.8 Despite these potential advantages, evidence of the efficacy of early treatment from randomized controlled trials is limited. Simmons et al designed the Treatment of Booking Gestational Diabetes Mellitus (TOBOGM) randomized trial to assess pregnancy outcomes after early treatment for GDM diagnosed prior to 20 weeks of gestation compared with deferred or no treatment, based on results of repeat oral glucose-tolerance testing (OGTT) at 24 to 28 weeks of gestation.9
The TOBOGM was a multi-country, multi-center, randomized clinical trial conducted at 17 sites in four countries (Australia, Austria, Sweden, and India). Inclusion criteria were pregnant women with singleton gestations, between four weeks and 19 weeks, six days gestational age, with at least one risk factor for hyperglycemia (age ≥ 40 years, non-European ancestry, body mass index > 30 kg/m2, a first-degree relative with a history of diabetes, history of polycystic ovarian syndrome [PCOS], and prior history of fetal macrosomia). Women were excluded if they had known pre-existing diabetes, a fasting glucose level of ≥ 110 mg/dL, a two-hour glucose level of ≥ 200 mg/dL, or any medical condition that was considered to be a contraindication by the site investigator.9
The trial had three primary outcomes. The first primary outcome was a composite of adverse neonatal outcomes: birth at < 37 weeks of gestation, birth weight of
≥ 4,500 grams, birth trauma, neonatal respiratory distress syndrome during the 24 hours after birth, need for phototherapy, shoulder dystocia, stillbirth, or neonatal death. The second primary outcome was pregnancy-related hypertension (preeclampsia, eclampsia, or gestational hypertension) and the third primary outcome was newborn lean body mass.
Secondary maternal outcomes included gestational weight gain, cesarean delivery, induction of labor, perineal injury, quality of life (as measured with the EQ-5D at 24 to 28 weeks of gestation), and maternal hypoglycemia. Secondary neonatal outcomes included birth weight, large-for-gestational-age (> 90th percentile), small-for-gestational-age (< 10th percentile), mean upper-arm circumference, neonatal fat mass, severe neonatal hypoglycemia up to 72 hours after birth, and neonatal intensive care unit (NICU) stay. A sample size of at least 800 pregnant individuals (400 women in each group) was required to provide the trial with > 80% power to detect a relative difference of six percentage points, at an alpha level of 0.05, with respect to the first primary outcome (a composite of adverse neonatal outcomes), assuming a type 1 error rate of 5% (two-sided). The primary analysis was by intention-to-treat.
Investigators in the TOBOGM study screened 43,721 pregnant women from May 17, 2017, through March 31, 2022. A total of 802 women met inclusion criteria and underwent randomization, with 406 assigned to receive immediate therapy and 396 assigned to the control group. Among the 793 women in the final sample who had follow-up data, data were available for 748 women (94.3%) regarding the composite adverse neonatal outcome, for 750 women (94.6%) regarding pregnancy-related hypertension, and for 492 women (62.0%) regarding neonatal lean-body mass.
Overall, the two groups were well balanced with respect to the baseline and demographic characteristics. The first OGTT was carried out at a mean (standard deviation [SD]) gestational age of 15.6 ± 2.5 weeks. In the immediate treatment group, 24.9% (94/378) of women experienced an unfavorable neonatal outcome event, compared to 30.5% (113/370) of women in the control group (adjusted risk difference, -5.6 percentage points; 95% confidence interval [CI], -10.1, -1.2). Approximately 10% (37/372) of women in the control group and 10.6% (40/378) of women in the immediate treatment group experienced pregnancy-related hypertension, respectively (adjusted risk difference, 0.7 percentage points; 95% CI, -1.6, 2.9). In the immediate treatment group, the mean newborn lean body mass was 2.86 kg, while in the control group, it was 2.91 kg (adjusted mean difference, -0.04 kg; 95% CI, -0.09, 0.02). There were no statistically significant differences between the two groups with respect to the secondary outcomes.
COMMENTARY
Early diagnosis and treatment of GDM can have advantages. Studies have shown that proper management of GDM can help reduce the risks of adverse fetal and neonatal outcomes, such as fetal macrosomia, large-for-gestational-age neonates, shoulder dystocia, birth injuries, and preterm birth.10 Early therapy for GDM potentially can contribute to better overall maternal health during pregnancy. However, the specific effect of initiating treatment before 20 weeks of gestation on outcomes remains less well established, which was the motivation for Simmons et al to design and complete this randomized trial.9
The investigators demonstrated that therapy for GDM diagnosed before 20 weeks of pregnancy was associated with a slightly decreased frequency of a composite of unfavorable neonatal outcomes compared to deferred or no therapy, with no significant changes in the rate of pregnancy-related hypertension or neonatal lean body mass between the two groups. Compelling evidence for early detection and treatment of hyperglycemia in pregnancy arises from three factors: a continuous positive relationship between maternal blood glucose concentrations and several adverse maternal and neonatal outcomes (as demonstrated by the Hyperglycemia and Adverse Pregnancy Outcome [HAPO] study); the effect of early maternal hyperglycemia on the increased risk for fetal macrosomia in women with type 1 diabetes; and severe adverse pregnancy outcomes described in the literature in women with early GDM.11-14
Despite these compelling reasons to screen for GDM earlier in pregnancy, the tremendous variations in plasma glucose concentrations during the first and early second trimesters of pregnancy remain a major concern when determining criteria for early GDM diagnosis.9 To better understand glycemic patterns in early pregnancy and develop criteria for the diagnosis of GDM in the first and early second trimester, the Glycemic Observation and Metabolic Outcomes in Mothers and Offspring (GO MOMs) study currently is evaluating the use of continuous glucose monitoring between 10 and 14 weeks of gestation. The results of the GO MOMs study will be critical to understanding the optimal timing for early GDM screening and to determine how to incorporate the findings of the TOBOGM trial into clinical practice.
In the United States, the preferred and recommended testing protocol for GDM involves a one-hour, 50-g OGTT without dietary restrictions, followed by a three-hour, 100-g fasting OGTT (if the one-hour OGTT result is ≥ 140 mg/dL but < 200 mg/dL), performed at 24 to 28 weeks of gestation. The current American College of Obstetricians and Gynecologists (ACOG) practice guidelines also recommend early (< 20 weeks) GDM screening for women at high risk of developing GDM, including those with pre-pregnancy BMI > 30 kg/m2, a first-degree relative with diabetes, prior history of GDM, history of PCOS, high-risk ethnicity (African American, Latino, Native American, Asian American, or Pacific Islander), and a known history of impaired glucose tolerance.15
The OGTT is repeated between 24 and 28 weeks of gestation if GDM is not diagnosed on an earlier screen. Treatment of GDM involves dietary modification, exercise, and medications.15 Insulin is the best studied and only Food and Drug Administration-approved medication for GDM therapy, and it remains the first-line medical therapy in pregnant women with GDM.15 Consultation with a nutritionist and co-management with an endocrinologist can be helpful in cases of poorly controlled GDM.
In summary, the findings of this study are premature to adopt into current obstetric practice. Findings from the GO MOMs study will shed more light on when optimally to screen for early GDM and the best management strategies. ACOG continues to recommend screening all pregnant women for GDM at 24 to 28 weeks of gestation with the one-hour, 50-g OGTT (reflexed to the three-hour fasting OGTT if the one-hour OGTT is at or above the 140 mg/dL threshold), and screening women at high risk
for GDM in the first trimester.15 Insulin remains the first-line medical therapy for GDM, as recommended by ACOG.15
REFERENCES
- Plows JF, Stanley JL, Baker PN, et al. The pathophysiology of gestational diabetes mellitus. Int J Mol Sci 2018;19:3342.
- McIntyre HD, Catalano P, Zhang C, et al. Gestational diabetes mellitus. Nat Rev Dis Primers 2019;5:47.
- Centers for Disease Control and Prevention. Gestational diabetes. Last reviewed Dec. 30, 2022. https://www.cdc.gov/diabetes/basics/gestational.html#:~:text=Gestational%20diabetes%20is%20a%20type,pregnancy%20and%20a%20healthy%20baby
- Zhu Y, Zhang C. Prevalence of gestational diabetes and risk of progression to type 2 diabetes: A global perspective. Curr Diab Rep 2016;16:7.
- Khan R, Ali K, Khan Z. Socio-demographic risk factors of gestational diabetes mellitus. Pak J Med Sci 2013;29:843-846.
- Sweeting AN, Ross GP, Hyett J, et al. Gestational diabetes mellitus in early pregnancy: Evidence for poor pregnancy outcomes despite treatment. Diabetes Care 2016;39:75-81.
- 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.
- Bianco ME, Josefson JL. Hyperglycemia during pregnancy and long-term offspring outcomes. Curr Diab Rep 2019;19:143.
- Simmons D, Immanuel J, Hague WM, et al. Treatment of gestational diabetes mellitus diagnosed early in pregnancy. N Engl J Med 2023;388:2132-2144.
- Buchanan TA, Xiang AH, Page KA. Gestational diabetes mellitus: Risks and management during and after pregnancy. Nat Rev Endocrinol 2012;8:639-649.
- HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: Associations with neonatal anthropometrics. Diabetes 2009;58:453-459.
- Wong SF, Chan FY, Oats JJ, McIntyre DH. Fetal growth spurt and pregestational diabetic pregnancy. Diabetes Care 2002;25:1681-1684.
- Page RC, Kirk BA, Fay T, et al. Is macrosomia associated with poor glycaemic control in diabetic pregnancy? Diabet Med 1996;13:170-174.
- Riskin-Mashiah S, Younes G, Damti A, Auslender R. First-trimester fasting hyperglycemia and adverse pregnancy outcomes. Diabetes Care 2009;32:1639-1643.
- [No authors listed]. ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol 2018;131:e49-e64.
Therapy for gestational diabetes diagnosed before 20 weeks of pregnancy was associated with a slightly decreased frequency of a composite of unfavorable neonatal outcomes compared to deferred treatment or no therapy. No significant changes were demonstrated for pregnancy-related hypertension or neonatal lean body mass between the two groups.
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