Early Screening for Gestational Diabetes Mellitus in a Low Risk Population

Overview

This new feasibility pilot study aims to refine the design and protocols for a larger trial that will investigate the potential benefits of early oral glucose tolerance test (OGTT) screening in a population traditionally defined as low-risk for development of gestational diabetes. The study will evaluate its potential effectiveness in reducing the risks of neonatal morbidity/mortality and obstetric complications. Additionally, a machine learning algorithm to predict gestational diabetes mellitus (GDM) risk based on routinely obtained clinical information at pregnancy booking, and minimally invasive methods, such as continuous glucose monitoring (CGM) and gingival crevicular fluid (GCF) sampling, are being explored to predict the risk of hyperglycaemia. This study aims to investigate the utility of early pregnancy screening to enable timely detection and management of early gestational diabetes development in a low-risk population, ultimately promoting better health outcomes for mothers and their babies.

Detailed description

The Early Screening for Gestational Diabetes Mellitus in a Low-Risk Population (EaGeR) pilot study aims to inform a future trial that would evaluate whether early oral glucose tolerance test (OGTT) screening can improve pregnancy and neonatal outcomes among low-risk pregnant women in Singapore, a country that has one of the highest global incidences of gestational diabetes mellitus (GDM). GDM is associated with higher risks of neonatal and obstetric complications in the short-term, and in the long-term increased cardiometabolic risks in both mothers and their children.

The current local GDM screening practice comprises universal screening of all pregnancies (without pre-existing diabetes) with an OGTT around 24-28 weeks' gestation, and only offering early pregnancy screening to women with traditional high-risk factors for GDM development. The issue is that around 70% of diagnosed GDM cases in Singapore do not possess traditional high-risk factors, and they could have been potentially picked up earlier in gestation, if screened. Conversely, many women identified as high-risk in early pregnancy show normal glucose concentrations in an OGTT when screened in early gestation and when re-screened at 24-28 weeks. This study builds on findings from previous trials, which showed that early screening and treatment of mild glucose intolerance in high-risk women can reduce neonatal complications. The EaGeR Trial seeks to determine whether similar benefits can be achieved in an apparently low-risk Asian population.

This pilot study will recruit 120 low-risk pregnant women before 16 weeks' gestation. All participants will undergo an early OGTT before 16 weeks' and be randomly assigned to one of two arms: the experimental arm, where early OGTT results are revealed and immediate follow-up actions taken if GDM is diagnosed using the WHO 2013 criteria, and the control arm, where early OGTT results are concealed, with follow-up in accordance with standard care involving the routine OGTT screen at 24-28 weeks' gestation.

Data will be collected from the medical records to evaluate the primary and secondary outcomes which include pregnancy and neonatal events, as well as infant measures. Additionally, maternal symptoms and biomarkers, infant anthropometry and breastfeeding will be evaluated. Outcomes will be compared between study arms.

Further, the study will also test the utility of a newly developed machine learning algorithm as a novel and non-invasive method which uses clinical factors available at pregnancy booking to assess individual risk for GDM development. It will also explore the utility of other minimally invasive methods of continuous glucose monitoring (CGM) and gingival crevicular fluid (GCF) sampling at an early stage of pregnancy, in predicting the risk of GDM development.

This initial pilot study will help to refine the design and protocols of the definitive EaGeR Trial which will eventually guide the development of the optimal screening strategy for GDM among low-risk pregnant women in Singapore for improved neonatal and obstetric outcomes.

Interventions

• Diagnostic test Early OGTT Results Revealed
  Early pregnancy screening with a three-time point (fasting, 1h, 2h) 75g oral glucose tolerance test before 16 weeks' gestation with plasma glucose results revealed to the patient and clinician for appropriate management of any diabetes (gestational and type 2, if diagnosed) from early pregnancy onwards.

Primary outcome measures

• Composite of perinatal/neonatal morbidity/mortality [Time frame: At birth to one month postpartum]

Secondary outcome measures (11)

• Pre-eclampsia and hypertensive disorders of pregnancy [Time frame: Up to 49 weeks, from the estimated date of conception (based on menstrual and ultrasound scan data) up to 6 weeks postpartum]
• Antenatal and Peripartum obstetric events [Time frame: Up to 49 weeks, from the estimated date of conception (based on menstrual and ultrasound scan data) up to 6 weeks postpartum]
• Birthweight [Time frame: At Birth]
• Neonatal complications and treatments [Time frame: From Birth to 3 months post-delivery]
• Maternal depression and anxiety symptoms [Time frame: Before 16 weeks' gestation, at around 24-28 weeks gestation (accepted up to 32 weeks and 6 days), postpartum (~1 month; accept 3-6 weeks post-delivery)]
• Breastfeeding [Time frame: Postpartum (~1 month; accept 3-6 weeks post-delivery)]
• Prevalences of pre-existing diabetes mellitus and postpartum dysglycaemia (diabetes and pre-diabetes) [Time frame: Oral glucose tolerance test (OGTT) before 16 weeks of gestation and at around 6-12 weeks postpartum]
• Gestational diabetes incidence (early and late diagnosis) [Time frame: Pregnancy Oral Glucose Tolerance Test (OGTT) before 16 weeks of gestation and/or at around 24-28 weeks of gestation (accept all results till 32 weeks and 6 days)]
• Predictive performance of a novel machine-learning-derived algorithm [Time frame: Up to 54 weeks, from the estimated date of conception (based on menstrual and ultrasound scan data) up to the time of latest OGTT (32 weeks and 6 days gestation or OGTT at 6-12 weeks postpartum)]
• Continuous Glucose Monitor (CGM) Data Measurements and predictive performance [Time frame: Up to 48 weeks, from recruitment up to the time of latest OGTT (32 weeks and 6 days gestation or OGTT at 6-12 weeks postpartum)]
• Gingival crevicular fluid (GCF) and circulating biomarkers [Time frame: Up to 48 weeks, from recruitment up to the time of latest OGTT (32 weeks and 6 days gestation or OGTT at 6-12 weeks postpartum)]

Eligibility criteria

Inclusion criteria

• Pregnant women aged 21-39 years at recruitment
• Singleton pregnancy
• Less than 16 weeks pregnant at recruitment
• Intend to receive antenatal care and give birth at the National University Hospital

Exclusion criteria

• Known pre-existing type 1 or type 2 diabetes mellitus at recruitment
• Classified as high-risk for GDM at pregnancy booking using the traditional checklist:

2.1) Age ≥40 years 2.2) Overweight/obese, i.e., body mass index (BMI) ≥25.0 kg/m2 2.3) First degree relative with diabetes mellitus 2.4) Previously delivered a baby ≥4 kg 2.5) Previously diagnosed with GDM 2.6) Impaired glucose tolerance (IGT) or impaired fasting glycaemia (IFG) on previous testing 2.7) Polycystic ovarian syndrome (PCOS) 2.8) Poor obstetric history (e.g. recurrent pregnancy loss, previous intrauterine death, congenital malformations) 2.9) History of chronic hypertension, hyperlipidaemia or cardiovascular disease 2.10) Glycosuria ≥ 2+ on urine dipstick

• Taking systemic steroid medication or metformin
• Participation in another intervention trial

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Screening

Study locations

Singapore · 1 center

• National University Hospital — Singapore

Publications

• Teo E, Hassan N, Tam W, Koh S. Effectiveness of continuous glucose monitoring in maintaining glycaemic control among people with type 1 diabetes mellitus: a systematic review of randomised controlled trials and meta-analysis. Diabetologia. 2022 Apr;65(4):604-619. doi: 10.1007/s00125-021-05648-4. Epub 2022 Feb 9. PMID 35141761
• Majewska A, Stanirowski PJ, Wielgos M, Bomba-Opon D. Efficacy of Continuous Glucose Monitoring on Glycaemic Control in Pregnant Women with Gestational Diabetes Mellitus-A Systematic Review. J Clin Med. 2022 May 23;11(10):2932. doi: 10.3390/jcm11102932. PMID 35629058
• HAPO Study Cooperative Research Group; Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008 May 8;358(19):1991-2002. doi: 10.1056/NEJMoa0707943. PMID 18463375
• Li LJ, Huang L, Tobias DK, Zhang C. Gestational Diabetes Mellitus Among Asians - A Systematic Review From a Population Health Perspective. Front Endocrinol (Lausanne). 2022 Jun 16;13:840331. doi: 10.3389/fendo.2022.840331. eCollection 2022. PMID 35784581
• Simmons D, Hague WM, Teede HJ, Cheung NW, Hibbert EJ, Nolan CJ, Peek MJ, Girosi F, Cowell CT, Wong VW, Flack JR, McLean M, Dalal R, Robertson A, Rajagopal R. Hyperglycaemia in early pregnancy: the Treatment of Booking Gestational diabetes Mellitus (TOBOGM) study. A randomised controlled trial. Med J Aust. 2018 Nov 5;209(9):405-406. doi: 10.5694/mja17.01129. Epub 2018 May 28. PMID 29793404
• Vinter CA, Tanvig MH, Christensen MH, Ovesen PG, Jorgensen JS, Andersen MS, McIntyre HD, Jensen DM. Lifestyle Intervention in Danish Obese Pregnant Women With Early Gestational Diabetes Mellitus According to WHO 2013 Criteria Does Not Change Pregnancy Outcomes: Results From the LiP (Lifestyle in Pregnancy) Study. Diabetes Care. 2018 Oct;41(10):2079-2085. doi: 10.2337/dc18-0808. Epub 2018 Jul 30. PMID 30061318
• 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 May;222(5):495.e1-495.e8. doi: 10.1016/j.ajog.2019.12.021. Epub 2020 Jan 9. PMID 31926951
• Minschart C, Beunen K, Benhalima K. An Update on Screening Strategies for Gestational Diabetes Mellitus: A Narrative Review. Diabetes Metab Syndr Obes. 2021 Jul 5;14:3047-3076. doi: 10.2147/DMSO.S287121. eCollection 2021. PMID 34262311

Identifiers

NCT: NCT06704035 · 2023/00970

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗