Intensive glycaemic targets in overweight and obese individuals with gestational diabetes mellitus: clinical trial protocol for the iGDM study

Abstract

Introduction

The prevalence of both obesity and gestational diabetes mellitus (GDM) has increased, and each is associated with adverse perinatal outcomes including fetal overgrowth, neonatal morbidity, hypertensive disorders of pregnancy and caesarean delivery. Women with GDM who are also overweight or obese have higher rates of pregnancy complications when compared with normal-weight women with GDM, which may occur in part due to suboptimal glycaemic control. The current recommendations for glycaemic targets in pregnant women with diabetes are based on limited evidence and exceed the mean fasting (70.9±7.8 mg/dL) and 1-hour postprandial (108.9±12.9 mg/dL) glucose values in pregnant individuals without diabetes. Our prior work demonstrated that the use of intensive (fasting <90 mg/dL and 1-hour postprandial <120 mg/dL) compared with standard (fasting <95 mg/dL and 1-hour postprandial <140 mg/dL) glycaemic targets resulted in improved glycaemic control without increasing the risk for hypoglycaemia in pregnant individuals with GDM, but the impact of intensive glycaemic targets on perinatal outcomes is unknown.

Methods and analysis

The Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus: A Multicenter Randomized Trial (iGDM Trial) is a large, pragmatic randomised clinical trial designed to investigate the impact of intensive versus standard glycaemic targets on perinatal outcomes in women with GDM who are overweight and obese. During the 5-year project period, a multidisciplinary team of investigators from five medical centres representing regions of the USA with high rates of obesity will randomise 828 overweight and obese women with GDM to either intensive or standard glycaemic targets. We will test the central hypothesis that intensive glycaemic targets will result in lower rates of neonatal composite morbidity including large for gestational age birth weight, neonatal hypoglycaemia, respiratory distress syndrome and need for phototherapy when compared with standard glycaemic targets using the intention-to-treat approach to analysis.

Ethics and dissemination

The Institutional Review Board (IRB) at Indiana University School of Medicine approved this study (IRB# 11435; initial approval date 25 August 2021). We will submit the results of the trial for publication in peer-reviewed journals and presentations at international scientific meetings.

Trial registration number

NCT05124808.

Strengths and limitations of this study.

• Strengths of our study include the randomised clinical trial design, which will provide data regarding the impact of maternal glucose levels on perinatal outcomes.

• Limitations include that this study is not blinded to providers and patients, as they need to be aware of intervention allocation to comply with the assigned glycaemic target group. The study arm will be blinded to the study statistician analysing and assessing the association between the intervention and primary and secondary outcomes.

• We are focusing our study on those women with gestational diabetes mellitus (GDM) who have a body mass index ≥25 kg/m², so our results will not be generalisable to all women with GDM.

• Our focus is on the impact of glycaemic levels during pregnancy, which does not allow for the evaluation of our study intervention regarding longer-term maternal or offspring health. In the future, planned maternal and offspring follow-up will shed light on the impact of glycaemic control in pregnancy on longer-term health outcomes.

Introduction

The prevalence of gestational diabetes mellitus (GDM) is increasing, affecting just over 280 000 pregnancies (7.8% of births) in the USA.¹ Offspring of individuals with GDM are at an increased risk for macrosomia, neonatal hypoglycaemia, hyperbilirubinaemia, respiratory distress, birth trauma and stillbirth.^2–4 Maternal risks associated with GDM include pre-eclampsia and caesarean delivery,^{2 5} and up to 70% of women with GDM will ultimately develop diabetes outside of pregnancy (predominantly type 2 diabetes).^{6 7} Exposure to maternal diabetes may contribute to childhood-onset and adult-onset obesity and diabetes in the offspring, which is independent of the association with maternal obesity and genetic predisposition.^{8 9}

Maternal overweight and obesity are also significant health concerns, as 64.3% of reproductive-age females in the USA are overweight or obese based on WHO body mass index (BMI) criteria.¹⁰ Pregnant individuals with a BMI ≥25 kg/m² are at an increased risk for complications such as gestational diabetes, pre-eclampsia, caesarean delivery, large for gestational age (LGA) birth weight and excess neonatal adiposity.^11–15 There may also be lifelong consequences for the offspring of women with obesity, as evidenced by increased adiposity in childhood, adolescence and adulthood.^16–18 Although there is a significant overlap between the risks associated with obesity and GDM, the extent to which obesity is associated with worse perinatal outcomes in women with GDM is incompletely understood,^19–24 in part because only one historical study contained information on glycaemic control.²¹ We previously found that individuals with GDM and obesity are at an increased risk for adverse perinatal outcomes including macrosomia (birth weight >4 kg), neonatal composite morbidity (respiratory distress syndrome, hypoglycaemia and hyperbilirubinemia), indicated preterm birth and hypertensive disorders of pregnancy when compared with individuals with GDM who are normal weight.²⁵ Importantly, individuals with GDM who are overweight and obese were also less likely to have optimal glycaemic control, and those who achieved tighter glycaemic control had rates of macrosomia that were similar to those with GDM and normal weight.²⁵

The American College of Obstetricians and Gynecologists (ACOG), the American Diabetes Association and the Endocrine Society’s recommended glycaemic targets for GDM (fasting <95 mg/dL, 1-hour postprandial <140 mg/dL and 2-hour postprandial <120 mg/dL^26–28) are based on limited supporting data.²⁹ Data from pregnant individuals without GDM demonstrate that the mean±SD fasting glucose is 71±8 mg/dL, with 1- and 2-hour postprandial glucose concentrations of 109±13 and 99±10 mg/dL, respectively, which are much lower than the current recommended glycaemic targets.³⁰ It has been suggested that postprandial targets +1 SD from these weighted means (1-hour pp <122 mg/dL and 2-hour pp <110 mg/dL) may result in improved outcomes when compared with the currently recommended targets.³⁰

We conducted a randomised feasibility trial³¹ of 60 individuals with GDM who were also overweight or obese. Participants were randomised to either standard (fasting <95 mg/dL and 1-hour postprandial <140 mg/dL) or intensive (fasting <90 mg/dL and 1-hour postprandial <120 mg/dL) glycaemic targets. Compared with the standard group, those in the intensive group had improved glycaemic control across a variety of timepoints as assessed by continuous glucose monitoring (CGM) and standard self-monitoring of blood glucose (median 1-hour postprandial glucose 111 (IQR 99–125) vs 124 (IQR 109–139) mg/dL, p<0.001). Notably, rates of maternal hypoglycaemia as assessed by CGM were low and not significantly different between the two groups. We therefore hypothesised that lower glycaemic targets than those currently used may improve perinatal outcomes in women with a BMI ≥25 kg/m² and GDM without causing harm.

Methods and analysis

The Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus: A Multicenter Randomized Trial (iGDM Trial) is a large, pragmatic multicentre randomised clinical trial of intensive (fasting <90 mg/dL and 1-hour postprandial <120 mg/dL) compared with standard (fasting <95 mg/dL and 1-hour postprandial <140 mg/dL) glycaemic targets in 828 individuals with GDM and either overweight or obesity. Our central hypothesis is that intensive glycaemic targets will result in lower rates of neonatal composite morbidity including LGA birth weight, neonatal hypoglycaemia, respiratory distress syndrome and need for phototherapy when compared with standard glycaemic targets. We chose a randomised controlled trial with the goal of obtaining the highest quality evidence to inform clinical practice. The broad inclusion criteria and evaluation of the effects of intensive glycaemic targets in standard clinical practice make this a pragmatic trial. The multicentre design and inclusion of hospitals in several regions of the USA with high rates of obesity (Indiana University School of Medicine, University of Pittsburgh School of Medicine, University of Alabama at Birmingham School of Medicine, University of Oklahoma College of Medicine and Women and Infants Hospital of Rhode Island) increase the generalisability and direct application of the findings. We will follow the Consolidated Standards of Reporting Trials (CONSORT) guidelines in the conduct and reporting of this trial.^{32 33} An independent data safety monitoring board will monitor and audit trial conduct, including a review of any adverse events, every 6–9 months during the clinical trial.

Inclusion criteria

Pregnant individuals are eligible if they are between the ages of 18 and 45 years, carrying a singleton gestation, between 12 0/7 and 32 6/7 weeks of gestation with gestational diabetes diagnosed using either a 50-g 1-hour glucose challenge test (GCT) ≥200 mg/dL or two or more abnormal values on a 100 g oral gluocse tolerance test (OGTT) using the Carpenter-Coustan criteria and who have an overweight or obese BMI at the first prenatal visit (BMI ≥25 kg/m² or ≥23 kg/m² in Asian Americans).

Exclusion criteria

We are excluding individuals who have an inability or unwillingness to provide informed consent or who have an inability to communicate with members of the study team, despite the presence of an interpreter. Individuals who plan to deliver at a non-study affiliated hospital are also excluded, as are those with a baseline creatinine >1.5 mg/dL, significant fetal anomalies diagnosed prior to study enrolment (examples include gastroschisis, spina bifida, complex congenital heart disease or serious karyotypic anomalies that may lead to early delivery or increased risk of neonatal death) and those who have used oral or intravenous/intramuscular steroids within 7 days of study enrolment.

Recruitment

All individuals with GDM who also have a BMI ≥25 kg/m² at the study sites are assessed for eligibility. Medical records of all potential participants are reviewed, and research personnel document the information used to confirm eligibility into the data management system. Once an individual is found to be eligible and agrees to participate, written informed consent is obtained (please see iGDM Consent Form in the online supplemental materials). Each centre has the flexibility to use an approach for screening and consent of patients that is most efficient and suitable for their system. A screening log is kept at all study sites to track exclusion criteria and potential subjects approached for the study.

Randomisation

Consented participants are randomised to either intensive or standard glycaemic targets by study personnel. A confidential web-based randomisation sequence with equal allocation to the intensive or standard glycaemic target groups stratified by study site and timing of GDM diagnosis (<24 weeks and ≥24 weeks) was created by the study statistician. Participants and their providers and clinic staff are notified of their assigned group at the time of randomisation.

Study procedures

Gestational diabetes care

After randomisation, participants continue to receive prenatal care and GDM management by their clinical obstetric provider. While the optimal diet for women with GDM is uncertain, for this study, participants receive standardised dietary counselling consisting of recommendations for three meals and two to three snacks per day with approximately 33%–40% of their calories from carbohydrates, with the remaining calories divided between protein (20%) and fat (40%) based on ACOG recommendations.²⁶ Participants are asked to monitor their glucose values at least four times daily including fasting and 1-hour postprandial values, record them on the provided study glucose logs and report them to their clinical obstetric providers every 1–2 weeks as clinically indicated. Study glucose logs also allow the patient to record any episodes of hypoglycaemia (glucose value <60 mg/dL) or symptoms of hypoglycaemia including their glucose value at the time. They also report any episodes of hypoglycaemia requiring assistance from a third party or any episodes of hypoglycaemia that require emergency medical treatment. All blood sugar logs are scanned into the electronic medical record (EMR) soon after they are received. Study staff view these logs either in-person at prenatal visits or via a review in the EMR. The study team tracks participants’ scheduled visits through the EMR. Study staff communicate with participants if they note that blood sugars have not been reported in the past 2 weeks, and if study staff have concerns about a glucose log, they contact both the patient and the primary care team. All glucose values and hypoglycaemia events are entered into REDCap and monitored centrally. Participants are instructed to contact the study team if they have an episode of hypoglycaemia requiring third-party assistance or emergency medical treatment. Surveillance of the glucose logs and EMR ensures the ascertainment of reported and unreported episodes of severe hypoglycaemia.

Decisions regarding the initiation of therapy are made by the patient’s provider, but the recommended approach for this study is to consider the initiation of medication when 30% or more of glucose values exceed the assigned study group targets. Insulin is recommended as the first-line therapy, but for women who decline insulin, providers discuss the risks and benefits of either metformin or glyburide. After initiation of medical therapy, providers continue to monitor maternal glucose values and titrate medical therapy as needed to achieve adequate control (<30% above the assigned glycaemic targets) while avoiding hypoglycaemia. Other components of standardised GDM management strategies across sites are shown in table 1.

Table 1.

Standardised approach to gestational diabetes mellitus (GDM) treatment at study sites

Nutritional counselling and glucose monitoring	Dietary counselling provided using ACOG recommendations26 Fasting and 1-hour postprandial glucose values reviewed every 1–2 weeks and as clinically indicated
Medical therapy	Insulin recommended as a first-line agent if ≥30% of glucose values exceed standard or intensive targets; if participants decline, then the risks and benefits of oral agents (metformin and glyburide) discussed
Fetal monitoring	At least one ultrasound to evaluate fetal growth performed between 32 and 39 weeks of gestation Antenatal surveillance (weekly biophysical profiles or two times weekly nonstress tests) initiated at 32 weeks of gestation for women who require pharmacotherapy
Delivery	Delivery to occur at or after 39 weeks of gestation unless other indications arise

ACOG, American College of Obstetricians and Gynecologists; BPPs, biophysical profiles; NSTs, non-stress tests.

Study assessments

Between 32 and 36 weeks of gestation, participants undergo a study visit where information on medication use is collected. Maternal glycated haemoglobin is assessed at this visit, and maternal fasting serum and plasma are collected and processed. These specimens are stored at −80°C and shipped to the Indiana University Biobank for assessment of study-specific measures, some of which include maternal cholesterol (total, low-density lipoproteins and high-density lipoproteins) and triglycerides stored for future ancillary studies.

Study outcomes

Primary outcome

The primary outcome for this trial is neonatal composite morbidity (LGA birth weight, neonatal hypoglycaemia, respiratory distress syndrome and need for phototherapy) (refer to the terms defined in table 2). We chose this primary outcome due to its clinical relevance. LGA birth weight is associated with both short-term and long-term risks for offspring,^34–36 and complications such as neonatal hypoglycaemia, respiratory distress syndrome and jaundice are associated with increased healthcare costs including neonatal intensive care unit (NICU) admission.^{37 38}

Table 2.

Primary and secondary study outcomes

Type	Name	Brief description
Primary	Composite of LGA birth weight, neonatal hypoglycaemia, neonatal jaundice and RDS	Definitions provided below as secondary outcomes. The composite primary outcome will be considered to have occurred if a participant has any one component
Secondary	LGA birth weight	≥90th percentile birth weight for gestational age, based on US birth weight nomograms54
Secondary	Neonatal hypoglycaemia	Blood glucose <40 mg/dL in the first 24 hours of life; neonatal glucose monitoring will be performed as per the American Academy of Pediatrics at all study sites40
Secondary	Neonatal jaundice	Documentation of phototherapy; monitoring for jaundice will occur at all study sites as per the American Academy of Pediatrics55
Secondary	RDS	Signs of respiratory distress (tachypnoea, grunting, nasal flaring and cyanosis) with an oxygen requirement within the first 24 hours of life and the presence of radiologic chest findings of hypoaeration and reticulogranular infiltrates or those needing immediate intubation for respiratory distress syndrome
Secondary	Markers of maternal glycaemic control	Per cent of values ≥120 and ≥140 mg/dL Mean fasting and postprandial values 1 week after randomisation Mean fasting and postprandial values in 2 weeks prior to delivery Mean fasting and postprandial values from study enrolment until delivery
Secondary	Maternal hypoglycaemia	Per cent of total glucose values <60 mg/dL Episodes of symptomatic hypoglycaemia, episodes of symptomatic hypoglycaemia requiring assistance
Secondary	SGA birth weight	≤10th percentile birth weight for gestational age, based on US birth weight nomograms54
Secondary	Hypertensive disorders of pregnancy including gestational hypertension and pre-eclampsia	Gestational hypertension56 Requires systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on two occasions at least for hours apart after 20 weeks of gestation in a woman with a previously normal blood pressure Pre-eclampsia Requires systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on two occasions at least for hours apart after 20 weeks of gestation in a woman with a previously normal blood pressure and at least one of the following: Proteinuria (≥300 mg/24-hour timed collection, protein/creatinine ratio >0.3 or 2+ proteinuria on dipstick) Thrombocytopaenia (platelets <100 000) Elevated blood concentrations of liver transaminases to two times the normal concentration Creatinine >1.1 mg/dL or a doubling of the serum creatinine concentration Headache, blurry vision or epigastric/right upper quadrant pain Pulmonary oedema OR Systolic blood pressure of 160 mm Hg or diastolic blood pressure of 110 mg Hg or more
Secondary	Caesarean delivery	Caesarean delivery for any indication
Secondary	Preterm birth <37 weeks	Gestational age at delivery <37 0/7 weeks (spontaneous or indicated)
Secondary	Shoulder dystocia	Failure to deliver the fetal shoulder with gentle downward traction on the fetal head, requiring additional obstetric manoeuvres to effect delivery, as documented by the delivery physician
Secondary	NICU admission	Admission to the neonatal intensive care unit for any indication in the first 7 days of life
Secondary	Infant adiposity	Calculated using a flank skinfold39

LGA, large for gestational age; NICU, neonatal intensive care unit; RDS, respiratory distress syndrome; RUQ, right upper quadrant; SGA, small for gestational age.

Secondary outcomes

Secondary outcomes are individual components of the composite primary outcome and other maternal and neonatal complications that are known to be increased in the setting of maternal GDM (table 2). All infants have their mid-arm circumference and triceps, subscapular and flank skinfolds measured in duplicate (with a third measurement obtained if the first two measurements vary by more than 10%) within 72 hours of birth to assess neonatal fat mass. Neonatal fat mass is then calculated from the mean of the flank skinfold measurements using the following neonatal adiposity formula: 0.54657 + 0.39055 * birth weight (kg) + 0.0453 * flank skinfold (mm) – 0.03237 * length (cm).³⁹ All study sites perform neonatal glucose monitoring consistent with the recommendations of the American Academy of Pediatrics.⁴⁰ Medical records for participants and their infants are reviewed during pregnancy and up to 30 days after delivery for all primary and secondary outcomes.

Sample size calculation

The total sample size for the trial is estimated based on the primary outcome. Observational and clinical data indicated that the baseline prevalence of the composite primary outcome among individuals with GDM and overweight or obese women with GDM at the study sites ranged from 30% at Pittsburgh²⁵ to 50% at the University of Oklahoma (unpublished data). Based on the baseline prevalence of the primary outcome and our prior dating demonstrating that lower maternal glucose values are associated with improved outcomes,²⁵ we assume that the primary outcome would occur in 30% of the standard glycaemic target group and we anticipate a 30% reduction in the prevalence of the composite primary outcome to 21% (ie, an absolute difference of 9%) with tighter glucose control, compared with standard control. To achieve this difference with 80% power and a type 1 error of 0.05, we estimate that we need 744 participants based on a logistic regression model with a two-sided Wald test. We are enrolling 828 participants to account for a 10% loss to follow-up or incomplete data. We anticipate one interim analysis after 50% of enrolled participants have delivered (n=414).

Statistical analysis

The analysis will follow the intention-to-treat principles to reflect the impact of practice change. In addition, we will conduct a per-protocol analysis to assess the impact of adherence to the study protocol on outcomes. We will compare randomisation results to a preplanned randomisation schedule to ensure randomisation integrity. To verify the balance between the randomised groups, we will compare selected baseline characteristics (eg, age, pre-pregnancy BMI, nulliparity, race, tobacco use, chronic hypertension, time of GDM diagnosis (weeks), insurance status, education levels, 50 g glucose challenge test results and 3-hour oral glucose tolerance test results) between the standard and intensive glycaemic target groups using analysis of covariance models for continuous variables and the Cochran-Mantel-Hansel statistic for categorical variables while controlling for the stratification variables of the study site (IU, Pitt, OU, UAB and WIH) and gestational age at diagnosis (<24 and ≥24 weeks). Although planned models for outcomes will only have stratification variables, if any baseline characteristics are found to be unbalanced, we will perform additional analyses including these covariates in the model. We will examine the distributions of continuous variables and use transformation or non-parametric methods in cases that violate the normal distribution assumption. We will also examine the frequency distribution of all categorical variables and use exact inference procedures in cases of zero or small cell size. While all participants are females, we will consider sex as a biological variable by testing whether newborn sex impacts our findings.

For the primary composite outcome (LGA birth weight, neonatal hypoglycaemia, neonatal jaundice requiring phototherapy or respiratory distress syndrome), we will report the OR and associated 95% CI and likelihood ratio p values corresponding to the treatment group indicator from a logistic regression model including as covariates of the stratification variables of the study site (IU, Pitt, OU, UAB and Brown) and gestational age at diagnosis (<24 and ≥24 weeks).

For the secondary outcomes, we will also report the ORs and associated 95% confidence intervals and likelihood ratio test p value corresponding to the treatment group indicator from a logistic regression model. Covariates of stratification variables (study site and time of diagnosis) will be included if sample size permits. For secondary outcomes with small prevalence, such as shoulder dystocia, Fisher’s exact test will be used to compare treatment groups and the OR and exact 95% CI will be reported. A linear model will be employed to compare the continuous outcome of % body fat between treatment groups while adjusting for stratification variables of the study site and gestational age at diagnosis. All model assumptions will be checked, and an appropriate transformation will be used if data are non-normal. For the two continuous blood glucose outcome measures (fasting and postprandial) and time periods (1 week after randomisation, 2 weeks prior to delivery or across all study weeks), a similar linear model will be fit to compare treatment groups. When comparing the mean across all study weeks, weeks in the study will be included as a covariate. An additional model will also be fit for this outcome including an interaction between weeks in the study and treatment group to determine if treatment groups deviate more for those with longer time in the study. Statistical significance will be set at 0.05 for all outcomes. Analyses will be conducted with SAS V9.4 (SAS Institute, Cary, NC).

We will also assess the safety of intensive glycaemic targets by testing the non-inferiority hypothesis that the mean proportion of the per cent of glucose values <60 mg/dL is not significantly greater in those randomly assigned to the intensive treatment group (ie, non-inferiority margin mean of 3.5%) (H₀: Diff ≥3.5% vs H₁: Diff <3.5%). With the sample size of n=744 (372 per group) from the primary aim after accounting for potential loss to follow-up, we will have over 99% power to detect non-inferiority using a one-sided, two-sample t-test with alpha=0.025 assuming the true difference between the means is 1.4% and that the data are drawn from populations with SD of 2.8% and 4.7% (data estimated from our feasibility trial³¹). Even if the true difference in means is as high as 2.5%, we will have 94% power to detect non-inferiority.

Patient and public involvement

Input regarding the study intervention was obtained from participants in the pilot trial, which enrolled similar participants to the current trial. Prior to trial initiation, we also obtained input on study design from diabetes educations and obstetric care providers.

Discussion

Glucose is well accepted to be a significant contributor to pregnancy outcomes. In 1954, Pedersen proposed that accelerated fetal growth in pregnancies complicated by diabetes occurred as a result of fetal hyperglycaemia leading to elevated levels of fetal insulin, which acts as a growth factor.⁴¹ More recently the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study found that adverse pregnancy outcomes including birth weight >90th percentile, primary caesarean delivery, clinical neonatal hypoglycaemia, cord-blood serum C peptide >90th percentile, preterm birth, shoulder dystocia or birth injury, NICU admission, hyperbilirubinaemia and preeclampsia were more common with increasing maternal glucose levels even below the diagnostic thresholds for GDM.⁴² In addition, follow-up data from the HAPO study highlighted that exposure to higher glucose levels in utero is significantly associated with higher childhood glucose and insulin resistance, independent of maternal or childhood BMI.⁴³

Identifying and treating GDM diagnosed between 24 and 28 weeks improves rates of some (but not all) maternal and neonatal outcomes.^{44 45} Therefore, most professional societies support universal GDM screening and treatment between 24 and 28 weeks of gestation.^{26–28 46} However, despite this recommendation for GDM testing and the known impact of maternal glucose levels on perinatal outcomes, less is known about the optimal glycaemic targets for GDM treatment. Prior observational studies have indicated that third-trimester postprandial glucose values are more strongly related to fetal overgrowth than fasting values,^47–49 but evidence-based postprandial glucose targets have not been identified. A few observational studies and one randomised clinical trial have examined the prevalence of LGA birth weight, birth weight >4 kg or neonatal hypocalcaemia among women with intensive versus standard glycaemic control. While these studies suggest a possible reduction in adverse outcomes, they are limited by their small sample size, focus on either insulin-requiring or pre-GDM and have outcomes limited to fetal overgrowth or neonatal hypocalcaemia.^49–51 The only other randomised clinical trial comparing standard with intensive glycaemic targets was recently completed in New Zealand. This stepped-wedge, cluster-randomised trial did not demonstrate an improvement in rates of LGA birth weight.⁵² However, this study was conducted outside the USA where patient demographics and clinical management are different; GDM was diagnosed using a 75 g oral glucose tolerance test with different cut-off than those used in the USA; it included normal weight women with GDM and compared glycaemic targets (standard: fasting <99 mg/dL and 1-hour postprandial <144 mg/dL; intensive: fasting <90 mg/dL and 1-hour postprandial <133 mg/dL) that differ from those in our study.⁵³ In addition, glycaemic control was not assessed as part of this trial. The results obtained from our study will provide valuable insight into how to optimise perinatal outcomes for pregnancy complicated by overweight and obesity as well as GDM.

Ethics and dissemination

Because the optimal glycaemic targets in pregnant patients with GDM are unknown, there is an equipoise for this study. The Indiana University IRB has approved this protocol and is acting as the central IRB for this study (IRB# 11435; initial approval date 25 August 2021). All protocol amendments will be communicated for approval to the IU IRB. We will follow CONSORT guidelines. We will submit study results for publication in peer-reviewed journals and presentation at international meetings, with a concurrent uploading of the manuscript content into PubMed Central for public access. There will be an initial period where the steering committee and investigators from the consortium sites will have access to the data, and it will then be made available to the larger community of investigators pending valid requests for secondary analyses and appropriate data-sharing agreements. This study is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number 5R01HD101476.

Limitations and strengths

This study is not blinded to providers and patients, as they need to be aware of intervention allocation to comply with the assigned glycaemic target group. However, the study arm will be blinded to the study statistician analysing and assessing the association between the intervention and primary and secondary outcomes. It is possible that local treatment protocols could be affected by study participation, as there may be blurring between the standard and intensive glycaemic target arms at the study sites as providers become more comfortable with the lower glycaemic targets. We have attempted to minimise this influence by ensuring that the assigned treatment group is clearly specified for each participant. Our preliminary data also suggest that few women with GDM who are also overweight or obese will meet the intensive glycaemic targets without pharmacologic therapy. In addition, we have set forth standard guidelines about when to initiate or titrate GDM treatment. Our focus is on the impact of glycaemic control during pregnancy, which does not allow for the evaluation of our study intervention regarding longer-term maternal or offspring health. In the future, planned maternal and offspring follow-up will shed light on the impact of glycaemic control in pregnancy on longer-term health outcomes. We are focusing our study on those women with GDM who also have overweight or obese, so our results will not be generalisable to all women with GDM. Strengths of our study include that GDM is one of the most frequent complications of pregnancy. Few studies have assessed the impact of glycaemic control on perinatal outcomes, so our data will fill an important clinical knowledge gap. If lower glycaemic targets improve perinatal outcomes, it may have a major public health impact.

Ethics statements

Patient consent for publication

Not applicable.