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GDM: Medical Nutrition Therapy (2016)

Citation:
Landon, M, Spong, C, Thom, E et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009 October 1; 361(14): 1,339-1,348. 
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To determine if treatment of women with mild gestational diabetes mellitus reduces perinatal and obstetrical complications. 
Inclusion Criteria:
  • Pregnant women
  • Between 24 weeks, zero days and 30 weeks, six days of gestation
  • Blood glucose concentration between 135mg and 200mg per dL one hour after a 50g glucose loading test
  • Provided written informed consent.
Exclusion Criteria:
  • Pre-existing diabetes
  • Abnormal glucose screening test result before 24 weeks of gestation
  • Prior gestational diabetes
  • History of stillbirth
  • Multi-fetal gestation
  • Asthma
  • Chronic hypertension
  • Taking corticosteroids
  • A known fetal anomaly
  • Imminent or pre-term delivery likely because of fetal conditions or maternal disease
  • A fasting glucose level of 95mg per dL or more on the diagnostic oral glucose tolerance test.
Description of Study Protocol:

Recruitment

Between October 2002 and mid-November 2007, women with an abnormal result on a glucose loading test were identified at treatment centers by health care providers. 

Design

In this randomized controlled trial, eligible women completed a blinded three-hour 100g oral glucose-tolerance test after an overnight fast. For this study, mild gestational diabetes was defined as a fasting glucose level of less than 95mg per dL and two or three timed glucose measurements exceeding established thresholds (one-hour level, 180mg per dL; two-hour level, 155mg per dL; and three-hour level, 140mg per dL. Women meeting these criteria were randomly assigned to either the treatment group (receiving formal nutrition counseling and diet therapy along with insulin if required) or to usual pre-natal care (control group). To further blind the control group, women with a positive result on the 50g glucose tolerance test but subsequent normal results were included in the control group although they did not have gestational diabetes. Prior to oral glucose tolerance tests, ultrasonography was performed on all subjects to confirm gestational age. Women receiving treatment performed daily self-monitoring of blood glucose, both fasting and two-hour post-prandial. Insulin was prescribed if the majority of fasting values or post-prandial values between visits were elevated (fasting, higher than 95mg per dL; post-prandial, higher than 120mg per dL). Blood glucose levels could be measured at the discretion of the health care provider during pre-natal visits if there was clinical suspicion of hyperglycemia in a control group patient. The primary study outcome was a composite including peri-natal mortality and complications associated with maternal hyperglycemia (hypoglycemia, hyperbilirubinemia, neonatal hyperinsulinemia and birth trauma). Secondary neonatal outcome measures included birth weight higher than 4,000g, large for gestational age (birth weight less than 10th percentile), admission to neonatal intensive care unit and the respiratory distress syndrome. Secondary maternal outcomes included weight gain from time of enrollment to time of delivery, gestational hypertension, pre-eclampsia, cesarean delivery, labor induction and shoulder dystocia. Records of all enrolled women and their infants were reviewed at time of discharge from hospital. All cases of hypertensive disorders and shoulder dystocia underwent masked central review by two of the study authors to ensure accurate diagnoses. 

Blinding Used

All eligible women completed a blinded three-hour 100g orl glucose tolerance test. Women without gestational diabetes (who had a positive result on the 50g glucose loading test but a normal result on subsequent oral glucose-tolerance tests) were included in the control group; patients, caregivers and study staff were blinded to whether or not women in the control group met criteria for mild gestational diabetes.

Intervention

Women in the treatment group received formal nutritional counseling and diet therapy, along with insulin if required. Women in the control group received usual pre-natal care. 

Statistical Analysis

Primary analysis was conducted according to the intention-to-treat principle. Chi-square test or Fisher's exact test was used to compare categorical variables and the Wilcoxon rank-sum test was used to compare continuous variables. 

Data Collection Summary:

Timing of Measurements

Neonatal cord blood was collected at birth. Neonatal blood for glucose level was collected within two hours after birth and before feeding. Neonatal serum bilirubin was determined between 16 hours and 36 hours after birth. Shortly after birth, trained research staff measured the infant's length, head and upper mid-arm circumferences and flank skinfold. Data on all women in the treatment group were collected by trained study personnel at the time of study visits. The records of all enrolled women and their infants were reviewed at time of discharge from the hospital.

Dependent Variables

  • Composite outcome (primary outcome): components were peri-natal mortality, neonatal hypoglycemia, hyperinsulinemia, hyperbilirubinemia and birth trauma
  • Peri-natal mortality (stillbirth or neonatal death)
  • Neonatal hyperinsulinemia (cord-blood C-peptide level greater than 95th percentile)
  • Neonatal hypoglycemia (blood glucose less than 35mg per dL)
  • Neonatal hyperbilirubinemia (level higher than 95th percentile)
  • Birth trauma (brachial plexus palsy; clavicular, humeral or skull fracture)
  • Birth weight (more than 4,000g)
  • Large for gestational age (birth weight higher than 90th percentile)
  • Small for gestational age (birth weight less than 10th percentile)
  • Admission to neonatal intensive care unit
  • Respiratory distress syndrome
  • Maternal weight gain (from enrollment to delivery)
  • Maternal hypertension
  • Maternal pre-eclampsia
  • Cesarean delivery
  • Labor induction
  • Neonatal shoulder dystocia.

Independent Variables

Women in the treatment group received:

  • Formal nutritional counseling and diet therapy
  • Insulin therapy, if required.

Control Variables

Women in the control group received usual prenatal care. 

Description of Actual Data Sample:
  • Initial N N=958 women (485 in treatment group, 473 in the control group)
  • Attrition (final N): N=900 women.

Age

  • Treatment group: Age of 29.2±5.7 years
  • Control group: Age of 2.9±5.6 years. 

Ethnicity

  • Treatment group:
    • Black: N=56 (11.5%)
    • White: N=123 (25.4%)
    • Asian: N=22 (4.5%)
    • Hispanic: N=281 (57.9%)
    • Other: N=3 (0.6%).
  • Control group:
    • Black: N=54 (11.4%)
    • White: N=119 (25.2%)
    • Asian: N=28 (5.9%)
    • Hispanic: N=265 (56.0%)
    • Other: N=7 (1.5%).

Other Relevant Demographics

  • Treatment group:
    • Primigravida: 21.4%
    • Reported smoking: 7.8%
    • Alcohol use: 4.7%.
  • Control group:
    • Primigravida: 26.0%
    • Reported smoking: 6.6%
    • Alcohol use: 2.3 %.

Anthropometrics

  • BMI at study entry for the treatment group was 30.1±5.0, and 30.2±5.1 for the control group
  • Glucose levels were similarly matched between groups after 50g glucose loading test and in a three-hour oral glucose tolerance test. 

Location

Multiple sites in the United States. 

 

Summary of Results:

Key Findings

  • There were no significant differences between groups in the frequency of the composite outcome (32.4% and 37.0% in the treatment and control groups; P=0.14)
  • There were no peri-natal deaths
  • There were significant differences between groups in:
    • Mean birth weight (3,302g vs. 3,408g, P<0.001)
    • Neonatal fat mass (427g vs. 464g, P=0.003)
    • Frequency of large-for-gestational age infants (7.1% vs. 14.5%, P<0.001)
    • Birth weight greater than 4,000g (5.9%percent vs. 14.3%, P<0.001)
    • Shoulder dystocia (1.5% vs. 4.0%, P=0.02)
    • Cesarean delivery (26.9% vs. 33.8%, P=0.02).
  • There was also an association between treatment and reduced rates of pre-eclampsia and gestational hypertension (combined rates for the two conditions, 8.6% vs. 13.6%, P=0.01)
  • There were no other significant differences between groups for any other dependent variables.
Author Conclusion:
Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or peri-natal death and several neonatal complications, it did reduce the risks of fetal overgrowth, shoulder dystocia, Cesarean delivery and hypertensive disorders. 
Funding Source:
Reviewer Comments:
  • The study authors did not describe what formal nutritional counseling and diet therapy (for the treatment group) entailed or who provided it. There was no mention of using RDs for this intervention
  • The study authors also did not disclose a funding source. 
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? No
  10.2. Was the study free from apparent conflict of interest? Yes