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Intensive glycemic control in gestational diabetes mellitus: a randomized controlled clinical feasibility trial
Original Research Intensive glycemic control in gestational diabetes mellitus: a randomized controlled clinical feasibility trial Christina M. Scifres, MD; Carolyn Mead-Harvey, MS; Hugh Nadeau, MD; Sean Reid, MD; Stephanie Pierce, MD; Maisa Feghali, MD; Dean Myers, PhD; David Fields, PhD; Julie A. Stoner, PhD
BACKGROUND: Overweight and obese women with gestational diabetes mellitus are at increased risk for adverse perinatal outcomes, and they are also more likely to have suboptimal glycemic control. However, there is a paucity of data evaluating whether lower glycemic targets could improve outcomes. OBJECTIVE: To evaluate the feasibility of intensive glycemic control in overweight and obese women with gestational diabetes mellitus. MATERIALS AND METHODS: We randomized 60 overweight or obese women with gestational diabetes mellitus, diagnosed between 12 and 32 weeks’ gestation to either intensive (fasting <90 mg/dL, 1 hour postprandial <120 mg/dL) or standard (fasting <95 mg/dL, 1 ho postprandial <140 mg/dL) glycemic targets. Maternal glucose was assessed in 2 ways: blinded continuous glucose monitors, worn for 5 days at 2 time points (at 1232 weeks and again at 3236 weeks), and self-monitored glucose measurement 4 times per day. All women underwent standardized dietary counseling, and medical therapy was prescribed as needed to achieve glycemic control. RESULTS: Between December 2015 and December 2017, we randomized 60 women to either intensive (n ¼ 30) or standard (n ¼ 30) glycemic control. Baseline characteristics including maternal age, body
T
he prevalence of obesity and gestational diabetes mellitus (GDM) have increased, and both increase the risk for pregnancy complications including fetal overgrowth, neonatal morbidity, hypertensive disorders of pregnancy, and cesarean delivery.1e3 We previously found that obese women with GDM had higher rates of pregnancy complications when compared to normal-weight women with GDM, and they also had higher mean fasting and postprandial glucose values despite more frequent use of medications.4 The strong linear relationship between maternal glucose and pregnancy outcomes is well established,5 but the current recommendations for
Cite this article as: Scifres CM, Mead-Harvey C, Nadeau H, et al. Intensive glycemic control in gestational diabetes mellitus: a randomized controlled clinical feasibility trial. Am J Obstet Gynecol MFM 2019;XX:x.ex-x.ex. 2589-9333/$36.00 ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajogmf.2019.100050
mass index, and gestational age at diagnosis were similar between the intensive and standard groups. Medical therapy was more common in women in the intensive group than those in the standard group (83 vs 57%, P ¼ .02). Women in the intensive glycemic control group had lower glucose values as assessed by continuous glucose monitors at including 24-hour mean (8.1; 95% confidence interval, 12.0 to 4.3 mg/dL; P < .0001) and 1-h postprandial (11.8; 95% confidence interval, 19.7 to 3.9 mg/dL, P ¼ .004) values. Hypoglycemia <60 mg/dL was uncommon and did not differ between groups. CONCLUSION: Intensive glycemic targets can be used in overweight and obese women with minimal hypoglycemia, and this approach results in improved glycemic control when compared to standard glycemic targets. Further studies are needed to determine whether intensive glycemic targets can improve maternal and neonatal outcomes in high-risk women with gestational diabetes mellitus. Clinical Trial Identifier: NCT02530866; clinicaltrials.gov Key words: continuous glucose monitoring, gestational diabetes
mellitus, glycemic control, hypoglycemia, obesity, overweight, pregnancy
glycemic targets in pregnant women with diabetes are less rigorously defined.6,7 In pregnant women without diabetes, mean fasting (70.9 7.8 mg/dL) and 1hour postprandial (108.9 12.9 mg/ dL) glucose values, as assessed by continuous glucose monitoring (CGM), are significantly lower than the current fasting (<95 mg/dL) and 1-hour postprandial (<140 mg/dL) treatment targets used after GDM is diagnosed.6,8 Lower glycemic targets have been suggested,8 but there are minimal data to indicate whether lower targets can improve glycemic control while avoiding hypoglycemia. The prevalence of hypoglycemia has not been reported in many of the GDM treatment trials,9,10 but a cohort study conducted in China that used blinded continuous glucose monitors in women with GDM found that 32.8% of women had glucose values <60 mg/dL for at least 30 minutes per day in the first week of monitoring.11 Given that overweight and obese women with GDM have the highest risk of both
suboptimal glycemic control and adverse pregnancy outcomes, we conducted a randomized clinical feasibility trial to compare glycemic control and the prevalence of hypoglycemia in overweight and obese women with GDM randomized to either current glycemic targets or lower glycemic targets. We hypothesized that lower glycemic targets would result in improved glycemic control. We also set out to characterize the prevalence of hypoglycemia using both home glucose monitoring and blinded continuous glucose monitoring (CGM), as well as changes in maternal lipids and cytokines, among women treated using intensive vs standard glycemic targets.
Materials and Methods Subjects and study procedures This feasibility and tolerability study was approved by the University of Oklahoma Institutional Review Board, and all participants provided written informed consent. This trial was registered as a randomized clinical trial (NCT02530866; clinicaltrials.gov). MONTH 2019 AJOG MFM
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Original Research AJOG MFM at a Glance Why was this study conducted? Overweight and obesity are associated with an increased risk for adverse outcomes in women with gestational diabetes, and this may be related to suboptimal glycemic control. We therefore set out to evaluate whether lower glycemic targets could improve glycemic control without causing excess hypoglycemia. Key findings Intensive glycemic targets result in improved glycemic control when compared to standard glycemic targets with no increase in the risk for hypoglycemia. What does this add to what is known? Intensive glycemic targets can be safely used to improve glycemic control in overweight and obese women with minimal hypoglycemia. Further studies are necessary to determine whether intensive glycemic targets can improve outcomes in this group of women.
Women with GDM diagnosed by the CarpenterCoustan Criteria between 12 and 32 weeks’ gestation who were either overweight (body mass index [BMI], 2529.9 kg/m2) or obese (BMI 30 kg/m2) pre-pregnancy were enrolled from prenatal clinics at the University of Oklahoma. Inclusion criteria included singleton pregnancies, age 1845 years, and planned delivery at the University of Oklahoma Medical Center. Exclusion criteria included maternal tobacco use, planned delivery prior to 34 weeks’ gestation, chronic hypertension requiring medical therapy, vascular disease, serum creatinine 1.5 mg/dL, rheumatologic disorders, or oral steroid use within 30 days of enrollment. For the first 6 months of the study, we included only women with an obese prepregnancy BMI (BMI 30 kg/m2) who were diagnosed with GDM between 20 and 30 weeks’ gestation. However, after low enrollment (5 patients) over this time period, we extended the enrollment criteria include both women with overweight and obesity and those diagnosed with GDM between 12 and 32 weeks’ gestation. After GDM diagnosis, all women who participated in the study were given instructions regarding their diet and recommended weight gain as part of routine clinical care, and they also initiated self-monitoring of glucose 4 times daily (fasting and 1 hour postprandial). After informed consent was obtained, 2 AJOG MFM MONTH 2019
women were randomized to either standard (fasting glucose <95 mg/dL, 1hour postprandial glucose <140 mg/dL), or intensive (fasting <90 mg/dL, 1-hour postprandial glucose <120 mg/dL.) glycemic targets. Randomization occurred via a computer-based platform programmed in REDCap.12 Randomization was stratified based on whether GDM was diagnosed before or after 24 weeks’ gestation. At the time of the first study visit, the prior glucose logs were reviewed, and patients were counseled regarding dietary changes or initiation of medical therapy as needed. Women were then encouraged to report their glucose targets weekly. Throughout the study, providers made the decision to initiate or titrate either insulin or glyburide as necessary to meet assigned glycemic targets. Two study visits occurred after randomization: the first between 12 and 32 weeks’ gestation (at the time of randomization), and the second between 32 and 36 weeks’ gestation and at least 4 weeks after the first visit. At each study visit, glucose logs were reviewed from the prior week with medications initiated or titrated as needed, and women also underwent a nonfasting blood draw. To assess the impact of intensive vs standard glycemic targets on maternal lipids, cytokines, and adipokines, we measured serum triglycerides, total high-density lipoprotein (HDL), lowdensity lipoprotein (LDL) cholesterol, and nonesterified fatty acids in the
clinical laboratory at the University of Oklahoma. Interleukin-6 (IL-6), tumor necrosis factora (TNF-a), leptin, and adiponectin were measured using Milliplex Adipokine Magnetic Bead Panels (MilliporeSigma, Burlington, MA) with an inter- and intra-assay coefficient of variation less than 10%. Interstitial glucose profiles were measured at each study visit using the Medtronic iPRO (Minneapolis, MN) continuous glucose monitoring system (CGMS) for 120 hours (5 days), and both patients and providers were blinded to the results. The CGMS system was calibrated against finger-stick glucose determinations obtained during clinical care, as per the manufacturer’s recommendations. As an additional marker of glycemic control, HbA1c was measured at the first and second study visits. The study protocol included a continuous (daily) process of monitoring and reporting of maternal and neonatal adverse events by the research team (research nurse and investigators). Adverse events were reported to the Human Research Protection Office and the institutional review board (IRB) as they occurred. In addition, the Data Safety Monitoring Board met at 6month intervals to assess protocol compliance and study outcomes.
Infant assessments Infant weight, length, and head circumference were measured at birth. Within the first 72 hours after delivery, infants underwent body composition assessment via air displacement plethysmography (ADP) using the PEA POD Body Infant Body Composition System (COSMED USA, Concord, CA). ADP testing and procedures have been described previously,13e15 and the body density converted to percent fat using sex-specific equations developed by Fomon et al.16
Statistical analysis Our primary outcome was the feasibility of lowering mean glycemic levels as assessed by continuous glucose monitoring in the intensive group by 10 mg/ dL compared to that in women in the standard control group. Our secondary
Original Research outcomes included differences in other CGM parameters including mean daytime, nighttime, and postprandial glucose values as well as the percentage of time that the maternal glucose was <60 mg/dL or >140 mg/dL. In addition, we compared the mean values of both fasting and 1-hour postprandial home glucose monitoring values across gestation. Differences in mean birthweight and measures of neonatal adiposity were also compared between groups. With regard to the CGM data, the fasting glucose was calculated as the mean of 6 consecutive values starting at 6 am and/or after at least 7 hours of fasting. Preprandial glucose was calculated as the mean of 3 consecutive values directly before the start of breakfast, lunch, and dinner meal start. The 1- and 2-hour postprandial glucose was calculated as the mean of 3 consecutive measures 1 or 2 hours after the meal start time. The mean daytime glucose was the mean of all measures between 6:30 am and 11:30 pm, and the mean nocturnal glucose was the mean of all measures between 11:30 pm and 6:30 am, whereas the mean 24-hour glucose was the mean of all measures in 24 hours (11:3011:30). The lowest nocturnal glucose was calculated as the mean of the 6 lowest consecutive measures between 11:30 pm and 6:30 am. The peak postprandial glucose was the highest postprandial glucose within 2 hours of the meal start time, and the time to postprandial peak was the time from meal start to peak postprandial glucose. The 1-hour postprandial excursion was calculated as the peak 1-hour postprandial glucose minus the pre-prandial glucose.17 Descriptive statistics of participant characteristics, glycemic control, metabolic assessment, and delivery outcomes were calculated, including means, standard deviations, frequencies, and percentages. Means were compared between the intensive and standard intervention groups using a 2-sample t test. Proportions were compared using a c2 test, a Fisher exact test when more than 25% of expected frequency counts were less than 5 or any 0 counts were observed in a category, or a CochranArmitage trend test for ordered categories. Metabolic
measures and glycemic control measures that did not derive from continuous glucose monitoring were compared between the intensive and standard intervention groups at the second study visit only. To account for the correlation among continuous glucose measures and first-visit and second-visit measures within an individual over time, generalized estimating equations (GEE) methodology was used to fit linear or logistic regression models for the outcome measures.18 Covariates in the regression models included study visit, treatment group, and their interaction. When not significant, interaction terms were dropped from subsequent models, and treatment groups were compared using data from the first and second study visits combined. The linear associations between infant adiposity measures and continuous glucose measures at the second visit were analyzed using GEE to fit a linear model with the glucose measure, treatment group, and the interaction between the glucose measure and treatment group as covariates. When not significant, interaction terms were dropped from subsequent models, and the analyses were performed using combined data from both treatment groups. Analyses reflect an intent-to treat paradigm in which all data were analyzed according to randomized treatment assignment. All hypothesis tests were performed at a 2-sided 0.05 significance level. SAS 9.4 (SAS Institute, Cary, NC) was used for all analyses.
Sample size calculation Prior studies have shown that the mean glucose assessed by CGM in women without GDM is 88 mg/dL for normal weight women and 105 5 mg/dL for women with obesity,19 but there are fewer data regarding glucose values assessed by CGM in women with GDM. However, the mean glucose, as assessed by taking the average fasting and postmeal values in 1151 women with GDM, is 114 11 mg/dL (unpublished personal observation). We hypothesized that randomizing overweight and obese women with GDM to lower glycemic targets would result in at least a 10-mg/ dL difference in mean glucose values at
3236 weeks’ gestation as assessed by CGM. To achieve 85% power to detect a difference in means of 10 mg/dL, assuming a standard deviation of 11 mg/dL, we estimated that 23 subjects would be required per group. To account for a 20% loss to follow-up rate, we estimated a total of 30 women in each group.
Results A total of 286 women were assessed for eligibility between December 2015 and December 2017. Of these women, 60 provided informed consent and were randomized to either standard (n ¼ 30) or intensive (n ¼ 30) glycemic control (Figure 1). All women remained in their assigned treatment group. All women completed the first study visit, and the majority in both the standard (27 of 30, 90%) and intensive (29 of 30, 96.7%) groups completed study visit 2. Delivery information was available for all women. Women randomized to the standard and intensive glycemic control groups were similar with regard to baseline characteristics, including maternal age, pre-pregnancy BMI, race/ethnicity, public insurance, education, marital status, and family income. In addition, rates of nulliparity, history of GDM, and diabetes in a first-degree relative were similar. Gestational age at GDM diagnosis and results of GDM testing were also similar between groups (Table 1). When CGM monitoring was compared between groups, there was no indication of a significant effect of the intensive therapy over time (P > .05 for the visit by treatment interaction), so the results for visit 1 and 2 were combined (Table 2). We determined that women in the intensive group had lower 24-hour glucose values compared to those in the standard glycemic target group (8.1; 95% CI, 12.0 to 4.3 mg/dL; P < .0001). Mean daytime (9.1; 95% CI, 16.2 to 2.0 mg/dL; P ¼ .01) and nocturnal (10.4; 95% CI, 19.8 to 1.0, P ¼ .03) values were also lower in the intensive vs standard group (Table 2). There was a trend towards lower fasting glucose levels (7.0; 95% CI, 14.5 to 0.6 mg/dL, P ¼ .07) in the MONTH 2019 AJOG MFM
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Original Research FIGURE 1
Randomization and follow-up of trial participants Assessed for eligibility (n=286)
Excluded (n=226) • Not meeting inclusion criteria (n=196) • GDM diagnosed outside of range n=92 • Pre-pregnancy BMI out of range n=42 • Other n=62 • Declined to participate (n=30)
Randomized (n=60)
Allocated to Intensive Glycemic Control (n=30) ¨ Received allocated intervention (n=30)
Allocated to Standard Glycemic Control (n=30) ¨ Received allocated intervention (n=30)¨
Lost to follow-up (n=0) • Completed Visit 1 (n=30) • Completed Visit 2 (n=29) • Completed Delivery Visit (n=30) Discontinued intervention (n=0))
Lost to follow-up (n=0) • Completed Visit 1 (n=30) • Completed Visit 2 (n=27) • Completed Delivery Visit (n=30) Discontinued intervention (n=0)
Analyzed (n=30) ¨ Excluded from analysis (n=0)
Analyzed (n=30) ¨ Excluded from analysis (n=0)
Scifres et al. Intensive glycemic control in gestational diabetes. AJOG MFM 2019.
intensive group. In addition, women in the intensive group had lower preprandial (7.1; 95% CI, 13.7 to 0.7 mg/dL; P ¼ .03), 1-hour postprandial (11.8; 95% CI, 19.7 to 3.9 mg/dL; P ¼ .004), 2-hour postprandial (10.5; 95% CI, 19.5 to 1.5 mg/dL; P ¼ .02), and peak postprandial (11.9; 95% CI, 21.3 to 2.4 mg/dL; P ¼ .01) glucose values (Table 2). Both the postprandial excursion (2.3; 95% CI, 8.2 to 3.5 mg/dL; P ¼ .44) and the time to postprandial excursion (3.4; 95% CI, 8.0 to 1.2 minutes; P ¼ .15) were similar between groups (Table 2). Rates 4 AJOG MFM MONTH 2019
of total, daytime, and nocturnal hypoglycemia did not differ between groups (Table 2). Because women may have behaved differently during the CGM monitoring periods, we also compared their fasting and postprandial glucose values across gestation. There was no indication of a significant effect of intensive therapy over time, so we considered all weeks combined. There were no differences in the mean fasting measures between groups (6.6; 95% CI, 6.6 to 19.9 mg/dL; P ¼ .34), but the postprandial values were lower
in the intensive compared to the standard group (9.7; 95% CI, 15.3 to 4.1 mg/dL; P < .001). There were also no differences in the percentage of values <60 mg/dL among women in the intensive compared to the standard glycemic targets group (0%; interquartile range [IQR], 00.40%; vs 0%; IQR, 00.36%, P ¼ .54), and no women reported symptomatic hypoglycemia. Although rates of medication use were similar between women in the standard and intensive groups at the first study visit (5 of 30 [17%] vs 10 of 30 [33%]; P ¼ .14) and second study visit (16 of 30 [53.3%] vs 23 of 30 [77%]; P ¼ .06), by delivery more women in the intensive group were receiving medication (17 of 30 [57%] vs 25 of 30 [83%]; P ¼ .02). At delivery, rates of glyburide use were similar between groups (10 of 30 [33%] vs 8 of 30 [27%]; P ¼ .57), but insulin use was more common in the intensive group (7 of 30 [23%] vs 17 of 30 [57%]; P ¼ .01). HbA1c concentrations were within recommended ranges and did not differ between groups. Maternal serum lipids including triglycerides, nonesterified fatty acids, total, HDL, and LDL cholesterol were similar between groups (Table 2), as were IL-6, leptin, and adiponectin. There was a trend toward higher levels of TNF-a in the intensive group (P ¼ .06) (Table 2). Mean birthweight (3431 623 vs 3351 518 g; P ¼ .59) and percentage of body fat (12.10 4.81 vs 11.48 5.47; P ¼ .67) were similar between women treated with intensive vs standard glycemic targets (Table 3). There were no differences in rates of SGA and LGA birthweight (Table 3).
Comment Principal findings We found that use of intensive glycemic targets requires more frequent use of medications and results in lower glucose concentrations. Importantly, this tighter glycemic control can be accomplished with minimal maternal hypoglycemia. We also found that two-thirds of eligible women were willing to enroll in a trial using lower glycemic targets.
Original Research TABLE 1
Characteristics of participants by study group assignment P valuea,b
Characteristic
Standard (n ¼ 30)
Intensive (n ¼ 30)
Maternal age
31.63 5.29
32.80 6.58
.45
219.1 59.57
213.7 46.36
.70
36.11 9.29
36.47 7.71
.87
Pre-pregnancy weight, lb 2
Pre-pregnancy BMI, kg/m
American Indian/Alaska Native Black or African American
4 (13.3)
4 (13.3)
.87b
2 (6.7)
4 (13.3)
23 (76.7)
21 (70.0)
1 (3.3)
1 (3.3)
Hispanic
10 (33.3)
4 (13.3)
.07
Public insurance
16 (53.3)
17 (56.7)
.80
9 (30.0)
10 (33.3)
21 (70.0)
20 (66.7)
White American Indian/black or African American
Education High school or less At least some college
.78
1.0b
Marital status Married
26 (86.7)
26 (86.7)
Single
4 (13.3)
4 (13.3) .32c
Family income 0e$30,000 $30,001e$60,000
14 (46.7)
16 (55.2)
7 (23.3)
8 (27.6)
>$60,001
9 (30.0)
Nulliparous
10 (33.3)
8 (26.7)
.57
History of GDM
7 (23.3)
10 (33.3)
.39
History of preeclampsia
7 (23.3)
4 (13.3)
.32
5 (17.2)
First-degree family member with DM
12 (40)
14 (46.7)
.60
Glucose challenge test results
184.3 33.74
170.8 29.29
.14
Gestational age at GCT
23.79 4.95
23.25 5.32
.72
Fasting OGTT value
94.46 15.09
99.69 13.82
.21
1-h OGTT value, mg/dL
198.3 28.46
194.2 26.10
.60
2-h OGTT value, mg/dL
182.6 24.68
169.1 28.06
.08
3-h OGTT value, mg/dL
122.5 33.74
117.5 30.84
.59
Gestational age at OGTT
25.19 4.75
24.31 5.31
.54
All variables presented as mean ( standard deviation) or n (%). BMI, body mass index; DM, diabetes mellitus; GCT, glucose challenge test; GDM, gestational diabetes mellitus; OGTT, oral glucose tolerance test. Hypothesis tests performed using a 2-sample t test to compare means and a c2 test to compare proportions unless otherwise indicated; b Hypothesis test performed using Fisher exact test; c Hypothesis test performed using CochranArmitage trend test. Scifres et al. Intensive glycemic control in gestational diabetes. AJOG MFM 2019. a
Results The current therapeutic targets of fasting glucose <95 mg/dL and <140 and <120 mg/dL at 1 and 2 hours postprandial are recommended by the American College of Obstetricians and Gynecologists (ACOG), the American Diabetes
Association (ADA), and the Endocrine Society.20e22 These targets were established using data from both women with pre-gestational and gestational diabetes that demonstrate the strong relationship between postprandial glucose, macrosomia, and neonatal outcomes.23e26
Smaller studies indicated that mean 24hour glucose concentrations >130 mg/ dL were associated with a high risk of fetal macrosomia,27 and data from women with pre-gestational diabetes demonstrated that a 1-hour postprandial target equal to 130 mg/dL was associated MONTH 2019 AJOG MFM
5
Glycemic control as assessed by continuous glucose monitoring at study visits 1 and 2 Study visit 1 12e32 wk
Study visit 2 32e36 wk
Standard (n ¼ 30)
Intensive (n ¼ 30)
Standard (n ¼ 27)
Intensive (n ¼ 29)
P valuea (visit by treatment)
Gestational age, wk
28.72 3.94
28.65 4.16
34.19 1.09
34.35 1.03
—
—
Hours since last meal
3.19 2.91
3.57 3.80
3.47 4.36
4.44 5.18
—
—
Maternal BMI, kg/m2
38.86 8.90
39.30 6.83
39.71 9.37
39.92 6.95
.70
Diabetes medication
P valueb (treatment)
.85 c
.05c
5 (17)
10 (33)
16 (57.1)
23 (79.3)
.84
Glyburide
3 (10)
4 (13)
10 (35.7)
9 (31.0)
.53c
.89c
Insulin
2 (6.7)
6 (20)
6 (21.4)
14 (48.3)
.98c
.03c
5.60 0.96
.90
.37
109 (97e117)
101 (93e108)
.25
<.0001
HbA1c, %
5.33 0.56
5.49 0.59
5.49 0.64
Glucose values, mg/dL 24-h
107 (99e117)
101 (94e110)
Daytime
108 (95e126)
102 (90e118)
107 (92e125)
101 (89e115)
.62
.01
Nocturnal
104 (92e118)
97 (83e112)
103 (87e121)
97 (85e112)
.48
.03
90 (78e102)
79 (67e92)
85 (69e98)
83 (72e92)
.02
.42
101 (89e110)
95 (82e106)
95 (82e112)
91 (81e101)
.74
.07
Lowest nocturnal Fasting 1-h pre-prandial
102 (92e120)
99 (88e112)
101 (89e120)
98 (88e111)
.47
.03
1-h postprandial
119 (105e139)
111 (98e125)
119 (103e139)
108 (96e122)
.93
.004
2-h postprandial
111 (98e131)
107 (94e121)
115 (101e132)
105 (93e117)
.84
.022
Peak postprandial
131.5 (114e154)
125 (109e138)
16.2 (8.2e18.7)
11.2 (5.1e18.6)
45 (25e1:25)
40 (15e1:10)
24-h
1.1
Daytime
0.7
1-h postprandial excursion Postprandial peak, min
131 (115e149)
119 (107e135.5)
.78
.014
10.6 (1.6e14.6)
.74
.44
45 (20e1:25)
45 (15e1:20)
.16
.15
2.5
1.9
1.5
.16c
.66c
1.6
1.5
1.1
.92c
.77c
c
.50c
12.2 (5e19.3)
Glucose <60 mg/dL (%)
Nocturnal
1.9
4.6
2.9
2.4
.59
Glucose >140 mg/dL (%)
14.3
6.7
11.6
5.4
.79c
.65c
Glucose >120 mg/dL(%)
28.6
20.3
28.8
17.4
.39c
.36c
Triglycerides, mg/dL
222.6 76.10
230.4 89.1
266.5 92.29
258.6 97.23
.29
.94d
NEFA, mmol/L
0.39 0.16
0.40 0.11
0.39 0.16
0.42 0.20
.80
.48d
Scifres et al. Intensive glycemic control in gestational diabetes. AJOG MFM 2019.
(continued)
Original Research
6 AJOG MFM MONTH 2019
TABLE 2
P value from test of interaction between study visit and treatment assignment; b P value from test of treatment effect combining data at visit 1 and visit 2 (postintervention), unless otherwise indicated; c Logistic regression model fit using generalized estimating equations; d P value from test of treatment effect at visit 2 (postintervention). Scifres et al. Intensive glycemic control in gestational diabetes. AJOG MFM 2019.
BMI, body mass index; HDL, high-density lipoprotein; IL, interleukin; LDL, low-density lipoprotein; NEFA, non-esterified fatty acids; TNF, tumor necrosis factor; —, hypothesis testing not performed.
Data are mean standard deviation, median (interquartile range), or n (%).
a
.78d .94 Adiponectin, mg/mL
6.3 (3.6e11.0) 11.9 (8.6e16.5) 11.7 (8.1e18.5)
7.9 (4.7e11.2)
.92d .60 Leptin, mg/L
23.7 (14.4e31.5) 26.6 (21.7e34.3) 27.6 (17.3e34.7)
23.7 (16.9e33.0)
.83d .09 IL-6, pg/dL
3.7 (2.4e4.8) 3.7 (3.2e4.8) 3.5 (2.2e5.3)
2.8(2.0e4.1)
.06d .91 TNF-a, pg/dL
2.8 (2.1e3.7) 3.7 (3.2e4.8) 3.2 (2.3e4.8)
3.4 (2.8e4.2)
.89d .05 HDL, mg/dL
59.29 11.01 58.6 12.9 62.6 10.2
58.83 14.87
.18d .86 LDL, mg/dL
Total cholesterol, mg/dL
111.9 37.90 107.1 42.3 111.2 39.6
107.5 45.83
.23d .54 205.7 41.9 218.3 48.4
208.8 43.14
Standard (n ¼ 27) Intensive (n ¼ 30) Standard (n ¼ 30)
223.3 58.94
Study visit 2 32e36 wk Study visit 1 12e32 wk
Glycemic control as assessed by continuous glucose monitoring at study visits 1 and 2 (continued)
TABLE 2
Intensive (n ¼ 29)
P valuea (visit by treatment)
P valueb (treatment)
Original Research with a reduction in macrosomia.28 Others noted that a mean glucose between 87 and 104 mg/dL can minimize the incidence of both SGA and LGA,29,30 although many women who have wellcontrolled GDM using current targets have a mean glucose that exceeds 104 mg/dL. de Veciana et al demonstrated that treatment decisions using a 1-hour glucose <140 mg/dL reduced the risk for LGA birthweight compared to targeting pre-prandial glucose values,23 and this target has been used in most interventional studies published after the year 2000.31e34 However, pooled CGM data from women without GDM demonstrates a weighted mean fasting glucose of 71 8 mg/dL, followed by 1- and 2-hour postprandial glucose concentrations of 109 13 and 99 10 mg/dL, respectively, and a 24-hour mean glucose of 88 10 mg/dL,8 which are well below current glycemic targets. We chose our 1-hour postprandial target value of <120 mg/dL because it represents a value close to 1 standard deviation above the mean in women without diabetes,8 and in our prior work 1-hour postprandial glucose values <123.8 mg/dL were associated with improved outcomes in obese women with GDM.4 We selected a fasting cut-off of 90 mg/dL using data from the Hyperglycemia and Adverse Pregnancy Outcomes Study, which demonstrated that a fasting glucose o92 mg/dL was associated with a 1.75 times increased risk of LGA and a cord blood c-peptide greater than or equal to the 90th percentile.5 We defined hypoglycemia as a glucose value <60 mg/dL, as this represented a value that was approximately 1.5 standard deviations below the mean fasting glucose value for pregnant women without diabetes.8
Clinical implications Our results support the feasibility of a randomized clinical trial comparing intensive to standard glycemic targets. If a larger trial found that intensive glycemic targets improve perinatal outcomes, this would have direct clinical implications for overweight and obese women with GDM. Although our results may be MONTH 2019 AJOG MFM
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Original Research TABLE 3
Neonatal outcomes by treatment group P valuea
Standard (n ¼ 30)
Intensive (n ¼ 30)
Gestational age at delivery, wk
37.8 (1.9)
38.2 (1.7)
.40
Birthweight
3431 623.3
3351 518.2
.59
SGA birthweight
0 (0.0)
3 (10.0)
LGA birthweight
6 (20.0)
6 (20.0)
.24b 1.0
Age at PEA POD, h
30.01 22.27
39.12 27.50
.20
Weight at PEA POD, g
3474 451
3166 805
.10
% Fat mass
12.10 4.81
11.48 5.47
.67
Fat mass, g
430 190
410 250
.79
Fat-free mass, g
3150 740
3020 860
.58
Composite neonatal morbidity
17 (56.7)
16 (53.3)
.80
NICU admission
8 (26.7)
6 (20.0)
.54
Supplemental oxygen
8 (26.7)
8 (26.7)
16 (53.3)
10 (33.3)
.12
9 (30)
8 (27)
.77
Hyperbilirubinemia Hypoglycemia
1.0
Data are mean standard deviation or n (%). Body composition assessments were available for 26 neonates per group. LGA, large for gestational age; NICU, neonatal intensive care unit; SGA, small for gestational age. Hypothesis tests performed using a 2-sample t test to compare means and a c2 test to compare proportions unless otherwise indicated; b Hypothesis test preformed using Fisher exact test. Scifres et al. Intensive glycemic control in gestational diabetes. AJOG MFM 2019. a
applied to women with gestational diabetes, it is possible that pre-gestational diabetes may require different targets because of the possibility of abnormal placentation from underlying vascular disease or hypertension that may limit glucose availability to the fetus.35 In addition, these results may not be generalizable to women with GDM who are of normal weight and at lower risk for fetal overgrowth.
Research implications Future trials to evaluate the optimal glycemic targets are important, because exposure to higher glucose levels in utero is associated with higher childhood glucose and insulin resistance independent of maternal or childhood BMI,36 and macrosomia may have a lasting metabolic impact on offspring.37,38 There is currently 1 ongoing study recruiting in New Zealand comparing intensive to standard glycemic targets.39 However, this study is outside the United States, where patient demographics and clinical management are different; it includes normal-weight 8 AJOG MFM MONTH 2019
women with GDM; and it is testing glycemic targets (standard: fasting <99, 1 hour postprandial <144 mg/dL; intensive: fasting <90, 1 hour postprandial <133 mg/dL) that differ from those in this proposal. There was no expectation that our study would be large enough to demonstrate a difference in neonatal outcomes including the prevalence of LGA birthweight or neonatal composite morbidity, but the differences in birthweight and fat mass between the standard and intensive group were in the direction and magnitude of change that would be expected based on prior treatment trials of GDM.32 Although other pathways including maternal serum triglycerides may lead to fetal overgrowth and excess adiposity,40 1 advantage to targeting maternal glucose is that these treatments are already used regularly in the care of women diagnosed with GDM.
Strengths and limitations Rates of maternal hypoglycemia are rarely reported in GDM treatment trials,9,10 and 1 strength of our study is
the use of CGM monitoring to assess both clinically recognized and subclinical hypoglycemia. One limitation is that because of the nature of this study, we were unable to blind clinicians and participants to the treatment groups. In addition, there was heterogeneity in treatment, with some women receiving insulin and some receiving glyburide. At the time that our trial started, glyburide was the most commonly used treatment for GDM,41 and we wanted to ensure that women and their providers had the autonomy to use shared decision making for treatment decisions.
Conclusions In summary, use of lower glycemic targets was feasible, with no increase in maternal hypoglycemia. In addition, use of lower glycemic targets resulted in improved glycemic control across a variety of time-points. Although a larger trial is still needed, these findings are promising and support the potential use of lower glycemic targets in overweight and obese women with GDM. n
Original Research References 1. Casey BM, Lucas MJ, McIntire DD, Leveno KJ. Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet Gynecol 1997;90: 869–73. 2. Sibai BM, Gordon T, Thom E, et al. Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 1995;172: 642–8. 3. Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study: associations with maternal body mass index. BJOG 2010;117: 575–84. 4. Scifres C, Feghali M, Althouse AD, Caritis S, Catov J. Adverse outcomes and potential targets for intervention in gestational diabetes and obesity. Obstet Gynecol 2015;126:316–25. 5. Hapo Study Cooperative Research Group, Metzger BE, Lowe LP, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991–2002. 6. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International WorkshopConference on Gestational Diabetes Mellitus. Diabetes Care 2007;30(Suppl 2):S251–60. 7. Wexler DJ, Powe CE, Barbour LA, et al. Research gaps in gestational diabetes mellitus: executive summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Obstet Gynecol 2018;132: 496–505. 8. Hernandez TL, Friedman JE, Van Pelt RE, Barbour LA. Patterns of glycemia in normal pregnancy: should the current therapeutic targets be challenged? Diabetes Care 2011;34: 1660–8. 9. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343: 1134–8. 10. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, Mi GTI. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003–15. 11. Yu F, Lv L, Liang Z, et al. Continuous glucose monitoring effects on maternal glycemic control and pregnancy outcomes in patients with gestational diabetes mellitus: a prospective cohort study. J Clin Endocrinol Metab 2014;99: 4674–82. 12. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)ea metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81. 13. Urlando A, Dempster P, Aitkens S. A new air displacement plethysmograph for the
measurement of body composition in infants. Pediatr Res 2003;53:486–92. 14. Ma G, Yao M, Liu Y, et al. Validation of a new pediatric air-displacement plethysmograph for assessing body composition in infants. Am J Clin Nutr 2004;79:653–60. 15. Fields DA, Demerath EW, Pietrobelli A, Chandler-Laney PC. Body composition at 6 months of life: comparison of air displacement plethysmography and dual-energy X-ray absorptiometry. Obesity (Silver Spring) 2012;20: 2302–6. 16. Fomon SJ, Haschke F, Ziegler EE, Nelson SE. Body composition of reference children from birth to age 10 years. Am J Clin Nutr 1982;35:1169–75. 17. Hernandez TL, Barbour LA. A standard approach to continuous glucose monitor data in pregnancy for the study of fetal growth and infant outcomes. Diabetes Technol Ther 2013;15: 172–9. 18. Kyas SL. Longitudinal data analysis using generalized linear model. Biometrika 1986;73: 13–22. 19. Harmon KA, Gerard L, Jensen DR, et al. Continuous glucose profiles in obese and normal-weight pregnant women on a controlled diet: metabolic determinants of fetal growth. Diabetes Care 2011;34:2198–204. 20. Committee on Practice BulletinsObstetrics. ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol 2018;131:e49–64. 21. American Diabetes Association. 14. Management of diabetes in pregnancy: standards of medical care in diabetese2019. Diabetes Care 2019;42:S165–72. 22. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013;98:4227–49. 23. de Veciana M, Major CA, Morgan MA, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995;333:1237–41. 24. Jovanovic-Peterson L, Peterson CM, Reed GF, et al. Maternal postprandial glucose levels and infant birthweight: the Diabetes in Early Pregnancy Study. The National Institute of Child Health and Human Developmente Diabetes in Early Pregnancy Study. Am J Obstet Gynecol 1991;164:103–11. 25. Parfitt VJ, Clark JD, Turner GM, Hartog M. Maternal postprandial blood glucose levels influence infant birthweight in diabetic pregnancy. Diabetes Res 1992;19:133–5. 26. Demarini S, Mimouni F, Tsang RC, Khoury J, Hertzberg V. Impact of metabolic control of diabetes during pregnancy on neonatal hypocalcemia: a randomized study. Obstet Gynecol 1994;83:918–22. 27. Willman SP, Leveno KJ, Guzick DS, Williams ML, Whalley PJ. Glucose threshold for macrosomia in pregnancy complicated by diabetes. Am J Obstet Gynecol 1986;154:470–5.
28. Combs CA, Gunderson E, Kitzmiller JL, Gavin LA, Main EK. Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy. Diabetes Care 1992;15: 1251–7. 29. Langer O, Levy J, Brustman L, Anyaegbunam A, Merkatz R, Divon M. Glycemic control in gestational diabetes mellitusehow tight is tight enough: small for gestational age versus large for gestational age? Am J Obstet Gynecol 1989;161:646–53. 30. Langer O, Mazze R. The relationship between large-for-gestational-age infants and glycemic control in women with gestational diabetes. Am J Obstet Gynecol 1988;159: 1478–83. 31. Parretti E, Mecacci F, Papini M, et al. Thirdtrimester maternal glucose levels from diurnal profiles in nondiabetic pregnancies: correlation with sonographic parameters of fetal growth. Diabetes Care 2001;24:1319–23. 32. 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. 33. Sivan E, Weisz B, Homko CJ, Reece EA, Schiff E. One or two hours postprandial glucose measurements: are they the same? Am J Obstet Gynecol 2001;185:604–7. 34. Weisz B, Shrim A, Homko CJ, Schiff E, Epstein GS, Sivan E. One hour versus two hours postprandial glucose measurement in gestational diabetes: a prospective study. J Perinatol 2005;25:241–4. 35. Howarth C, Gazis A, James D. Associations of type 1 diabetes mellitus, maternal vascular disease and complications of pregnancy. Diabet Med 2007;24:1229–34. 36. Scholtens DM, Kuang A, Lowe LP, et al. Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study (HAPO FUS): maternal glycemia and childhood glucose metabolism. Diabetes Care 2019. 37. Dabelea D, Knowler WC, Pettitt DJ. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. J Matern Fetal Med 2000;9:83–8. 38. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism. Diabetes Care 1995;18:611–7. 39. Crowther CA, Alsweiler JM, Hughes R, Brown J, Target Study G. Tight or less tight glycaemic targets for women with gestational diabetes mellitus for reducing maternal and perinatal morbidity? (TARGET): study protocol for a stepped wedge randomised trial. BMC Pregnancy Childbirth 2018;18:425. 40. Barbour LA, Hernandez TL. Maternal lipids and fetal overgrowth: making fat from fat. Clin Ther 2018;40:1638–47. 41. Camelo Castillo W, Boggess K, Sturmer T, Brookhart MA, Benjamin DK Jr, Jonsson Funk M. Trends in glyburide compared with insulin use for gestational diabetes treatment in the
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Original Research United States, 2000-2011. Obstet Gynecol 2014;123:1177–84.
Author and article information From the Department of Obstetrics and Gynecology (Dr Scifres), Indiana University School of Medicine, Indianapolis, IN; Department of Biostatistics and Epidemiology (Ms Mead-Harvey and Dr Stoner), University of Oklahoma Hudson College of Public Health, OK; Department of
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Obstetrics and Gynecology (Drs Nadeau, Reid, Pierce, and Meyers), University of Oklahoma College of Medicine, OK; Department of Obstetrics, Gynecology and Reproductive Sciences (Dr Feghali), Magee Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Pediatrics (Dr Fields), University of Oklahoma College of Medicine, OK. Received June 25, 2019; revised Aug. 28, 2019; accepted Sept. 22, 2019. The authors report no conflict of interest.
Supported in part by the University of Oklahoma College of Medicine Alumni Association and by National Institutes of Health, National Institute of General Medical Sciences (Grant 1 U54GM104938, PI James). This work was presented in part at the Society for Maternal Fetal Medicine 39th Annual Pregnancy Meeting, Las Vegas, NV, February 16, 2019. Corresponding author: Christina M. Scifres, MD [email protected]
BACKGROUND: Overweight and obese women with gestational diabetes mellitus are at increased risk for adverse perinatal outcomes, and they are also more likely to have suboptimal glycemic control. However, there is a paucity of data evaluating whether lower glycemic targets could improve outcomes. OBJECTIVE: To evaluate the feasibility of intensive glycemic control in overweight and obese women with gestational diabetes mellitus. MATERIALS AND METHODS: We randomized 60 overweight or obese women with gestational diabetes mellitus, diagnosed between 12 and 32 weeks’ gestation to either intensive (fasting <90 mg/dL, 1 hour postprandial <120 mg/dL) or standard (fasting <95 mg/dL, 1 ho postprandial <140 mg/dL) glycemic targets. Maternal glucose was assessed in 2 ways: blinded continuous glucose monitors, worn for 5 days at 2 time points (at 1232 weeks and again at 3236 weeks), and self-monitored glucose measurement 4 times per day. All women underwent standardized dietary counseling, and medical therapy was prescribed as needed to achieve glycemic control. RESULTS: Between December 2015 and December 2017, we randomized 60 women to either intensive (n ¼ 30) or standard (n ¼ 30) glycemic control. Baseline characteristics including maternal age, body
T
he prevalence of obesity and gestational diabetes mellitus (GDM) have increased, and both increase the risk for pregnancy complications including fetal overgrowth, neonatal morbidity, hypertensive disorders of pregnancy, and cesarean delivery.1e3 We previously found that obese women with GDM had higher rates of pregnancy complications when compared to normal-weight women with GDM, and they also had higher mean fasting and postprandial glucose values despite more frequent use of medications.4 The strong linear relationship between maternal glucose and pregnancy outcomes is well established,5 but the current recommendations for
Cite this article as: Scifres CM, Mead-Harvey C, Nadeau H, et al. Intensive glycemic control in gestational diabetes mellitus: a randomized controlled clinical feasibility trial. Am J Obstet Gynecol MFM 2019;XX:x.ex-x.ex. 2589-9333/$36.00 ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajogmf.2019.100050
mass index, and gestational age at diagnosis were similar between the intensive and standard groups. Medical therapy was more common in women in the intensive group than those in the standard group (83 vs 57%, P ¼ .02). Women in the intensive glycemic control group had lower glucose values as assessed by continuous glucose monitors at including 24-hour mean (8.1; 95% confidence interval, 12.0 to 4.3 mg/dL; P < .0001) and 1-h postprandial (11.8; 95% confidence interval, 19.7 to 3.9 mg/dL, P ¼ .004) values. Hypoglycemia <60 mg/dL was uncommon and did not differ between groups. CONCLUSION: Intensive glycemic targets can be used in overweight and obese women with minimal hypoglycemia, and this approach results in improved glycemic control when compared to standard glycemic targets. Further studies are needed to determine whether intensive glycemic targets can improve maternal and neonatal outcomes in high-risk women with gestational diabetes mellitus. Clinical Trial Identifier: NCT02530866; clinicaltrials.gov Key words: continuous glucose monitoring, gestational diabetes
mellitus, glycemic control, hypoglycemia, obesity, overweight, pregnancy
glycemic targets in pregnant women with diabetes are less rigorously defined.6,7 In pregnant women without diabetes, mean fasting (70.9 7.8 mg/dL) and 1hour postprandial (108.9 12.9 mg/ dL) glucose values, as assessed by continuous glucose monitoring (CGM), are significantly lower than the current fasting (<95 mg/dL) and 1-hour postprandial (<140 mg/dL) treatment targets used after GDM is diagnosed.6,8 Lower glycemic targets have been suggested,8 but there are minimal data to indicate whether lower targets can improve glycemic control while avoiding hypoglycemia. The prevalence of hypoglycemia has not been reported in many of the GDM treatment trials,9,10 but a cohort study conducted in China that used blinded continuous glucose monitors in women with GDM found that 32.8% of women had glucose values <60 mg/dL for at least 30 minutes per day in the first week of monitoring.11 Given that overweight and obese women with GDM have the highest risk of both
suboptimal glycemic control and adverse pregnancy outcomes, we conducted a randomized clinical feasibility trial to compare glycemic control and the prevalence of hypoglycemia in overweight and obese women with GDM randomized to either current glycemic targets or lower glycemic targets. We hypothesized that lower glycemic targets would result in improved glycemic control. We also set out to characterize the prevalence of hypoglycemia using both home glucose monitoring and blinded continuous glucose monitoring (CGM), as well as changes in maternal lipids and cytokines, among women treated using intensive vs standard glycemic targets.
Materials and Methods Subjects and study procedures This feasibility and tolerability study was approved by the University of Oklahoma Institutional Review Board, and all participants provided written informed consent. This trial was registered as a randomized clinical trial (NCT02530866; clinicaltrials.gov). MONTH 2019 AJOG MFM
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Original Research AJOG MFM at a Glance Why was this study conducted? Overweight and obesity are associated with an increased risk for adverse outcomes in women with gestational diabetes, and this may be related to suboptimal glycemic control. We therefore set out to evaluate whether lower glycemic targets could improve glycemic control without causing excess hypoglycemia. Key findings Intensive glycemic targets result in improved glycemic control when compared to standard glycemic targets with no increase in the risk for hypoglycemia. What does this add to what is known? Intensive glycemic targets can be safely used to improve glycemic control in overweight and obese women with minimal hypoglycemia. Further studies are necessary to determine whether intensive glycemic targets can improve outcomes in this group of women.
Women with GDM diagnosed by the CarpenterCoustan Criteria between 12 and 32 weeks’ gestation who were either overweight (body mass index [BMI], 2529.9 kg/m2) or obese (BMI 30 kg/m2) pre-pregnancy were enrolled from prenatal clinics at the University of Oklahoma. Inclusion criteria included singleton pregnancies, age 1845 years, and planned delivery at the University of Oklahoma Medical Center. Exclusion criteria included maternal tobacco use, planned delivery prior to 34 weeks’ gestation, chronic hypertension requiring medical therapy, vascular disease, serum creatinine 1.5 mg/dL, rheumatologic disorders, or oral steroid use within 30 days of enrollment. For the first 6 months of the study, we included only women with an obese prepregnancy BMI (BMI 30 kg/m2) who were diagnosed with GDM between 20 and 30 weeks’ gestation. However, after low enrollment (5 patients) over this time period, we extended the enrollment criteria include both women with overweight and obesity and those diagnosed with GDM between 12 and 32 weeks’ gestation. After GDM diagnosis, all women who participated in the study were given instructions regarding their diet and recommended weight gain as part of routine clinical care, and they also initiated self-monitoring of glucose 4 times daily (fasting and 1 hour postprandial). After informed consent was obtained, 2 AJOG MFM MONTH 2019
women were randomized to either standard (fasting glucose <95 mg/dL, 1hour postprandial glucose <140 mg/dL), or intensive (fasting <90 mg/dL, 1-hour postprandial glucose <120 mg/dL.) glycemic targets. Randomization occurred via a computer-based platform programmed in REDCap.12 Randomization was stratified based on whether GDM was diagnosed before or after 24 weeks’ gestation. At the time of the first study visit, the prior glucose logs were reviewed, and patients were counseled regarding dietary changes or initiation of medical therapy as needed. Women were then encouraged to report their glucose targets weekly. Throughout the study, providers made the decision to initiate or titrate either insulin or glyburide as necessary to meet assigned glycemic targets. Two study visits occurred after randomization: the first between 12 and 32 weeks’ gestation (at the time of randomization), and the second between 32 and 36 weeks’ gestation and at least 4 weeks after the first visit. At each study visit, glucose logs were reviewed from the prior week with medications initiated or titrated as needed, and women also underwent a nonfasting blood draw. To assess the impact of intensive vs standard glycemic targets on maternal lipids, cytokines, and adipokines, we measured serum triglycerides, total high-density lipoprotein (HDL), lowdensity lipoprotein (LDL) cholesterol, and nonesterified fatty acids in the
clinical laboratory at the University of Oklahoma. Interleukin-6 (IL-6), tumor necrosis factora (TNF-a), leptin, and adiponectin were measured using Milliplex Adipokine Magnetic Bead Panels (MilliporeSigma, Burlington, MA) with an inter- and intra-assay coefficient of variation less than 10%. Interstitial glucose profiles were measured at each study visit using the Medtronic iPRO (Minneapolis, MN) continuous glucose monitoring system (CGMS) for 120 hours (5 days), and both patients and providers were blinded to the results. The CGMS system was calibrated against finger-stick glucose determinations obtained during clinical care, as per the manufacturer’s recommendations. As an additional marker of glycemic control, HbA1c was measured at the first and second study visits. The study protocol included a continuous (daily) process of monitoring and reporting of maternal and neonatal adverse events by the research team (research nurse and investigators). Adverse events were reported to the Human Research Protection Office and the institutional review board (IRB) as they occurred. In addition, the Data Safety Monitoring Board met at 6month intervals to assess protocol compliance and study outcomes.
Infant assessments Infant weight, length, and head circumference were measured at birth. Within the first 72 hours after delivery, infants underwent body composition assessment via air displacement plethysmography (ADP) using the PEA POD Body Infant Body Composition System (COSMED USA, Concord, CA). ADP testing and procedures have been described previously,13e15 and the body density converted to percent fat using sex-specific equations developed by Fomon et al.16
Statistical analysis Our primary outcome was the feasibility of lowering mean glycemic levels as assessed by continuous glucose monitoring in the intensive group by 10 mg/ dL compared to that in women in the standard control group. Our secondary
Original Research outcomes included differences in other CGM parameters including mean daytime, nighttime, and postprandial glucose values as well as the percentage of time that the maternal glucose was <60 mg/dL or >140 mg/dL. In addition, we compared the mean values of both fasting and 1-hour postprandial home glucose monitoring values across gestation. Differences in mean birthweight and measures of neonatal adiposity were also compared between groups. With regard to the CGM data, the fasting glucose was calculated as the mean of 6 consecutive values starting at 6 am and/or after at least 7 hours of fasting. Preprandial glucose was calculated as the mean of 3 consecutive values directly before the start of breakfast, lunch, and dinner meal start. The 1- and 2-hour postprandial glucose was calculated as the mean of 3 consecutive measures 1 or 2 hours after the meal start time. The mean daytime glucose was the mean of all measures between 6:30 am and 11:30 pm, and the mean nocturnal glucose was the mean of all measures between 11:30 pm and 6:30 am, whereas the mean 24-hour glucose was the mean of all measures in 24 hours (11:3011:30). The lowest nocturnal glucose was calculated as the mean of the 6 lowest consecutive measures between 11:30 pm and 6:30 am. The peak postprandial glucose was the highest postprandial glucose within 2 hours of the meal start time, and the time to postprandial peak was the time from meal start to peak postprandial glucose. The 1-hour postprandial excursion was calculated as the peak 1-hour postprandial glucose minus the pre-prandial glucose.17 Descriptive statistics of participant characteristics, glycemic control, metabolic assessment, and delivery outcomes were calculated, including means, standard deviations, frequencies, and percentages. Means were compared between the intensive and standard intervention groups using a 2-sample t test. Proportions were compared using a c2 test, a Fisher exact test when more than 25% of expected frequency counts were less than 5 or any 0 counts were observed in a category, or a CochranArmitage trend test for ordered categories. Metabolic
measures and glycemic control measures that did not derive from continuous glucose monitoring were compared between the intensive and standard intervention groups at the second study visit only. To account for the correlation among continuous glucose measures and first-visit and second-visit measures within an individual over time, generalized estimating equations (GEE) methodology was used to fit linear or logistic regression models for the outcome measures.18 Covariates in the regression models included study visit, treatment group, and their interaction. When not significant, interaction terms were dropped from subsequent models, and treatment groups were compared using data from the first and second study visits combined. The linear associations between infant adiposity measures and continuous glucose measures at the second visit were analyzed using GEE to fit a linear model with the glucose measure, treatment group, and the interaction between the glucose measure and treatment group as covariates. When not significant, interaction terms were dropped from subsequent models, and the analyses were performed using combined data from both treatment groups. Analyses reflect an intent-to treat paradigm in which all data were analyzed according to randomized treatment assignment. All hypothesis tests were performed at a 2-sided 0.05 significance level. SAS 9.4 (SAS Institute, Cary, NC) was used for all analyses.
Sample size calculation Prior studies have shown that the mean glucose assessed by CGM in women without GDM is 88 mg/dL for normal weight women and 105 5 mg/dL for women with obesity,19 but there are fewer data regarding glucose values assessed by CGM in women with GDM. However, the mean glucose, as assessed by taking the average fasting and postmeal values in 1151 women with GDM, is 114 11 mg/dL (unpublished personal observation). We hypothesized that randomizing overweight and obese women with GDM to lower glycemic targets would result in at least a 10-mg/ dL difference in mean glucose values at
3236 weeks’ gestation as assessed by CGM. To achieve 85% power to detect a difference in means of 10 mg/dL, assuming a standard deviation of 11 mg/dL, we estimated that 23 subjects would be required per group. To account for a 20% loss to follow-up rate, we estimated a total of 30 women in each group.
Results A total of 286 women were assessed for eligibility between December 2015 and December 2017. Of these women, 60 provided informed consent and were randomized to either standard (n ¼ 30) or intensive (n ¼ 30) glycemic control (Figure 1). All women remained in their assigned treatment group. All women completed the first study visit, and the majority in both the standard (27 of 30, 90%) and intensive (29 of 30, 96.7%) groups completed study visit 2. Delivery information was available for all women. Women randomized to the standard and intensive glycemic control groups were similar with regard to baseline characteristics, including maternal age, pre-pregnancy BMI, race/ethnicity, public insurance, education, marital status, and family income. In addition, rates of nulliparity, history of GDM, and diabetes in a first-degree relative were similar. Gestational age at GDM diagnosis and results of GDM testing were also similar between groups (Table 1). When CGM monitoring was compared between groups, there was no indication of a significant effect of the intensive therapy over time (P > .05 for the visit by treatment interaction), so the results for visit 1 and 2 were combined (Table 2). We determined that women in the intensive group had lower 24-hour glucose values compared to those in the standard glycemic target group (8.1; 95% CI, 12.0 to 4.3 mg/dL; P < .0001). Mean daytime (9.1; 95% CI, 16.2 to 2.0 mg/dL; P ¼ .01) and nocturnal (10.4; 95% CI, 19.8 to 1.0, P ¼ .03) values were also lower in the intensive vs standard group (Table 2). There was a trend towards lower fasting glucose levels (7.0; 95% CI, 14.5 to 0.6 mg/dL, P ¼ .07) in the MONTH 2019 AJOG MFM
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Original Research FIGURE 1
Randomization and follow-up of trial participants Assessed for eligibility (n=286)
Excluded (n=226) • Not meeting inclusion criteria (n=196) • GDM diagnosed outside of range n=92 • Pre-pregnancy BMI out of range n=42 • Other n=62 • Declined to participate (n=30)
Randomized (n=60)
Allocated to Intensive Glycemic Control (n=30) ¨ Received allocated intervention (n=30)
Allocated to Standard Glycemic Control (n=30) ¨ Received allocated intervention (n=30)¨
Lost to follow-up (n=0) • Completed Visit 1 (n=30) • Completed Visit 2 (n=29) • Completed Delivery Visit (n=30) Discontinued intervention (n=0))
Lost to follow-up (n=0) • Completed Visit 1 (n=30) • Completed Visit 2 (n=27) • Completed Delivery Visit (n=30) Discontinued intervention (n=0)
Analyzed (n=30) ¨ Excluded from analysis (n=0)
Analyzed (n=30) ¨ Excluded from analysis (n=0)
Scifres et al. Intensive glycemic control in gestational diabetes. AJOG MFM 2019.
intensive group. In addition, women in the intensive group had lower preprandial (7.1; 95% CI, 13.7 to 0.7 mg/dL; P ¼ .03), 1-hour postprandial (11.8; 95% CI, 19.7 to 3.9 mg/dL; P ¼ .004), 2-hour postprandial (10.5; 95% CI, 19.5 to 1.5 mg/dL; P ¼ .02), and peak postprandial (11.9; 95% CI, 21.3 to 2.4 mg/dL; P ¼ .01) glucose values (Table 2). Both the postprandial excursion (2.3; 95% CI, 8.2 to 3.5 mg/dL; P ¼ .44) and the time to postprandial excursion (3.4; 95% CI, 8.0 to 1.2 minutes; P ¼ .15) were similar between groups (Table 2). Rates 4 AJOG MFM MONTH 2019
of total, daytime, and nocturnal hypoglycemia did not differ between groups (Table 2). Because women may have behaved differently during the CGM monitoring periods, we also compared their fasting and postprandial glucose values across gestation. There was no indication of a significant effect of intensive therapy over time, so we considered all weeks combined. There were no differences in the mean fasting measures between groups (6.6; 95% CI, 6.6 to 19.9 mg/dL; P ¼ .34), but the postprandial values were lower
in the intensive compared to the standard group (9.7; 95% CI, 15.3 to 4.1 mg/dL; P < .001). There were also no differences in the percentage of values <60 mg/dL among women in the intensive compared to the standard glycemic targets group (0%; interquartile range [IQR], 00.40%; vs 0%; IQR, 00.36%, P ¼ .54), and no women reported symptomatic hypoglycemia. Although rates of medication use were similar between women in the standard and intensive groups at the first study visit (5 of 30 [17%] vs 10 of 30 [33%]; P ¼ .14) and second study visit (16 of 30 [53.3%] vs 23 of 30 [77%]; P ¼ .06), by delivery more women in the intensive group were receiving medication (17 of 30 [57%] vs 25 of 30 [83%]; P ¼ .02). At delivery, rates of glyburide use were similar between groups (10 of 30 [33%] vs 8 of 30 [27%]; P ¼ .57), but insulin use was more common in the intensive group (7 of 30 [23%] vs 17 of 30 [57%]; P ¼ .01). HbA1c concentrations were within recommended ranges and did not differ between groups. Maternal serum lipids including triglycerides, nonesterified fatty acids, total, HDL, and LDL cholesterol were similar between groups (Table 2), as were IL-6, leptin, and adiponectin. There was a trend toward higher levels of TNF-a in the intensive group (P ¼ .06) (Table 2). Mean birthweight (3431 623 vs 3351 518 g; P ¼ .59) and percentage of body fat (12.10 4.81 vs 11.48 5.47; P ¼ .67) were similar between women treated with intensive vs standard glycemic targets (Table 3). There were no differences in rates of SGA and LGA birthweight (Table 3).
Comment Principal findings We found that use of intensive glycemic targets requires more frequent use of medications and results in lower glucose concentrations. Importantly, this tighter glycemic control can be accomplished with minimal maternal hypoglycemia. We also found that two-thirds of eligible women were willing to enroll in a trial using lower glycemic targets.
Original Research TABLE 1
Characteristics of participants by study group assignment P valuea,b
Characteristic
Standard (n ¼ 30)
Intensive (n ¼ 30)
Maternal age
31.63 5.29
32.80 6.58
.45
219.1 59.57
213.7 46.36
.70
36.11 9.29
36.47 7.71
.87
Pre-pregnancy weight, lb 2
Pre-pregnancy BMI, kg/m
American Indian/Alaska Native Black or African American
4 (13.3)
4 (13.3)
.87b
2 (6.7)
4 (13.3)
23 (76.7)
21 (70.0)
1 (3.3)
1 (3.3)
Hispanic
10 (33.3)
4 (13.3)
.07
Public insurance
16 (53.3)
17 (56.7)
.80
9 (30.0)
10 (33.3)
21 (70.0)
20 (66.7)
White American Indian/black or African American
Education High school or less At least some college
.78
1.0b
Marital status Married
26 (86.7)
26 (86.7)
Single
4 (13.3)
4 (13.3) .32c
Family income 0e$30,000 $30,001e$60,000
14 (46.7)
16 (55.2)
7 (23.3)
8 (27.6)
>$60,001
9 (30.0)
Nulliparous
10 (33.3)
8 (26.7)
.57
History of GDM
7 (23.3)
10 (33.3)
.39
History of preeclampsia
7 (23.3)
4 (13.3)
.32
5 (17.2)
First-degree family member with DM
12 (40)
14 (46.7)
.60
Glucose challenge test results
184.3 33.74
170.8 29.29
.14
Gestational age at GCT
23.79 4.95
23.25 5.32
.72
Fasting OGTT value
94.46 15.09
99.69 13.82
.21
1-h OGTT value, mg/dL
198.3 28.46
194.2 26.10
.60
2-h OGTT value, mg/dL
182.6 24.68
169.1 28.06
.08
3-h OGTT value, mg/dL
122.5 33.74
117.5 30.84
.59
Gestational age at OGTT
25.19 4.75
24.31 5.31
.54
All variables presented as mean ( standard deviation) or n (%). BMI, body mass index; DM, diabetes mellitus; GCT, glucose challenge test; GDM, gestational diabetes mellitus; OGTT, oral glucose tolerance test. Hypothesis tests performed using a 2-sample t test to compare means and a c2 test to compare proportions unless otherwise indicated; b Hypothesis test performed using Fisher exact test; c Hypothesis test performed using CochranArmitage trend test. Scifres et al. Intensive glycemic control in gestational diabetes. AJOG MFM 2019. a
Results The current therapeutic targets of fasting glucose <95 mg/dL and <140 and <120 mg/dL at 1 and 2 hours postprandial are recommended by the American College of Obstetricians and Gynecologists (ACOG), the American Diabetes
Association (ADA), and the Endocrine Society.20e22 These targets were established using data from both women with pre-gestational and gestational diabetes that demonstrate the strong relationship between postprandial glucose, macrosomia, and neonatal outcomes.23e26
Smaller studies indicated that mean 24hour glucose concentrations >130 mg/ dL were associated with a high risk of fetal macrosomia,27 and data from women with pre-gestational diabetes demonstrated that a 1-hour postprandial target equal to 130 mg/dL was associated MONTH 2019 AJOG MFM
5
Glycemic control as assessed by continuous glucose monitoring at study visits 1 and 2 Study visit 1 12e32 wk
Study visit 2 32e36 wk
Standard (n ¼ 30)
Intensive (n ¼ 30)
Standard (n ¼ 27)
Intensive (n ¼ 29)
P valuea (visit by treatment)
Gestational age, wk
28.72 3.94
28.65 4.16
34.19 1.09
34.35 1.03
—
—
Hours since last meal
3.19 2.91
3.57 3.80
3.47 4.36
4.44 5.18
—
—
Maternal BMI, kg/m2
38.86 8.90
39.30 6.83
39.71 9.37
39.92 6.95
.70
Diabetes medication
P valueb (treatment)
.85 c
.05c
5 (17)
10 (33)
16 (57.1)
23 (79.3)
.84
Glyburide
3 (10)
4 (13)
10 (35.7)
9 (31.0)
.53c
.89c
Insulin
2 (6.7)
6 (20)
6 (21.4)
14 (48.3)
.98c
.03c
5.60 0.96
.90
.37
109 (97e117)
101 (93e108)
.25
<.0001
HbA1c, %
5.33 0.56
5.49 0.59
5.49 0.64
Glucose values, mg/dL 24-h
107 (99e117)
101 (94e110)
Daytime
108 (95e126)
102 (90e118)
107 (92e125)
101 (89e115)
.62
.01
Nocturnal
104 (92e118)
97 (83e112)
103 (87e121)
97 (85e112)
.48
.03
90 (78e102)
79 (67e92)
85 (69e98)
83 (72e92)
.02
.42
101 (89e110)
95 (82e106)
95 (82e112)
91 (81e101)
.74
.07
Lowest nocturnal Fasting 1-h pre-prandial
102 (92e120)
99 (88e112)
101 (89e120)
98 (88e111)
.47
.03
1-h postprandial
119 (105e139)
111 (98e125)
119 (103e139)
108 (96e122)
.93
.004
2-h postprandial
111 (98e131)
107 (94e121)
115 (101e132)
105 (93e117)
.84
.022
Peak postprandial
131.5 (114e154)
125 (109e138)
16.2 (8.2e18.7)
11.2 (5.1e18.6)
45 (25e1:25)
40 (15e1:10)
24-h
1.1
Daytime
0.7
1-h postprandial excursion Postprandial peak, min
131 (115e149)
119 (107e135.5)
.78
.014
10.6 (1.6e14.6)
.74
.44
45 (20e1:25)
45 (15e1:20)
.16
.15
2.5
1.9
1.5
.16c
.66c
1.6
1.5
1.1
.92c
.77c
c
.50c
12.2 (5e19.3)
Glucose <60 mg/dL (%)
Nocturnal
1.9
4.6
2.9
2.4
.59
Glucose >140 mg/dL (%)
14.3
6.7
11.6
5.4
.79c
.65c
Glucose >120 mg/dL(%)
28.6
20.3
28.8
17.4
.39c
.36c
Triglycerides, mg/dL
222.6 76.10
230.4 89.1
266.5 92.29
258.6 97.23
.29
.94d
NEFA, mmol/L
0.39 0.16
0.40 0.11
0.39 0.16
0.42 0.20
.80
.48d
Scifres et al. Intensive glycemic control in gestational diabetes. AJOG MFM 2019.
(continued)
Original Research
6 AJOG MFM MONTH 2019
TABLE 2
P value from test of interaction between study visit and treatment assignment; b P value from test of treatment effect combining data at visit 1 and visit 2 (postintervention), unless otherwise indicated; c Logistic regression model fit using generalized estimating equations; d P value from test of treatment effect at visit 2 (postintervention). Scifres et al. Intensive glycemic control in gestational diabetes. AJOG MFM 2019.
BMI, body mass index; HDL, high-density lipoprotein; IL, interleukin; LDL, low-density lipoprotein; NEFA, non-esterified fatty acids; TNF, tumor necrosis factor; —, hypothesis testing not performed.
Data are mean standard deviation, median (interquartile range), or n (%).
a
.78d .94 Adiponectin, mg/mL
6.3 (3.6e11.0) 11.9 (8.6e16.5) 11.7 (8.1e18.5)
7.9 (4.7e11.2)
.92d .60 Leptin, mg/L
23.7 (14.4e31.5) 26.6 (21.7e34.3) 27.6 (17.3e34.7)
23.7 (16.9e33.0)
.83d .09 IL-6, pg/dL
3.7 (2.4e4.8) 3.7 (3.2e4.8) 3.5 (2.2e5.3)
2.8(2.0e4.1)
.06d .91 TNF-a, pg/dL
2.8 (2.1e3.7) 3.7 (3.2e4.8) 3.2 (2.3e4.8)
3.4 (2.8e4.2)
.89d .05 HDL, mg/dL
59.29 11.01 58.6 12.9 62.6 10.2
58.83 14.87
.18d .86 LDL, mg/dL
Total cholesterol, mg/dL
111.9 37.90 107.1 42.3 111.2 39.6
107.5 45.83
.23d .54 205.7 41.9 218.3 48.4
208.8 43.14
Standard (n ¼ 27) Intensive (n ¼ 30) Standard (n ¼ 30)
223.3 58.94
Study visit 2 32e36 wk Study visit 1 12e32 wk
Glycemic control as assessed by continuous glucose monitoring at study visits 1 and 2 (continued)
TABLE 2
Intensive (n ¼ 29)
P valuea (visit by treatment)
P valueb (treatment)
Original Research with a reduction in macrosomia.28 Others noted that a mean glucose between 87 and 104 mg/dL can minimize the incidence of both SGA and LGA,29,30 although many women who have wellcontrolled GDM using current targets have a mean glucose that exceeds 104 mg/dL. de Veciana et al demonstrated that treatment decisions using a 1-hour glucose <140 mg/dL reduced the risk for LGA birthweight compared to targeting pre-prandial glucose values,23 and this target has been used in most interventional studies published after the year 2000.31e34 However, pooled CGM data from women without GDM demonstrates a weighted mean fasting glucose of 71 8 mg/dL, followed by 1- and 2-hour postprandial glucose concentrations of 109 13 and 99 10 mg/dL, respectively, and a 24-hour mean glucose of 88 10 mg/dL,8 which are well below current glycemic targets. We chose our 1-hour postprandial target value of <120 mg/dL because it represents a value close to 1 standard deviation above the mean in women without diabetes,8 and in our prior work 1-hour postprandial glucose values <123.8 mg/dL were associated with improved outcomes in obese women with GDM.4 We selected a fasting cut-off of 90 mg/dL using data from the Hyperglycemia and Adverse Pregnancy Outcomes Study, which demonstrated that a fasting glucose o92 mg/dL was associated with a 1.75 times increased risk of LGA and a cord blood c-peptide greater than or equal to the 90th percentile.5 We defined hypoglycemia as a glucose value <60 mg/dL, as this represented a value that was approximately 1.5 standard deviations below the mean fasting glucose value for pregnant women without diabetes.8
Clinical implications Our results support the feasibility of a randomized clinical trial comparing intensive to standard glycemic targets. If a larger trial found that intensive glycemic targets improve perinatal outcomes, this would have direct clinical implications for overweight and obese women with GDM. Although our results may be MONTH 2019 AJOG MFM
7
Original Research TABLE 3
Neonatal outcomes by treatment group P valuea
Standard (n ¼ 30)
Intensive (n ¼ 30)
Gestational age at delivery, wk
37.8 (1.9)
38.2 (1.7)
.40
Birthweight
3431 623.3
3351 518.2
.59
SGA birthweight
0 (0.0)
3 (10.0)
LGA birthweight
6 (20.0)
6 (20.0)
.24b 1.0
Age at PEA POD, h
30.01 22.27
39.12 27.50
.20
Weight at PEA POD, g
3474 451
3166 805
.10
% Fat mass
12.10 4.81
11.48 5.47
.67
Fat mass, g
430 190
410 250
.79
Fat-free mass, g
3150 740
3020 860
.58
Composite neonatal morbidity
17 (56.7)
16 (53.3)
.80
NICU admission
8 (26.7)
6 (20.0)
.54
Supplemental oxygen
8 (26.7)
8 (26.7)
16 (53.3)
10 (33.3)
.12
9 (30)
8 (27)
.77
Hyperbilirubinemia Hypoglycemia
1.0
Data are mean standard deviation or n (%). Body composition assessments were available for 26 neonates per group. LGA, large for gestational age; NICU, neonatal intensive care unit; SGA, small for gestational age. Hypothesis tests performed using a 2-sample t test to compare means and a c2 test to compare proportions unless otherwise indicated; b Hypothesis test preformed using Fisher exact test. Scifres et al. Intensive glycemic control in gestational diabetes. AJOG MFM 2019. a
applied to women with gestational diabetes, it is possible that pre-gestational diabetes may require different targets because of the possibility of abnormal placentation from underlying vascular disease or hypertension that may limit glucose availability to the fetus.35 In addition, these results may not be generalizable to women with GDM who are of normal weight and at lower risk for fetal overgrowth.
Research implications Future trials to evaluate the optimal glycemic targets are important, because exposure to higher glucose levels in utero is associated with higher childhood glucose and insulin resistance independent of maternal or childhood BMI,36 and macrosomia may have a lasting metabolic impact on offspring.37,38 There is currently 1 ongoing study recruiting in New Zealand comparing intensive to standard glycemic targets.39 However, this study is outside the United States, where patient demographics and clinical management are different; it includes normal-weight 8 AJOG MFM MONTH 2019
women with GDM; and it is testing glycemic targets (standard: fasting <99, 1 hour postprandial <144 mg/dL; intensive: fasting <90, 1 hour postprandial <133 mg/dL) that differ from those in this proposal. There was no expectation that our study would be large enough to demonstrate a difference in neonatal outcomes including the prevalence of LGA birthweight or neonatal composite morbidity, but the differences in birthweight and fat mass between the standard and intensive group were in the direction and magnitude of change that would be expected based on prior treatment trials of GDM.32 Although other pathways including maternal serum triglycerides may lead to fetal overgrowth and excess adiposity,40 1 advantage to targeting maternal glucose is that these treatments are already used regularly in the care of women diagnosed with GDM.
Strengths and limitations Rates of maternal hypoglycemia are rarely reported in GDM treatment trials,9,10 and 1 strength of our study is
the use of CGM monitoring to assess both clinically recognized and subclinical hypoglycemia. One limitation is that because of the nature of this study, we were unable to blind clinicians and participants to the treatment groups. In addition, there was heterogeneity in treatment, with some women receiving insulin and some receiving glyburide. At the time that our trial started, glyburide was the most commonly used treatment for GDM,41 and we wanted to ensure that women and their providers had the autonomy to use shared decision making for treatment decisions.
Conclusions In summary, use of lower glycemic targets was feasible, with no increase in maternal hypoglycemia. In addition, use of lower glycemic targets resulted in improved glycemic control across a variety of time-points. Although a larger trial is still needed, these findings are promising and support the potential use of lower glycemic targets in overweight and obese women with GDM. n
Original Research References 1. Casey BM, Lucas MJ, McIntire DD, Leveno KJ. Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet Gynecol 1997;90: 869–73. 2. Sibai BM, Gordon T, Thom E, et al. Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 1995;172: 642–8. 3. Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study: associations with maternal body mass index. BJOG 2010;117: 575–84. 4. Scifres C, Feghali M, Althouse AD, Caritis S, Catov J. Adverse outcomes and potential targets for intervention in gestational diabetes and obesity. Obstet Gynecol 2015;126:316–25. 5. Hapo Study Cooperative Research Group, Metzger BE, Lowe LP, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991–2002. 6. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International WorkshopConference on Gestational Diabetes Mellitus. Diabetes Care 2007;30(Suppl 2):S251–60. 7. Wexler DJ, Powe CE, Barbour LA, et al. Research gaps in gestational diabetes mellitus: executive summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Obstet Gynecol 2018;132: 496–505. 8. Hernandez TL, Friedman JE, Van Pelt RE, Barbour LA. Patterns of glycemia in normal pregnancy: should the current therapeutic targets be challenged? Diabetes Care 2011;34: 1660–8. 9. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343: 1134–8. 10. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, Mi GTI. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003–15. 11. Yu F, Lv L, Liang Z, et al. Continuous glucose monitoring effects on maternal glycemic control and pregnancy outcomes in patients with gestational diabetes mellitus: a prospective cohort study. J Clin Endocrinol Metab 2014;99: 4674–82. 12. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)ea metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81. 13. Urlando A, Dempster P, Aitkens S. A new air displacement plethysmograph for the
measurement of body composition in infants. Pediatr Res 2003;53:486–92. 14. Ma G, Yao M, Liu Y, et al. Validation of a new pediatric air-displacement plethysmograph for assessing body composition in infants. Am J Clin Nutr 2004;79:653–60. 15. Fields DA, Demerath EW, Pietrobelli A, Chandler-Laney PC. Body composition at 6 months of life: comparison of air displacement plethysmography and dual-energy X-ray absorptiometry. Obesity (Silver Spring) 2012;20: 2302–6. 16. Fomon SJ, Haschke F, Ziegler EE, Nelson SE. Body composition of reference children from birth to age 10 years. Am J Clin Nutr 1982;35:1169–75. 17. Hernandez TL, Barbour LA. A standard approach to continuous glucose monitor data in pregnancy for the study of fetal growth and infant outcomes. Diabetes Technol Ther 2013;15: 172–9. 18. Kyas SL. Longitudinal data analysis using generalized linear model. Biometrika 1986;73: 13–22. 19. Harmon KA, Gerard L, Jensen DR, et al. Continuous glucose profiles in obese and normal-weight pregnant women on a controlled diet: metabolic determinants of fetal growth. Diabetes Care 2011;34:2198–204. 20. Committee on Practice BulletinsObstetrics. ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol 2018;131:e49–64. 21. American Diabetes Association. 14. Management of diabetes in pregnancy: standards of medical care in diabetese2019. Diabetes Care 2019;42:S165–72. 22. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013;98:4227–49. 23. de Veciana M, Major CA, Morgan MA, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995;333:1237–41. 24. Jovanovic-Peterson L, Peterson CM, Reed GF, et al. Maternal postprandial glucose levels and infant birthweight: the Diabetes in Early Pregnancy Study. The National Institute of Child Health and Human Developmente Diabetes in Early Pregnancy Study. Am J Obstet Gynecol 1991;164:103–11. 25. Parfitt VJ, Clark JD, Turner GM, Hartog M. Maternal postprandial blood glucose levels influence infant birthweight in diabetic pregnancy. Diabetes Res 1992;19:133–5. 26. Demarini S, Mimouni F, Tsang RC, Khoury J, Hertzberg V. Impact of metabolic control of diabetes during pregnancy on neonatal hypocalcemia: a randomized study. Obstet Gynecol 1994;83:918–22. 27. Willman SP, Leveno KJ, Guzick DS, Williams ML, Whalley PJ. Glucose threshold for macrosomia in pregnancy complicated by diabetes. Am J Obstet Gynecol 1986;154:470–5.
28. Combs CA, Gunderson E, Kitzmiller JL, Gavin LA, Main EK. Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy. Diabetes Care 1992;15: 1251–7. 29. Langer O, Levy J, Brustman L, Anyaegbunam A, Merkatz R, Divon M. Glycemic control in gestational diabetes mellitusehow tight is tight enough: small for gestational age versus large for gestational age? Am J Obstet Gynecol 1989;161:646–53. 30. Langer O, Mazze R. The relationship between large-for-gestational-age infants and glycemic control in women with gestational diabetes. Am J Obstet Gynecol 1988;159: 1478–83. 31. Parretti E, Mecacci F, Papini M, et al. Thirdtrimester maternal glucose levels from diurnal profiles in nondiabetic pregnancies: correlation with sonographic parameters of fetal growth. Diabetes Care 2001;24:1319–23. 32. 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. 33. Sivan E, Weisz B, Homko CJ, Reece EA, Schiff E. One or two hours postprandial glucose measurements: are they the same? Am J Obstet Gynecol 2001;185:604–7. 34. Weisz B, Shrim A, Homko CJ, Schiff E, Epstein GS, Sivan E. One hour versus two hours postprandial glucose measurement in gestational diabetes: a prospective study. J Perinatol 2005;25:241–4. 35. Howarth C, Gazis A, James D. Associations of type 1 diabetes mellitus, maternal vascular disease and complications of pregnancy. Diabet Med 2007;24:1229–34. 36. Scholtens DM, Kuang A, Lowe LP, et al. Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study (HAPO FUS): maternal glycemia and childhood glucose metabolism. Diabetes Care 2019. 37. Dabelea D, Knowler WC, Pettitt DJ. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. J Matern Fetal Med 2000;9:83–8. 38. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism. Diabetes Care 1995;18:611–7. 39. Crowther CA, Alsweiler JM, Hughes R, Brown J, Target Study G. Tight or less tight glycaemic targets for women with gestational diabetes mellitus for reducing maternal and perinatal morbidity? (TARGET): study protocol for a stepped wedge randomised trial. BMC Pregnancy Childbirth 2018;18:425. 40. Barbour LA, Hernandez TL. Maternal lipids and fetal overgrowth: making fat from fat. Clin Ther 2018;40:1638–47. 41. Camelo Castillo W, Boggess K, Sturmer T, Brookhart MA, Benjamin DK Jr, Jonsson Funk M. Trends in glyburide compared with insulin use for gestational diabetes treatment in the
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Original Research United States, 2000-2011. Obstet Gynecol 2014;123:1177–84.
Author and article information From the Department of Obstetrics and Gynecology (Dr Scifres), Indiana University School of Medicine, Indianapolis, IN; Department of Biostatistics and Epidemiology (Ms Mead-Harvey and Dr Stoner), University of Oklahoma Hudson College of Public Health, OK; Department of
10 AJOG MFM MONTH 2019
Obstetrics and Gynecology (Drs Nadeau, Reid, Pierce, and Meyers), University of Oklahoma College of Medicine, OK; Department of Obstetrics, Gynecology and Reproductive Sciences (Dr Feghali), Magee Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Pediatrics (Dr Fields), University of Oklahoma College of Medicine, OK. Received June 25, 2019; revised Aug. 28, 2019; accepted Sept. 22, 2019. The authors report no conflict of interest.
Supported in part by the University of Oklahoma College of Medicine Alumni Association and by National Institutes of Health, National Institute of General Medical Sciences (Grant 1 U54GM104938, PI James). This work was presented in part at the Society for Maternal Fetal Medicine 39th Annual Pregnancy Meeting, Las Vegas, NV, February 16, 2019. Corresponding author: Christina M. Scifres, MD [email protected]