Objective
The purpose of this study was to examine the association between gestational age (GA) at the time of treatment initiation for gestational diabetes mellitus (GDM) and maternal and perinatal outcomes.
Study Design
We conducted a secondary analysis of a multicenter randomized treatment trial of mild GDM in which women with mild GDM were assigned randomly to treatment vs usual care. The primary outcome of the original trial, as well as this analysis, was a composite perinatal adverse outcome that included neonatal hypoglycemia, hyperbilirubinemia, hyperinsulinemia, and perinatal death. Other outcomes that were examined included the frequency of large for GA, birthweight, neonatal intensive care unit admission, gestational hypertension/preeclampsia, and cesarean delivery. The interaction between GA at treatment initiation (stratified as 24-26, 27, 28, 29, and ≥30 weeks of gestation) and treatment group (treated vs routine care), with the outcomes of interest, was used to determine whether GA at treatment initiation was associated with outcome differences.
Results
Of 958 women whose cases were analyzed, those who initiated treatment at an earlier GA did not gain an additional treatment benefit compared with those who initiated treatment at a later GA (probability value for interaction with the primary outcome, .44). Similarly, there was no evidence that other outcomes were improved significantly by earlier initiation of GDM treatment (large for GA, P = .76; neonatal intensive care unit admission, P = .8; cesarean delivery, P = .82). The only outcome that had a significant interaction between GA and treatment was gestational hypertension/preeclampsia ( P = .04), although there was not a clear cut GA trend where this outcome improved with treatment.
Conclusion
Earlier initiation of treatment of mild GDM was not associated with stronger effect of treatment on perinatal outcomes.
High-quality evidence now exists regarding the association of maternal hyperglycemia with adverse perinatal outcomes; these outcomes may be improved with the treatment of mild gestational diabetes mellitus (GDM). However, international consensus is still lacking on optimal screening and diagnostic guidelines.
In the United States, pregnant women undergo universal screening and a 2-step approach for GDM diagnosis. This approach involves performing a 50-g glucose challenge test (GCT), followed by an oral 100-g glucose tolerance test (OGTT) when the GCT results are beyond a certain threshold. The optimal time to perform these tests remains uncertain and may differ depending on the population that is screened. Currently, the American College of Obstetricians and Gynecologists recommends screening women without risk factors for GDM at 24-28 weeks of gestation. However, when the screening and subsequent diagnostic testing is done at the end of this range, the interval from subsequent therapeutic intervention to delivery is obviously shorter than with earlier testing and diagnosis. We hypothesized that earlier diagnosis and a corresponding longer period of treatment would result in improved outcomes compared with later diagnosis and treatment, after controlling for clinical covariates. Therefore, the objective of this analysis was to examine whether earlier initiation of screening and subsequently treatment of mild GDM can lead to improved maternal and perinatal outcomes.
Materials and Methods
This was a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network randomized GDM treatment trial. The trial was designed to determine whether treatment of mild GDM reduces perinatal and obstetric complications. Pregnant women between 24 weeks 0 days and 30 weeks 6 days of gestation were screened for GDM with a 50-g GCT and those with a 1-hour blood glucose value of 135-200 mg/dL underwent a 3-hour OGTT. Ultrasonography was performed on all subjects before the OGTT to confirm the gestational age (GA). Samples for the OGTT were analyzed at a central laboratory. Mild GDM was defined as a fasting blood glucose level of <95 mg/dL and ≥2 postchallenge glucose level above the following thresholds: 1-hour, >180 mg/dL; 2-hour, >155 mg/dL; 3-hour, >140 mg/dL. Women who met these criteria were assigned randomly to treatment that included nutritional counseling, diet therapy, and, if required, insulin vs usual prenatal care. The details of the study protocol have been reported previously. All women with mild GDM who participated in the parent study and who had complete maternal and perinatal outcome data were eligible for this analysis. Each center’s institutional review board approved the study protocol.
The aim of this analysis was to determine whether there is an association between GA at the time of treatment initiation for GDM and perinatal outcomes. The primary outcome was a composite outcome that included perinatal death and complications that have been associated with maternal hyperglycemia: neonatal hypoglycemia (defined as a glucose value of <35 mg/dL), hyperbilirubinemia (defined as bilirubin value >95th percentile for any given point after birth), hyperinsulinemia (defined as a cord-blood C-peptide level >95th percentile), and birth trauma (defined as brachial plexus palsy or clavicular, humeral, or skull fracture). This was the same as the primary outcome of the original trial. Secondary outcomes were prespecified in the original trial and included the occurrence of large size for GA (LGA; defined as birthweight at >90th percentile of a US reference population ), neonatal intensive care unit admission, gestational hypertension/preeclampsia, and cesarean delivery. Shoulder dystocia was not included in the analysis because there were only 25 cases. Trained study personnel collected antepartum, intrapartum, and postdelivery data for enrolled women and their newborn infants at the time of discharge from the hospital. All cases of hypertensive disorders underwent masked central review by 2 of the investigators to ensure accurate diagnosis.
Women were stratified by 5 categories of GA at the time of treatment randomization (24-26 weeks, 27 weeks, 28 weeks, 29 weeks, ≥30 weeks of gestation). The decision to select GA at the time of treatment initiation compared with GA at the time of GDM diagnosis was made to avoid bias for unaccounted time lag that may have occurred between a positive GCT and OGTT performance and between positive OGTT and treatment initiation. Univariable analysis was performed to compare demographic characteristics of patients by GA group, with the use of the chi-square test for categoric variables and the Kruskal-Wallis test for continuous variables. To examine whether GA at treatment initiation had an impact on the treatment effect, the interaction between GA category and treatment group (treated vs routine care) with the outcomes of interest was examined with the use of the Breslow-Day test for homogeneity. We examined the interaction between GA category and treatment group with birthweight Z-scores that were based on a sex- and ethnicity-specific US reference population with analysis of variance. Additionally, regression analysis was performed to examine the interaction between GA category and treatment group for the outcomes of interest and to adjust for the potential confounding effect of race/ethnicity. No adjustments were made for multiple comparisons. Statistical analysis was conducted with SAS software (SAS Institute Inc, Cary, NC).
Results
Of 19,665 women who had an abnormal result on a glucose loading test, 7298 women underwent a 3-h OGTT. After exclusion of the women with OGTT fasting values >95 mg/dL, 958 women were assigned randomly; 485 women were allocated to the treatment group, and 473 women were allocated to the control group. Full outcomes were available for 477 women in the treatment group and 455 women in the control group ( Figure 1 ).
Maternal characteristics of the study population that were stratified by GA group at the time of treatment are depicted in Table 1 . Women in each GA group differed only according to race and ethnicity. Specifically, black and Hispanic women were assigned randomly to treatment or usual care at an earlier GA. There were no significant differences in maternal body mass index, GCT, and OGTT results between the GA groups.
| Variable | Gestational age at initiation of treatment, wk | P value | |||||
|---|---|---|---|---|---|---|---|
| 24-26 (n = 116) | 27 (n = 170) | 28 (n = 193) | 29 (n = 221) | 30+ (n = 258) | Total (n = 958) | ||
| Maternal age, y a | 28.7 ± 5.5 | 29.0 ± 5.6 | 29.1 ± 5.5 | 29.2 ± 5.9 | 29.2 ± 5.6 | 29.0 ± 5.6 | .91 |
| Race/ethnicity, n (%) | < .001 | ||||||
| Black | 16 (13.8) | 22 (12.9) | 16 (8.3) | 25 (11.3) | 31 (12.0) | 110 (11.5) | |
| Hispanic | 81 (69.8) | 112 (65.9) | 126 (65.3) | 111 (50.2) | 116 (45.0) | 546 (57.0) | |
| White | 16 (13.8) | 26 (15.3) | 40 (20.7) | 74 (33.5) | 86 (33.3) | 242 (25.3) | |
| Other | 3 (2.6%) | 10 (5.9) | 11 (5.7) | 11 (5.0) | 25 (9.7) | 60 (6.3) | |
| Body mass index at entry, kg/m 2 a | 30.0 ± 4.8 | 31.0 ± 5.5 | 30.4 ± 5.2 | 29.9 ± 4.7 | 29.7 ± 5.0 | 30.1 ± 5.1 | .23 |
| Nulliparity, n (%) | 33 (28.5) | 52 (30.6) | 72 (37.3) | 66 (29.9) | 83 (32.2) | 306 (31.9) | .43 |
| Alcohol use, n (%) | 1 (0.9) | 4 (2.4) | 6 (3.1) | 13 (5.9) | 10 (3.9) | 34 (3.6) | .14 |
| Tobacco use, n (%) | 8 (6.9) | 11 (6.5) | 13 (6.7) | 16 (7.2) | 21 (8.1) | 69 (7.2) | .97 |
| 50 g 1-hr oral glucose load, mg/dL | 158.9 ± 15.4 | 158.9 ± 15.3 | 158.4 ± 15.3 | 160.2 ± 15.5 | 159.8 ± 15.5 | 159.4 ± 15.4 | .74 |
| 100 g 3-hr oral glucose tolerance test, mg/dL a | |||||||
| Fasting | 87.2 ± 5.9 | 86.3 ± 5.7 | 86.4 ± 5.6 | 85.7 ± 6.1 | 86.8 ± 5.4 | 86.4 ± 5.7 | .15 |
| 1 hr | 194.1 ± 21.2 | 194.4 ± 18.7 | 190.9 ± 23.6 | 193.5 ± 20.0 | 191.3 ± 20.0 | 192.6 ± 20.7 | .33 |
| 2 hr | 177.2 ± 22.6 | 173.8 ± 18.6 | 171.8 ± 19.5 | 174.0 ± 21.3 | 172.5 ± 21.4 | 173.5 ± 20.7 | .42 |
| 3 hr | 136.2 ± 30.5 | 131.1 ± 29.3 | 136.5 ± 30.7 | 136.3 ± 30.1 | 137.5 ± 30.5 | 135.7 ± 30.3 | .16 |
Table 2 and Figure 2 describe perinatal and maternal outcomes that were stratified by GA and treatment group. There was no significant interaction between the GA and treatment group with respect to the primary and most of the secondary outcomes. The only significant interaction between GA and treatment was for gestational hypertension/preeclampsia ( P = .04). However, there was not a clear GA trend where this outcome improved with treatment. To control for potentially confounding effects of race, we performed logistic regression analysis that included race/ethnicity in the model and treatment group, GA at randomization, and an interaction term between treatment group and GA. The probability values for each of the outcomes were similar to probability values reported in Table 2 (data not shown). Similarly, additional analysis that stratified women by 2 groups of GA (24-26 and 27-29 weeks of gestation, with the ≥30-week group excluded because of much smaller window for therapeutic intervention), to enlarge the sample size of each GA group, showed that there were no significant interactions between GA and treatment groups with the outcomes of interest ( Table 3 ). Birthweight Z-scores based on a US reference population were also examined, and there was no significant interaction between GA and treatment group for this outcome ( P = .86 for the interaction of GA and treatment group; Table 4 ).
| Gestational age at treatment initiation, wk | Composite outcome, n (%) a | Neonatal intensive care unit admission, n (%) a | Large for gestational age, n (%) a | Cesarean delivery, n (%) a | Gestational hypertension/ preeclampsia, n (%) a | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Treated (n = 460) b | Usual care (n = 440) b | Treated (n = 477) | Usual care (n = 455) | Treated (n = 477) | Usual care (n = 454) b | Treated (n = 476) b | Usual care (n = 455) | Treated (n = 476) b | Usual care (n = 455) | |
| 24-26 | 25 (37.3) | 20 (50.0) | 10 (14.5) | 7 (16.3) | 8 (11.6) | 6 (14.0) | 23 (33.8) | 15 (34.9) | 7 (10.3) | 6 (14.0) |
| 27 | 30 (40.0) | 28 (32.9) | 9 (11.7) | 13 (14.8) | 5 (6.5) | 12 (13.6) | 22 (28.6) | 32 (36.4) | 4 (5.2) | 19 (21.6) |
| 28 | 33 (33.7) | 33 (38.4) | 7 (6.9) | 12 (13.8) | 8 (7.8) | 14 (16.3) | 29 (28.4) | 28 (32.2) | 15 (14.7) | 8 (9.2) |
| 29 | 27 (25.5) | 32 (31.1) | 9 (8.3) | 13 (12.2) | 7 (6.4) | 14 (13.1) | 26 (23.9) | 33 (30.8) | 7 (6.4) | 10 (9.4) |
| 30+ | 34 (29.8) | 50 (39.7) | 8 (6.7) | 8 (6.2) | 6 (5.0) | 20 (15.4) | 28 (23.3) | 46 (35.4) | 8 (6.7) | 19 (14.6) |
| Probability value interaction of gestational age and treatment group | .44 | .80 | .76 | .82 | .04 | |||||
| Probability value for the interaction of gestational age and treatment group controlled for race/ethnicity | .50 | .61 | .85 | .85 | .04 | |||||
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