Objective
We evaluated whether improvements in pregnancy outcomes after treatment of mild gestational diabetes mellitus differed in magnitude on the basis of fetal gender.
Study Design
This is a secondary analysis of a masked randomized controlled trial of treatment for mild gestational diabetes mellitus. The results included preeclampsia or gestational hypertension, birthweight, neonatal fat mass, and composite adverse outcomes for both neonate (preterm birth, small for gestational age, or neonatal intensive care unit admission) and mother (labor induction, cesarean delivery, preeclampsia, or gestational hypertension). After stratification according to fetal gender, the interaction of gender with treatment status was estimated for these outcomes.
Results
Of the 469 pregnancies with male fetuses, 244 pregnancies were assigned randomly to treatment, and 225 pregnancies were assigned randomly to routine care. Of the 463 pregnancies with female fetuses, 233 pregnancies were assigned randomly to treatment, and 230 pregnancies were assigned randomly to routine care. The interaction of gender with treatment status was significant for fat mass ( P = .04) and birthweight percentile ( P = .02). Among women who were assigned to the treatment group, male offspring were significantly more likely to have both a lower birthweight percentile (50.7 ± 29.2 vs 62.5 ± 30.2 percentile; P < .0001) and less neonatal fat mass (487 ± 229.6 g vs 416.6 ± 172.8 g; P = .0005,) whereas these differences were not significant among female offspring. There was no interaction between fetal gender and treatment group with regard to other outcomes.
Conclusion
The magnitude of the reduction of a newborn’s birthweight percentile and neonatal fat mass that were related to the treatment of mild gestational diabetes mellitus appears greater for male neonates.
Two recent randomized studies reported that therapy of mild gestational diabetes mellitus (GDM) results in a reduction of birthweight. In 1 of these studies, which was performed by the National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network, we also reported a significant reduction in neonatal fat mass in the treatment vs the standard clinical care group.
GDM is characterized by increased oxidative stress (OS) in both maternal blood and placental tissues. Recent laboratory studies of hepatic cells in culture demonstrated that hydrogen peroxide therapy increased the production of sterol regulatory element-binding protein-1c, which is a transcription factor that controls the expression of fatty acid and cholesterol biosynthesis genes. Hydrogen peroxide treatment resulted in increased lipid accumulation in these cells. Interesting reports have surfaced that suggest that vascular tissues from male animals generate more OS and also that cells from males are more susceptible to OS. In humans, treatment of disorders in which increased OS is a pathologic feature reportedly results in a greater therapeutic response in male fetuses.
Given that lipogenesis has been associated with increased OS and that male fetuses appear to be more sensitive to the insults of OS, we hypothesized that fetal gender could affect outcomes that are related to the treatment of GDM. Thus, we sought to determine whether treatment of mild GDM differentially affected maternal and perinatal outcomes on the basis of the fetal gender.
Materials and Methods
This is a secondary analysis of data that were collected during a randomized trial of treatment for mild GDM at 10 participating centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network between October 2002 and November 2007. Institutional research board approval was obtained from each of the participating centers for the conduct of the primary study.
The details of study design, outcomes, and statistical analyses were published previously in the principal analysis of these data. In brief, women who were between 24 and 30 weeks 6 days gestation at the time of 50-g glucose challenge test and whose 1-hour blood glucose value was 135-200 mg/dL (7.5-11.1 mmol/L) underwent a 3-hour oral glucose tolerance test. Mild GDM was defined, on the basis of this oral glucose tolerance test, with the use of criteria that were proposed by the Workshop of the Fourth International conference of Gestational Diabetes Mellitus, namely fasting blood sugar <95 mg/dL (5.3 mmol/L) and ≥2 elevated postchallenge thresholds: 1-hour, >180 mg/dL (10.0 mmol/L); 2-hour, >155 mg/dL (8.6 mmol/L), and 3-hour, >140 mg/dL (7.8 mmol/L). Exclusion criteria were preexisting diabetes mellitus, history of stillbirth, multifetal pregnancy, asthma or chronic hypertension, current use of corticosteroids, known fetal anomaly, or anticipated imminent preterm delivery. Those who had no exclusion criteria, who had mild GDM, and who consented to participation were then assigned randomly by the coordinating center to nutritional counseling and diet with insulin use as needed (treatment group) or to routine prenatal care (control group). An additional group of women who had a normal oral glucose tolerance test result were also enrolled by the coordinating center into the group of women who received routine prenatal care to ensure that medical personnel would be unaware whether patients in the group had mild GDM. Insulin therapy was initiated if most of the fasting or postprandial values were elevated (fasting ≥95 mg/dL or 2-hour postprandial ≥120 mg/dL [6.7 mmol/L]). Random values of >160 mg/dL (8.9 mmol/L) or fasting values ≥95 mg/dL were used as criteria for the initiation of insulin in the control group. Such patients were not removed from the control group because the analysis was conducted according to the intention-to-treat principle.
Maternal outcomes that were assessed included hypertensive disease of pregnancy, shoulder dystocia, and cesarean delivery. Neonatal outcomes included hypoglycemia, hyperinsulinemia, hyperbilirubinemia, elevated cord-blood C-peptide levels, birthweight, fat mass, stillbirth or neonatal death, and birth trauma. For this secondary analysis, the outcomes were evaluated with the use of not only raw birthweight but also percentiles and z-scores that were based on published standard populations. Additionally, the effect of therapy on lean body mass (defined as birthweight minus fat mass) of the neonate was determined. Composite adverse outcomes for both the neonate (preterm birth, small for gestational age, or neonatal intensive care unit admission) and the mother (labor induction, cesarean delivery, preeclampsia, or gestational hypertension) were evaluated. Hyperinsulinemia was defined as cord blood C-peptide level >95th percentile (1.77 ng/mL); hypoglycemia was defined as glucose level <35 mg/dL (1.9 mmol/L). Neonatal fat mass was estimated based on the technique described by Catalano et al, which combines measurement of chest and limb circumferences with caliper measurement of skinfold thickness to estimate subcutaneous fat mass.
The focus of this secondary analysis was whether there was an interaction between fetal gender and treatment group with regard to obstetric and perinatal outcomes. Thus, the frequencies of outcomes that were based on treatment status (ie, treatment vs routine care) were stratified according to a newborn’s gender. For categoric variables, the Breslow-Day test for homogeneity of the odds ratios was used to test for the presence of interactions. For continuous variables, the Student t test was used for univariate analysis, and analysis of variance was used to test for the presence of interactions. Last, because the study groups were not balanced with regard to alcohol use, which was more prevalent in the treatment group, regression models were generated that estimated the interactions between fetal gender and outcome while controlling for the potentially confounding variable of alcohol use.
Statistical analyses were conducted with SAS software (SAS Institute Inc, Cary, NC). A nominal 2-sided probability value of < .05 was considered to indicate statistical significance, and no adjustments were made for multiple comparisons.
Results
There were 469 women with male fetuses and 463 women with female fetuses in the study population who met inclusion criteria for this analysis and for whom delivery data were available. As noted in the primary analysis, there was no significant difference in maternal body mass index on entry into the study. There were no significant interactions between fetal gender and treatment group with regard to most perinatal ( Table 1 ) or maternal ( Table 2 ) outcomes. There were, however, significant interactions between treatment group and gender for birthweight percentile ( P = .02) and for neonatal fat mass ( P = .04; Table 1 ). Specifically, male offspring were significantly more likely to have both a lower birthweight percentile (50.7 ± 29.2 vs 62.5 ± 30.2 percentile; P < .0001) and less neonatal fat mass (487 ± 229.5 vs 416.6 ± 172.8 g; P = .0005), whereas these differences were not significant among female offspring. Conversely, there was no significant difference in lean body mass ( Table 1 ), which may indicate that the weight difference that was observed with treatment was due to the effect on fat accretion. Results were similar after adjustment for alcohol use.
| Variable Outcome variable | Male | Female | P value a | ||
|---|---|---|---|---|---|
| Treatment (n = 244) | Control (n = 225) | Treatment (n = 233) | Control (n = 230) | ||
| Gestational age at birth, wk b | 39.0 ± 1.7 | 39.0 ± 1.7 | 39.0 ± 1.8 | 38.9 ± 1.8 | .25 |
| Birthweight, g b | 3333.6 ± 498.3 | 3520.3 ± 573.9 | 3269.5 ± 505.7 | 3298.6 ± 584.9 | .03 |
| Birthweight percentile b | 50.7 ± 29.2 | 62.5 ± 30.2 | 54.7 ± 29.9 | 56.7 ± 31.3 | .02 |
| Large for gestational age: >90th percentile, n/N (%) | 14/244 (5.7) | 35/224 (15.6) | 20/233 (8.6) | 31/230 (13.5) | .18 |
| Fat mass, g b , c | 416.6 ± 172.8 | 487.0 ± 229.5 | 429.7 ± 185.7 | 442.1 ± 213.2 | .04 |
| Lean mass, g b , c | 2939.3 ± 315.1 | 3059.2 ± 393.2 | 2849.5 ± 370.9 | 2886.8 ± 394.7 | .11 |
| Small for gestational age: <10th percentile, n/N (%) | 19/244 (7.8) | 11/224 (4.9) | 17/233 (7.3) | 18/230 (7.8) | .28 |
| Composite adverse neonatal outcome, n/N (%) | 49/244 (20.1) | 49/225 (21.8) | 50/233 (21/5) | 52/230 (22.6) | .91 |
| Hypoglycemia, n/N (%) | 31/194 (16.0) | 24/175 (13.7) | 31/187 (16.6) | 31/182 (17.0) | .60 |
| Hyperbilirubinemia, n/N (%) | 25/227 (11.0) | 22/206 (10.7) | 18/223 (8.1) | 32/212 (15.1) | .09 |
| Elevated C-peptide, n/N (%) | 31/217 (14.3) | 48/205 (23.4) | 44/206 (21.4) | 44/198 (22.2) | .11 |
| Birth trauma, n/N (%) | 0/243 | 1/225 (0.4) | 3/233 (1.3) | 5/230 (2.2) | .44 |
| Neonatal intensive care unit, n/N (%) | 19/244 (7.8) | 27/225 (12.0) | 24/233 (10.3) | 26/230 (11.3) | .39 |
| Intravenous glucose, n/N (%) | 12/242 (5.0) | 13/225 (5.8) | 13/233 (5.6) | 18/230 (7.8) | .72 |
| Respiratory distress syndrome, n/N (%) | 4/244 (1.6) | 5/225 (2.2) | 5/233 (2.2) | 8/230 (3.5) | .83 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
