Hyperinsulinism, neonatal obesity and placental immaturity in infants born to women with one abnormal glucose tolerance test value

Abstract

Several groups have reported a risk of fetal macrosomia in pregnancies with maternal glucose intolerance which is intermediate between gestational diabetes (GDM) and normal glucose tolerance. The present study was designed to determine whether these pregnancies are also at risk for fetal obesity, hyperinsulinism and placental villous immaturity. 325 women with risk factors for GDM underwent a 75 g OGTT interpreted according to the O'Sullivan criteria. All women who met the criteria for GDM were managed with diet therapy. Insulin therapy was added for women with a mean serum glucose value > 100 mg/dl on a 24 hour glucose profile. Patients not meeting the GDM criteria were managed without special intervention. Primary outcome variables were measures of neonatal weight and skinfold thickness, fetal and neonatal insulin and glucose concentration, and placental villous maturation. Outcome parameters were compared among three groups: pregnancies with normal OGTT (control, n = 95), 1 abnormal value in the OGTT (1 abnl, n = 76) and GDM (n = 154). The outcome of pregnancies with 1 abnormal value in the OGTT was different from those with normal OGTT. Regarding fetal growth, rates of LGA were approximately twice as high in groups with one abnormal value and GDM (21% and 24%) compared to women with normal OGTTs (11%: p < 0.05 vs GDM and p = 0.07 vs 1 abnormal value). The percent of infants with skinfold thickness > 90th percentile was also greater in the 1 abnormal value and GDM groups (31.1 and 31.6% respectively) compared to controls (19.2%; p < 0.05 for GDM vs control only). Regarding fetal hyperinsulinism, AFI concentrations were similar in control and GDM groups (3.1 +/- 0.4 and 3.4 +/- 0.8 microU/ml, respectively), but were higher in the group with one abnormal OGTT value (4.3 +/- 1.2 microU/ml, p < 0.05 vs controls). Cord blood insulin: glucose ratios were elevated in both the 1 abnormal value and GDM groups (0.22 +/- 0.05 and 0.20 +/- 0.02 microU/ml per mg/dl), compared to controls (0.12 +/- 0.01 microU/ml per mg/dl, p < 0.05 vs 1 abnormal value). Neonatal glycemia < 30 mg/dl was significantly more common in the one abnormal value than in the control group (49% vs 34% of infants) and intermediate in the GDM group (40%). Severe placental villous immaturity was more than twice as frequent in the 1 abnormal value group compared to controls (24% vs 9%, p < 0.05) and the most frequent in the GDM group (33%; p < 0.001 vs controls). Pregnancies with glucose intolerance below the thresholds for diagnosis of GDM have an increased risk for fetal obesity, hyperinsulinism, postpartum hypoglycemia and placental immaturity. These findings indicate the continuum of risk for fetal morbidity associated with increasing maternal glucose intolerance in pregnancy.

A Randomized Trial Evaluating a Predominately Fetal Growth–Based Strategy to Guide Management of Gestational Diabetes in Caucasian Women

“…The LGA rate in the standard group was much lower than in our prior observational studies in women with GDM (18 or 24%, respectively) (7,12). A similar low rate of LGA was observed in our pilot study in a hyperglycemic Latino population known to have high macrosomia rates (5).…”

“…A minimum sample size of 178 women was calculated to detect a difference in birth weight of 225 g between the study groups based on an SD of 530 g in prior studies in our GDM population (7,8) (power 80%, ␣ ϭ 0.05, two-sided test). Neonatal outcome was compared by intent-to-treat-analysis.…”

“…The decades-long discussion about the diagnostic criteria for GDM and glycemic targets reflects the difficulty to assess the risk for adverse outcome solely based on maternal glycemia. Rather, the relation between maternal glycemia and neonatal and maternal outcome behaves as a continuum (7,15) In addition, other maternal factors besides glucose metabolism have an influence on fetal growth (11,16). Risk assessment by fetal growth might be used to adjust the intensity of glucose monitoring.…”

CCAAT-enhancer-binding Protein β (C/EBPβ) and Downstream Human Placental Growth Hormone Genes Are Targets for Dysregulation in Pregnancies Complicated by Maternal Obesity

“…In a recent study no substantial difference in placental maturity and the degree of terminal villi formation was observed in placentas from obese compared with lean women; placental immaturity was characterized as larger chorionic villi and more centered blood vessels (71). By comparison, in an earlier study, severe placental villous immaturity as defined by delayed villous maturation was detected in some obese women (BMI Ͼ 30 kg/m 2 ) who showed signs of mild glucose intolerance but did not meet the criteria for gestational diabetes (72). Placentas from obese non-human primates also showed signs of decreased placental syncytiotrophoblast amplification factor and thicker villi, which is consistent with structural impairment of the syncytiotrophoblast microvilli surface (73).…”

Metabolic Syndrome in Childhood: Association With Birth Weight, Maternal Obesity, and Gestational Diabetes Mellitus

“…This is consistent with other studies showing that maternal obesity is a risk factor for LGA birth in the absence of frank GDM. 36 However, unknown genetic factors and environmental influences may also contribute to obesity and subsequent MS risk. …”