OBJECTIVE: This randomized, controlled noninferiority trial aimed to compare the efficacy and safety of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) (both with prandial insulin aspart) in pregnant women with type 1 diabetes. RESEARCH DESIGN AND METHODS: Patients were randomized and exposed to IDet or NPH up to 12 months before pregnancy or at 8–12 weeks gestation. The primary analysis aimed to demonstrate noninferiority of IDet to NPH with respect to A1C at 36 gestational weeks (GWs) (margin of 0.4%). The data were analyzed using linear regression, taking several baseline factors and covariates into account. RESULTS: A total of 310 type 1 diabetic women were randomized and exposed to IDet (n = 152) or NPH (n = 158) up to 12 months before pregnancy (48%) or during pregnancy at 8–12 weeks (52%). The estimated A1C at 36 GWs was 6.27% for IDet and 6.33% for NPH in the full analysis set (FAS). IDet was declared noninferior to NPH (FAS, –0.06% [95% CI –0.21 to 0.08]; per protocol, –0.15% [–0.34 to 0.04]). Fasting plasma glucose (FPG) was significantly lower with IDet versus NPH at both 24 GWs (96.8 vs. 113.8 mg/dL, P = 0.012) and 36 GWs (85.7 vs. 97.4 mg/dL, P = 0.017). Major and minor hypoglycemia rates during pregnancy were similar between groups. CONCLUSIONS: Treatment with IDet resulted in lower FPG and noninferior A1C in late pregnancy compared with NPH insulin. Rates of hypoglycemia were comparable.

Objective: This randomized controlled trial aimed to compare the efficacy and safety of insulin detemir (IDet) with neutral protamine Hagedorn (NPH), both with insulin aspart, in pregnant women with type 1 diabetes. The perinatal and obstetric pregnancy outcomes are presented. Methods: Subjects were randomized to IDet (n = 152) or NPH (n = 158) ≤12 months before pregnancy or at 8–12 gestational weeks. Results: For IDet and NPH, there were 128 and 136 live births, 11 and 9 early fetal losses, and two and one perinatal deaths, respectively. Gestational age at delivery was greater for children from the IDet arm than the NPH arm (treatment difference: 0.49 weeks [95% CI 0.11;0.88], p = 0.012, linear regression). Sixteen children had a malformation (IDet: n = 8/142, 5.6%; NPH: n = 8/145, 5.5%). The incidence of adverse events was similar between treatments. Conclusion: IDet is as well tolerated as NPH as regards perinatal outcomes in pregnant women with type 1 diabetes and no safety issues were identified.

The transcription factors signal transducer and activator of transcription 5a and 5b (Stat5) are activated by the neuroprotective and neurotrophic cytokines, erythropoietin (EPO) and growth hormone (GH). Here, we show a dissociation of the intracellular pathway mediating the protective effect of EPO against glutamate toxicity from that needed for its neurotrophic activity using hippocampal neuronal cultures from Stat5a/b-knockout (Stat5^−/−) mouse fetuses. Both pretreatment and post-treatment with EPO counteracted glutamate-induced cell death in Stat5^+/+ and Stat5^−/− neurons. Acute pharmacological inhibition of Janus kinase 2 (JAK2)/Stat signalling had no effect on EPO neuroprotection, whereas inhibition of phosphatidylinositol-3′ kinase (PI3K)/Akt pathway abolished the protective effect of EPO in both Stat5^+/+ and Stat5^−/− neurons. GH effectively protected Stat5^+/+ cells against glutamate toxicity but had no effect in Stat5^−/− neurons or in Stat5^+/+ neurons treated with JAK2/Stat or PI3K inhibitor. EPO and GH stimulated neurite outgrowth and branching of Stat5^+/+ neurons by activating PI3K/Akt signalling but had no trophic effect in Stat5^−/− cells. We conclude that in hippocampal neurons, Stat5 is not required for neuroprotection by EPO but is together with Akt essential for its neurotrophic activity. Both Stat5 and Akt are needed for neuroprotective and neurotrophic signalling of GH in neurons.

Objective: The aim of this study was to evaluate perinatal outcome in newborns of mothers who are smokers. Methods: The study included 87 pregnant women with a single pregnancy in the cephalic position, 64 of them nonsmokers (group 1), 13 who smoked 5–20 cigarettes per day (group 2) and 10 who smoked more than 20 cigarettes per day (group 3). Maternal demographic variables and laboratory hemoglobin concentration, hematocrit and erythrocyte count in the last trimester were recorded. Perinatal outcome included type of delivery (vaginal or cesarean section), birth weight, occurrence of meconium in the amniotic fluid, 5-min Apgar score, umbilical arterial blood pH postpartum, sex of the newborn, need for treatment at a neonatal intensive care unit (NICU) and clinically and neurosonographically verified postpartum neurologic complications in the newborn. Results: A statistically significant correlation (p < 0.01) was found with the mean gestational age at delivery in all three groups of women, especially in those smoking >20 cigarettes per day, who had a higher incidence of premature deliveries. Maternal laboratory findings also differed significantly among the three groups of women, i.e. erythrocyte count (p < 0.01), hemoglobin concentration (p < 0.01) and hematocrit (p < 0.001). The rate of delivery by cesarean section was significantly higher in the groups of smokers, irrespective of the number of cigarettes per day (groups 2 and 3). Birth weight was lower by about 250 and 350 g (p < 0.001) in groups 2 and 3, respectively. Five-minute Apgar score and umbilical arterial blood pH were lower in group 3 as compared with groups 1 and 2 (p < 0.01). NICU treatment was required in more than 50% of infants born to group 3 mothers, in whom 70% of perinatal neurologic complications such as subependymal hemorrhage, periventricular hemorrhage, porencephalic cysts, intracranial hemorrhage and swallowing disturbance of the newborn were recorded (p < 0.001). The infants born to group 3 mothers had a longer and more difficult period of adaptation, thus often requiring an NICU stay. Conclusion: Our study confirmed that pregnancy burdened with smoking, especially in the case of >20 cigarettes a day, is associated with a high risk due to the development of maternal anemia and fetal hypoxia and polyglobulia, which in turn result in a significantly poorer perinatal outcome in infants born to smoking mothers and compromised subsequent development of the child, as evidenced by the morphological substrates on the brain resulting from the fetal mechanism of defense against hypoxia. Clinically, there was no other (etiologic) reason for (chronic) fetal hypoxia; thus, the clinical substrate of fetal tobacco syndrome could be presumed to have developed consequentially to chronic smoking during pregnancy, as a preuterine factor of fetal hypoxia. Other gestational or gestation-related diseases (e.g., gestosis, diabetes) that may potentially cause nutritional and respiratory insufficiency of the placenta were ruled out.

OBJECTIVE—In pregestational diabetes, the placenta at term of gestation is characterized by various structural and functional changes. Whether similar alterations occur in the first trimester has remained elusive. Placental development requires proper trophoblast invasion and tissue remodeling, processes involving matrix metalloproteinases (MMPs) of which the membrane-anchored members (MT-MMPs) such as MT1-MMPs are key players. Here, we hypothesize a dysregulation of placental MT1-MMP in the first trimester of type 1 diabetic pregnancies induced by the diabetic environment. RESEARCH DESIGN AND METHODS—MT1-MMP protein was measured in first-trimester placentas of healthy (n = 13) and type 1 diabetic (n = 13) women. To identify potential regulators, first-trimester trophoblasts were cultured under hyperglycemia and various insulin, IGF-I, IGF-II, and tumor necrosis factor-α (TNF-α) concentrations in presence or absence of signaling pathway inhibitors. RESULTS—MT1-MMP was strongly expressed in first-trimester trophoblasts. In type 1 diabetes, placental pro–MT1-MMP was upregulated, whereas active MT1-MMP expression was only increased in late first trimester. In isolated primary trophoblasts, insulin, IGF-I, IGF-II, and TNF-α upregulated MT1-MMP expression, whereas glucose had no effect. The insulin effect was dependent on phosphatidylinositol 3-kinase, the IGF-I effect on mitogen-activated protein kinase, and the IGF-II effect on both. CONCLUSIONS—This is the first study reporting alterations in the first-trimester placenta in type 1 diabetes. The upregulated MT1-MMP expression in type 1 diabetes may be the result of higher maternal insulin and TNF-α levels. We speculate that the elevated MT1-MMP will affect placental development and may thus contribute to long-term structural alterations in the placenta in pregestational diabetes.