Metformin use in pregnancy: What about long-term effects in offspring?

Metformin use in pregnancy is increasing worldwide. Unlike insulin, metformin crosses the placenta. Consequently, maternal and fetal concentrations are comparable. Teratogenic effects are not reported, nor are adverse pregnancy outcomes. Reduced risk of hypertensive disorders, hypoglycemia, and macrosomia are potential benefits, together with lower gestational weight gain. Although metformin has been prescribed for pregnant women during the last 40 years, long-term data regarding offspring outcomes are still lacking. Independent of maternal glycemic control, recent meta-analyses report lower birthweight but accelerated postnatal growth and higher body mass index in metformin-exposed children. The longest follow-up study of placebo-controlled metformin exposure in utero found an increased prevalence of central adiposity and obesity among children 5-10 years old. Recently, a Danish study reported a threefold increased risk of genital anomalies in boys, whose fathers used metformin around the time of conception. This commentary addresses the current controversies on metformin use in pregnancy.

Glycated albumin and continuous glucose monitoring metrics across pregnancy in women with pre-gestational diabetes.

INTRODUCTION: Glycated albumin (GA), a biomarker reflecting short-term glycaemia, may be useful to assess glycaemic control in pregnancy. We examined the association between GA and continuous glucose monitoring (CGM) metrics across gestation. METHODS: In this prospective cohort study including 40 women with pre-gestational diabetes, blood samples for analysis of GA and glycated haemoglobin A1c (HbA1c) were collected at pregnancy week 12, 20, 24, 28, 32 and 36. In the CGM-group (n = 19), CGM data were collected from first trimester until pregnancy week 36. Receiver operating characteristic (ROC) curves were used to assess the accuracy of GA and HbA1c to detect poor glycaemic control, using CGM metrics as the reference standard. This study was conducted at Stavanger University Hospital, Norway, in 2016-2018. RESULTS: Glycaemic control improved across gestation with more time spent in target range, coinciding with decreased glycaemic variability and lower mean GA level. There was statistically significant correlation between GA and most CGM metrics. The area under the ROC curves (AUC) for detecting time in range <70% and time above range >25% for the pregnancy glucose target 63-140 mg/dl (3.5-7.8 mmol/L) were 0.78 and 0.82 for GA, whereas AUCs of 0.60 and 0.72 were found for HbA1c, respectively. CONCLUSIONS: Higher GA levels were associated with less time spent in target range, more time spent in the above range area and increased glycaemic variability. GA was more accurate than HbA1c to detect time above range >25% and time in range <70%.

Glycated albumin in pregnancy: LC-MS/MS-based reference interval in healthy, nulliparous Scandinavian women and its diagnostic accuracy in gestational diabetes mellitus.

Glycated albumin (GA) may be a useful biomarker of glycemia in pregnancy. The aim of this study was to establish the reference interval (RI) for GA, analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), in healthy, nulliparous pregnant women. In addition, we assessed the accuracy of GA and glycated hemoglobin A1c (HbA1c) in the diagnosis of gestational diabetes mellitus (GDM). Finally, we explored the prevalence of GDM in healthy nulliparas, comparing three diagnostic guidelines (WHO-1999, WHO-2013 and the Norwegian guideline). The study was carried out at Stavanger University Hospital, Norway, and included a study population of 147 pregnant nulliparous women. An oral glucose tolerance test (OGTT) was performed and used as the gold standard for GDM diagnosis. Blood samples for analysis of GA and HbA1c were collected at pregnancy week 24-28. A nonparametric approach was chosen for RI calculation, and receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of GA and HbA1c. The established RI for GA in 121 pregnant women was 7.1-11.6%. The area under the ROC curves (AUCs) were 0.531 (GA) and 0.627 (HbA1c). According to the WHO-1999, WHO-2013 and the Norwegian guideline, respectively, 24 (16%), 36 (24%) and 21 (14%) women were diagnosed with GDM. Only nine women (6%) fulfilled the GDM-criteria of all guidelines. In conclusion, we established the first LC-MS/MS-based RI for GA in pregnant women. At pregnancy weeks 24-28, neither GA nor HbA1c discriminated between those with and without GDM. Different women were diagnosed with GDM using the three guidelines.

Whole-genome microarray and targeted analysis of angiogenesis-regulating gene expression (ENG, FLT1, VEGF, PlGF) in placentas from pre-eclamptic and small-for-gestational-age pregnancies.

OBJECTIVE: To compare the placental pathology associated with pre-eclampsia (PE) and/or fetal growth restriction, the transcriptomes of placental tissues from PE and small-for-gestational-age (SGA) pregnancies were explored. In addition, a targeted analysis of angiogenesis-regulating gene expression was performed. METHODS: Whole-genome microarray analysis was performed on placental tissue from gestational age-matched PE (n = 10), SGA (n = 8) and PE + SGA (n = 10) pregnancies. The expression of genes regulating angiogenesis (endoglin (ENG), fms-related tyrosine kinase 1 (FLT1), vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)) was analyzed by quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: Microarray analysis did not reveal any significant differences between groups. However, an increased expression of ENG and FLT1 was detected by qRT-PCR in the PE + SGA group. CONCLUSIONS: The placental transcriptome did not differ between groups, although an increased anti-angiogenic gene expression in PE + SGA was observed with qRT-PCR analysis. Based on this, we conclude that although microarray technology may represent a powerful tool in generating new hypothesis in complex fields, it may not be sensitive enough to detect subtle changes in gene expression.