Large maternal waist circumference in relation to height is associated with high glucose concentrations in an early-pregnancy oral glucose tolerance test: A population-based study.

INTRODUCTION: To explore the role of maternal anthropometric characteristics in early-pregnancy glycemia, we analyzed the associations and interactions of maternal early-pregnancy waist circumference (WC), height and pre-pregnancy body mass index (BMI) with plasma glucose concentrations in an oral glucose tolerance test (OGTT) at 12-16 weeks' gestation. MATERIAL AND METHODS: A population-based cohort of 1361 pregnant women was recruited in South Karelia, Finland, from March 2013 to December 2016. All participants had their WC, weight, height, HbA1c , and blood pressure measured at 8-14 weeks' gestation and subsequently underwent a 2-h 75-g OGTT, including assessment of fasting insulin concentrations, at 12-16 weeks' gestation. BMI (kg/m2 ) was calculated using self-reported pre-pregnancy weight. Maternal WC ≥80 cm was defined as large. Maternal height ≥166 cm was defined as tall. Data on gestational diabetes treatment was extracted from hospital records. RESULTS: In the total cohort, 901 (66%) of women had an early-pregnancy WC ≥80 cm, which was associated with higher early-pregnancy HbA1c, higher concentrations of  fasting plasma glucose and serum insulin, higher post-load plasma glucose concentrations, higher HOMA-IR indices, higher blood pressure levels, and higher frequencies of pharmacologically treated gestational diabetes, than early-pregnancy WC <80 cm. Maternal height ≥166 cm was negatively associated with 1- and 2-h post-load plasma glucose concentrations. Waist-to-height ratio (WHtR) >0.5 was positively associated with both fasting and post-load plasma glucose concentrations at 12-16 weeks' gestation, even when adjusted for age, smoking, nulliparity, and family history of type 2 diabetes. The best cut-offs for WHtR (0.58 for 1-h plasma glucose, and 0.54 for 2-h plasma glucose) were better predictors of post-load glucose concentrations >90th percentile than the best cut-offs for BMI (28.1 kg/m2 for 1-h plasma glucose, and 26.6 kg/m2 for 2-h plasma glucose), with areas-under-the-curve (95% confidence interval) 0.73 (0.68-0.79) and 0.73 (0.69-0.77), respectively, for WHtR, and 0.68 (0.63-0.74) and 0.69 (0.65-0.74), respectively, for BMI. CONCLUSIONS: In our population-based cohort, early-pregnancy WHtR >0.5 was positively associated with both fasting and post-load glucose concentrations at 12-16 weeks' gestation and performed better than BMI in the prediction of post-load glucose concentrations >90th percentile. Overall, our results underline the importance of evaluating maternal abdominal adiposity in gestational diabetes risk assessment.

Genetic risk of type 2 diabetes modifies the effects of a lifestyle intervention aimed at the prevention of gestational and postpartum diabetes.

AIMS/HYPOTHESIS: The aim of this study was to assess the interaction between genetic risk and lifestyle intervention on the occurrence of gestational diabetes mellitus (GDM) and postpartum diabetes. METHODS: The RADIEL study is an RCT aimed at prevention of GDM and postpartum diabetes through lifestyle intervention. Participants with a BMI ≥30 kg/m2 and/or prior GDM were allocated to intervention and control groups before pregnancy or in early pregnancy. The study visits took place every 3 months before pregnancy, once in each trimester, and at 6 weeks and 6 and 12 months postpartum. We calculated a polygenic risk score (PRS) based on 50 risk variants for type 2 diabetes. RESULTS: Altogether, 516 participants provided genetic and GDM data. The PRS was associated with higher glycaemic levels (fasting glucose and/or HbA1c) and a lower insulin secretion index in the second and third trimesters and at 12 months postpartum, as well as with a higher occurrence of GDM and glycaemic abnormalities at 12 months postpartum (n = 356). There was an interaction between the PRS and lifestyle intervention (p=0.016 during pregnancy and p=0.024 postpartum) when analysing participants who did not have GDM at the first study visit during pregnancy (n = 386). When analysing women in tertiles according to the PRS, the intervention was effective in reducing the age-adjusted occurrence of GDM only among those with the highest genetic risk (OR 0.37; 95% CI 0.17, 0.82). The risk of glycaemic abnormalities at 12 months postpartum was reduced in the same group after adjusting additionally for BMI, parity, smoking and education (OR 0.35; 95% CI 0.13, 0.97). CONCLUSIONS/INTERPRETATION: Genetic predisposition to diabetes modifies the response to a lifestyle intervention aimed at prevention of GDM and postpartum diabetes. This suggests that lifestyle intervention may benefit from being tailored according to genetic risk. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01698385.

Higher pulse wave velocity in young adult offspring of mothers with type 1 diabetes: a case-control study.

BACKGROUND: Offspring of mothers with type 1 diabetes have an increased risk for acquiring early onset cardiovascular disease (CVD). Arterial stiffness, measured as pulse wave velocity (PWV), is a non-invasive biomarker for CVD risk assessment. Our aim is to determine whether PWV is increased in young adult offspring of mothers with type 1 diabetes. METHODS: This is a case-control study carried out in the hospital district of Helsinki and Uusimaa, Finland. 75 offspring of mothers with type 1 diabetes (cases) and 84 offspring of mothers without diabetes (controls), aged 18-23 years, were enrolled in this study. All participants attended clinical assessments, including questionnaires and laboratory tests. Carotid-femoral PWV (cfPWV), carotid-radial PWV (crPWV), and PWV ratio were measured from each participant using the Complior Analyse mechanotransducer (Alam Medical, France). Student's t-test and chi-squared test were used to assess differences between the groups. Stata 17.0, StataCorp LP (College Station, TX, USA) statistical package was used for the analysis. RESULTS: We did not observe any differences in conventional CVD risk factors: systolic blood pressure, LDL, HbA1c, and smoking between cases and controls. We detected higher cfPWV in cases 6.5 (SD ± 1.2) m/s than in controls 6.2 (SD ± 0.7) m/s, p = 0.049, after adjustments for BMI, smoking, mean arterial pressure, height, and pulse rate was made. We did not observe any difference between cases and controls regarding crPWV or PWV ratio. Additionally, we detected no sex differences. CONCLUSIONS: We report a novel finding of signs of increased arterial stiffness already in young adult offspring of mothers with type 1 diabetes compared to matched offspring of mothers without diabetes. Our finding suggests that exposure to an adverse intrauterine environment of type 1 diabetes mothers may affect the vascular health of offspring already in young adulthood. Additional research within this topic is warranted.

Macronutrient intake during pregnancy in women with a history of obesity or gestational diabetes and offspring adiposity at 5 years of age.

BACKGROUND/OBJECTIVES: The impact of maternal macronutrient intake during pregnancy on offspring childhood adiposity is unclear. We assessed the associations between maternal macronutrient intake during and after pregnancy with offspring adiposity at 5 years of age. Additionally, we investigated whether gestational diabetes (GDM), BMI, or breastfeeding modified these associations. SUBJECTS/METHODS: Altogether, 301 mother-child dyads with maternal prepregnancy BMI ≥ 30 and/or previous GDM participated in the Finnish Gestational Diabetes Prevention Study (RADIEL) and its 5 years follow-up. Macronutrient intakes (E%) were calculated from 3-day food records collected at 5-18 weeks' gestation, in the third trimester, and at 12 months and 5 years after pregnancy. Offspring body fat mass (BFM) and fat percentage (BF%) at 5 years were measured by bioimpedance. Statistical analyses were multivariate linear regression. RESULTS: Mean (SD) prepregnancy BMI was 33(4) kg/m2. GDM was diagnosed in 47%. In normoglycemic women, higher first half of pregnancy n-3 PUFA intake was associated with lower offspring BFM (g) (ß -0.90; 95% CI -1.62, -0.18) and BF% (ß -3.45; 95% CI -6.17, -0.72). In women with GDM, higher first half of pregnancy n-3 PUFA intake was associated with higher offspring BFM (ß 0.94; 95% CI 0.14, 1.75) and BF% (ß 3.21; 95% CI 0.43, 5.99). Higher SFA intake in the third trimester and cumulative intake across pregnancy (mean of the first half and late pregnancy) was associated with higher BFM and BF% (across pregnancy: ß 0.12; 95% CI 0.03, 0.20 and ß 0.44; 95% CI 0.15, 0.73, respectively). Higher carbohydrate intake across pregnancy was associated with lower BFM (ß -0.044; 95% CI -0.086, -0.003), and borderline associated with BF% (ß -0.15; 95% CI -0.31, 0.00). CONCLUSIONS: The macronutrient composition of maternal diet during pregnancy is associated with offspring BFM and BF% at 5 years. GDM modifies the association between prenatal n-3 PUFA intake and offspring anthropometrics.

Robust increases in erythropoietin production by the hypoxic fetus is a response to protect the brain and other vital organs.

Fetal erythropoietin (EPO), in addition to regulating erythropoiesis, has also tissue-protective properties based on its anti-inflammatory, anti-apoptotic, antioxidant, and neurotrophic effects. Notably, EPO concentrations needed for tissue protection are 100-1000 times higher than concentrations needed for regulating erythropoiesis. This dual effect of EPO is based on EPO-receptor (EPO-R) isoforms, which differ structurally and functionally. We hypothesize in this Integrated Mechanism Review that during severe fetal hypoxia the observed, but poorly understood, marked increases of fetal plasma EPO concentrations occur to protect the brain, heart, and other vital fetal organs. We further hypothesize that the concurrent marked increases of EPO in the amniotic fluid during fetal hypoxia, occur to protect newborn infants from necrotizing enterocolitis. This review presents experimental and clinical evidence in support of these hypotheses and points out unknown or poorly understood functions of EPO in the fetus. If these novel hypotheses are correct, the importance of fetal EPO as an antenatal hypoxia biomarker will become apparent. It will also likely point the way to important diagnostic and therapeutic fetal and neonatal interventions.

White's classification and pregnancy outcome in women with type 1 diabetes: a population-based cohort study.

AIMS/HYPOTHESIS: Our aim was to examine the association of White's classification with obstetric and perinatal risk factors and outcomes in type 1 diabetic patients. METHODS: Obstetric records of a population-based cohort of 1,094 consecutive type 1 diabetic patients with a singleton childbirth during 1988-2011 were studied. The most recent childbirth of each woman was included. RESULTS: The prepregnancy and the first trimester HbA1c increased from White's class B to F (p for trend <0.001). Systolic and diastolic blood pressure and pre-eclampsia frequencies increased stepwise from class B to F (p for trends <0.001). Vaginal deliveries decreased and Caesarean sections and deliveries before 37 weeks increased from class B to F (p for trends <0.001). Fetal macrosomia (p for trend=0.003) decreased and small-for-gestational age infants (p for trend=0.002) and neonatal intensive care unit admissions (p for trend=0.001) increased from class B to F. In logistic regression analysis, White's classes were associated with pre-eclampsia but, with the exception of class R (proliferative retinopathy) and F (nephropathy), not with other adverse outcomes when adjusted for first trimester HbA1c ≥7% (≥53 mmol/mol) and blood pressure ≥140/90 mmHg. First trimester HbA1c ≥7% was associated with pre-eclampsia, preterm delivery, fetal macrosomia and neonatal intensive care unit admission. CONCLUSIONS/INTERPRETATION: White's classification is useful in estimating the risk of pre-eclampsia in early pregnancy independently of suboptimal glycaemic control and hypertension. However, its utility in predicting adverse perinatal outcomes seems limited when information on first trimester HbA1c, blood pressure and diabetic microvascular complications is available.

An RGS2 3'UTR polymorphism is associated with preeclampsia in overweight women.

BACKGROUND: Preeclampsia is a common and heterogeneous vascular syndrome of pregnancy. Its genetic risk profile is yet unknown and may vary between individuals and populations. The rs4606 3' UTR polymorphism of the Regulator of G-protein signaling 2 gene (RGS2) in the mother has been implicated in preeclampsia as well as in the development of chronic hypertension after preeclampsia. The RGS2 protein acts as an inhibitor of physiological vasoconstrictive pathways, and a low RGS2 level is associated with hypertension and obesity, two conditions that predispose to preeclampsia. We genotyped the rs4606 polymorphism in 1339 preeclamptic patients and in 697 controls from the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort to study the association of the variant with preeclampsia. RESULTS: No association between rs4606 and preeclampsia was detected in the analysis including all women. However, the polymorphism was associated with preeclampsia in a subgroup of overweight women (body mass index ≥ 25 kg/m(2), and < 30 kg/m(2)) (dominant model; odds ratio, 1.64; 95 % confidence interval, 1.10-2.42). CONCLUSIONS: Our results suggest that RGS2 might be involved in the pathogenesis of preeclampsia particularly in overweight women and contribute to their increased risk for hypertension and other types of cardiovascular disease later in life.

Obstetric and perinatal outcome in type 1 diabetes patients with diabetic nephropathy during 1988-2011.

AIMS/HYPOTHESIS: Our aim was to analyse possible changes in the glycaemic control, BP, markers of renal function, and obstetric and perinatal outcomes of parturients with diabetic nephropathy during 1988-2011. METHODS: The most recent childbirth of 108 consecutive type 1 diabetes patients with diabetic nephropathy and a singleton pregnancy were studied. Two periods, 1988-1999 and 2000-2011, were compared. RESULTS: The prepregnancy and the first trimester median HbA1c values persisted at high levels (8.2% [66 mmol/mol] vs 8.5% [69 mmol/mol], p = 0.16 and 8.3% [67 mmol/mol] vs 8.4% [68 mmol/mol], p = 0.67, respectively), but decreased by mid-pregnancy (6.7% [50 mmol/mol] vs 6.9% [52 mmol/mol], p = 0.11). Antihypertensive medication usage increased before pregnancy (34% vs 65%, p = 0.002) and in the second and third trimesters of pregnancy (25% vs 47%, p = 0.02, and 36% vs 60%, p = 0.01, respectively). BP exceeded 130/80 mmHg in 62% and 61% (p = 0.87) of patients in the first trimester, and in 95% and 93% (p = 0.69) in the third trimester, respectively. No changes were observed in the markers of renal function. Pre-eclampsia (52% vs 42%, p = 0.29) and preterm birth rates before 32 and 37 gestational weeks (14% vs 21%, p = 0.33, and 71% vs 77%, p = 0.49, respectively) remained high. The elective and emergency Caesarean section rates were 71% and 45% (p = 0.01) and 29% and 48% (p = 0.05), respectively. Neonatal intensive care unit admissions increased from 26% to 49% (p = 0.02). CONCLUSIONS/INTERPRETATION: Early pregnancy glycaemic control and hypertension management were suboptimal in both time periods. Pre-eclampsia and preterm delivery rates remained high in patients with diabetic nephropathy.

Prevention of gestational diabetes through lifestyle intervention: study design and methods of a Finnish randomized controlled multicenter trial (RADIEL).

BACKGROUND: Maternal overweight, obesity and consequently the incidence of gestational diabetes are increasing rapidly worldwide. The objective of the study was to assess the efficacy and cost-effectiveness of a combined diet and physical activity intervention implemented before, during and after pregnancy in a primary health care setting for preventing gestational diabetes, later type 2 diabetes and other metabolic consequences. METHODS: RADIEL is a randomized controlled multi-center intervention trial in women at high risk for diabetes (a previous history of gestational diabetes or prepregnancy BMI ≥30 kg/m2). Participants planning pregnancy or in the first half of pregnancy were parallel-group randomized into an intervention arm which received lifestyle counseling and a control arm which received usual care given at their local antenatal clinics. All participants visited a study nurse every three months before and during pregnancy, and at 6 weeks, 6 and 12 months postpartum. Measurements and laboratory tests were performed on all participants with special focus on dietary and exercise habits and metabolic markers.Of the 728 women [mean age 32.5 years (SD 4.7); median parity 1 (range 0-9)] considered to be eligible for the study 235 were non-pregnant and 493 pregnant [mean gestational age 13 (range 6 to 18) weeks] at the time of enrollment. The proportion of nulliparous women was 29.8% (n = 217). Out of all participants, 79.6% of the non-pregnant and 40.4% of the pregnant women had previous gestational diabetes and 20.4% of the non-pregnant and 59.6% of the pregnant women were recruited because of a prepregnancy BMI ≥30 kg/m2. Mean BMI at first visit was 30.1 kg/m2 (SD 6.2) in the non-pregnant and 32.7 kg/m2 (SD 5.6) in the pregnant group. DISCUSSION: To our knowledge, this is the first randomized lifestyle intervention trial, which includes, besides the pregnancy period, both the prepregnancy and the postpartum period. This study design also provides an opportunity to focus upon the health of the next generation. The study is expected to produce novel information on the optimal timing and setting of interventions and for allocating resources to prevent obesity and diabetes in women of reproductive age.

First-trimester HbA1c in relation to plasma glucose concentrations in an oral glucose tolerance test at 12 to 16 weeks' gestation-a population-based study.

BACKGROUND: Early-onset GDM often requires pharmacological treatment and is associated with adverse perinatal outcomes, but data is insufficient regarding the best methods to identify high-risk women requiring early GDM screening. The aim of this study was to analyze the diagnostic accuracy of HbA1c in the prediction of (1) plasma glucose concentrations > 90th percentile in an oral glucose tolerance test (OGTT) at 12-16 weeks' gestation; and (2) pharmacologically treated early- or late-onset GDM. METHODS: HbA1c was measured at 8-14 weeks' gestation in a population-based cohort of 1394 Finnish women recruited for the Early Diagnosis of Diabetes in Pregnancy (EDDIE) study between 3/2013 and 12/2016. Information on maternal risk factors were collected at recruitment. Subsequently, a 2-hour 75 g OGTT was performed at 12-16 weeks' gestation (OGTT1), and if normal, repeated at 24-28 weeks' gestation (OGTT2). Early- and late-onset GDM were diagnosed using the same nationally endorsed cut-offs for fasting, 1 h- and 2 h-plasma glucose: ≥5.3, ≥ 10.0mmol/l, and/or ≥ 8.6mmol/l, respectively. In total, 52/1394 (3.7%) women required metformin or insulin treatment for GDM, including 39 women with early-onset GDM diagnosed at OGTT1 and 13 women with late-onset GDM diagnosed at OGTT2. RESULTS: Maternal early-pregnancy HbA1c ≥ 35mmol/mol (≥ 5.4%) was the best cut-off to predict fasting or post-load plasma glucose > 90th percentile in OGTT1, but its diagnostic accuracy was low [AUC (95% CI) 0.65 (0.62 to 0.69), sensitivity 0.55 (0.49 to 0.60) and specificity 0.67 (0.64 to 0.70)] both alone and in combination with other maternal risk factors. However, HbA1c ≥ 35mmol/mol correlated positively with plasma glucose concentrations at all time points of OGTT1 and predicted pharmacologically treated GDM diagnosed at OGTT1 or OGTT2; AUC (95% CI) 0.75 (0.68 to 0.81), sensitivity 0.75 (0.61 to 0.86), specificity 0.64 (0.61 to 0.66). CONCLUSIONS: In our population-based cohort, early-pregnancy HbA1c ≥ 35mmol/mol was positively associated with fasting and post-load plasma glucose concentrations in an OGTT at 12-16 weeks' gestation and predicted pharmacologically-treated early- and late-onset GDM, suggesting potential utility in first-trimester identification of women at high risk of severe GDM subtypes.

Lipid profile of circulating placental extracellular vesicles during pregnancy identifies foetal growth restriction risk.

Small-for-gestational age (SGA) neonates exhibit increased perinatal morbidity and mortality, and a greater risk of developing chronic diseases in adulthood. Currently, no effective maternal blood-based screening methods for determining SGA risk are available. We used a high-resolution MS/MSALL shotgun lipidomic approach to explore the lipid profiles of small extracellular vesicles (sEV) released from the placenta into the circulation of pregnant individuals. Samples were acquired from 195 normal and 41 SGA pregnancies. Lipid profiles were determined serially across pregnancy. We identified specific lipid signatures of placental sEVs that define the trajectory of a normal pregnancy and their changes occurring in relation to maternal characteristics (parity and ethnicity) and birthweight centile. We constructed a multivariate model demonstrating that specific lipid features of circulating placental sEVs, particularly during early gestation, are highly predictive of SGA infants. Lipidomic-based biomarker development promises to improve the early detection of pregnancies at risk of developing SGA, an unmet clinical need in obstetrics.

Distinct Changes in Placental Ceramide Metabolism Characterize Type 1 and 2 Diabetic Pregnancies with Fetal Macrosomia or Preeclampsia.

Disturbances of lipid metabolism are typical in diabetes. Our objective was to characterize and compare placental sphingolipid metabolism in type 1 (T1D) and 2 (T2D) diabetic pregnancies and in non-diabetic controls. Placental samples from T1D, T2D, and control pregnancies were processed for sphingolipid analysis using tandem mass spectrometry. Western blotting, enzyme activity, and immunofluorescence analyses were used to study sphingolipid regulatory enzymes. Placental ceramide levels were lower in T1D and T2D compared to controls, which was associated with an upregulation of the ceramide degrading enzyme acid ceramidase (ASAH1). Increased placental ceramide content was found in T1D complicated by preeclampsia. Similarly, elevated ceramides were observed in T1D and T2D pregnancies with poor glycemic control. The protein levels and activity of sphingosine kinases (SPHK) that produce sphingoid-1-phosphates (S1P) were highest in T2D. Furthermore, SPHK levels were upregulated in T1D and T2D pregnancies with fetal macrosomia. In vitro experiments using trophoblastic JEG3 cells demonstrated increased SPHK expression and activity following glucose and insulin treatments. Specific changes in the placental sphingolipidome characterize T1D and T2D placentae depending on the type of diabetes and feto-maternal complications. Increased exposure to insulin and glucose is a plausible contributor to the upregulation of the SPHK-S1P-axis in diabetic placentae.

Fatty liver index in young adult offspring of women with type 1 diabetes.

BACKGROUND: Exposure to a hyperglycemic environment during prenatal life may result in an unfavorable metabolic profile later in adulthood. We aimed to assess whether fatty liver index, a non-invasive indicator of nonalcoholic fatty liver disease risk, differs in young adult offspring of women with type 1 diabetes from offspring of women without diabetes. METHODS: This cohort study was conducted within the hospital district of Helsinki and Uusimaa, Finland. Between 1996 and 2000, we identified 238 singleton offspring of women with type 1 diabetes, born at the Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland. From the Finnish Medical Birth Register, we identified 476 singleton age- and region-matched offspring of women without diabetes. At 18-23 years of age, 70 offspring of women with type 1 diabetes and 83 offspring of women without diabetes participated in a clinical study, including laboratory tests, clinical assessments, and self-reported questionnaires. The noninvasive fatty liver index was used to estimate nonalcoholic fatty liver disease. RESULTS: Fatty liver index (FLI) was similar between offspring of women with type 1 diabetes and offspring of women without diabetes (p = 0.59). Additionally, no differences between the groups could be observed for FLI ≥ 60, i.e., to cut-off value for NAFLD. Likewise, we could not find any statistically significant differences between young adult offspring of women with type 1 diabetes (20.4 years [SD 1.6]) and young adult offspring of women without diabetes (20.6 years [SD 1.6]) regarding metabolic characteristics: BMI 24.5 kg/m2 vs. 24.0 kg/m2, fasting plasma glucose 5.39 mmol/L vs. 5.40 mmol/L, fasting insulin 11.0 mU/L vs. 10.6 mU/L, total cholesterol 4.36 mmol/L vs. 4.30 mmol/L, systolic BP 117 mmHg vs. 119 mmHg, triglycerides 0.89 mmol/L vs. 0.96 mmol/L, and Waist-to-height ratio 0.41 vs. 0.42. CONCLUSIONS: Our results suggest that fatty liver index is not elevated in young adult offspring of women with type 1 diabetes. Further research on whether pregestational type 1 diabetes in pregnancy affects offspring's nonalcoholic fatty liver disease risk is warranted.

Fibronectin and JMJD6 Signature in Circulating Placental Extracellular Vesicles for the Detection of Preeclampsia.

Preeclampsia (PE) is a major obstetric complication that is challenging to predict. Currently, there are limited tools to assess placental health/function in crucial gestational periods for diagnosis and early prediction. The glycoprotein fibronectin (FN) is augmented in PE placentae, and associated with reduced activity of JMJD6, an oxygen sensor that regulates placental FN processing. Evidence implicates placenta-derived small extracellular vesicles (sEVs) in the pathogenesis of pregnancy-associated disorders. Here, we examined the utility of FN and JMJD6 in placental sEVs as putative markers for early- and late-onset PE (E-PE and L-PE). Maternal plasma was obtained from venous blood collected longitudinally during pregnancy (10-14, 16-22, and 26-32 weeks of gestation and at delivery) in normotensive term control, preterm control, L-PE, E-PE, and gestational hypertensive individuals. Placenta-derived sEVs were isolated and their FN and JMJD6 content and JMJD6 activity were measured. In women that went on to develop preeclampsia, FN content of circulating placental sEVs was significantly elevated as early as 10 to 14 weeks of gestation and remained augmented until the time of delivery. This was accompanied by a depletion in JMJD6 content. Multivariate receiver operating characteristic analysis revealed high predictive power for FN and JMJD6 as early markers of E-PE and L-PE. In vitro, hypoxia or JMJD6 loss promoted FN accumulation in sEVs that was reverted on restoring cellular iron balance with the natural compound, Hinokitiol. Elevated FN, along with diminished JMJD6 in circulating placental sEVs, serves as an early molecular signature for the detection of different hypertensive disorders of pregnancy and their severity.

Circulating Cytokine Levels and Cardiovascular Disease Risk Profile in Young Adult Offspring of Women with Type 1 Diabetes.

INTRODUCTION: Cytokines are key players in the development of both type 1 diabetes (T1D) and cardiovascular disease (CVD). Offspring of women with T1D are known to have an increased risk of early-onset CVD. We studied whether an increased risk of CVD can be observed in the cytokine profile among young adult offspring of women with T1D. METHODS: This cross-sectional case-control study included 67 offspring of women with T1D (cases) and 79 control participants (controls). At an age of 18-23 years, they participated in a clinical assessment including laboratory tests and questionnaires. Cytokine levels were analyzed from venous blood samples after 10 h fasting using Quansys biosciences Q-Plex™ High Sensitivity Human Cytokine Array. RESULTS: Circulating cytokine levels were in general similar between the groups. The circulating levels of interferon-γ (1.78 [IQR 1.20, 2.36] pg/mL versus 2.57 [IQR 1.50, 3.89] pg/mL) (p = 0.006) were lower in cases than controls. CONCLUSION: The findings did not support our hypothesis that serum cytokine profile, determined in early adulthood, was associated with a more adverse CVD risk profile in offspring of women with T1D. Further studies are warranted to find out whether cytokines could serve as early biomarkers of CVD development or whether changes in the cytokine levels over years could be used to monitor CVD progression in offspring of women with T1D.

Genetic Risk Factors and Gene-Lifestyle Interactions in Gestational Diabetes.

Paralleling the increasing trends of maternal obesity, gestational diabetes (GDM) has become a global health challenge with significant public health repercussions. In addition to short-term adverse outcomes, such as hypertensive pregnancy disorders and fetal macrosomia, in the long term, GDM results in excess cardiometabolic morbidity in both the mother and child. Recent data suggest that women with GDM are characterized by notable phenotypic and genotypic heterogeneity and that frequencies of adverse obstetric and perinatal outcomes are different between physiologic GDM subtypes. However, as of yet, GDM treatment protocols do not differentiate between these subtypes. Mapping the genetic architecture of GDM, as well as accurate phenotypic and genotypic definitions of GDM, could potentially help in the individualization of GDM treatment and assessment of long-term prognoses. In this narrative review, we outline recent studies exploring genetic risk factors of GDM and later type 2 diabetes (T2D) in women with prior GDM. Further, we discuss the current evidence on gene-lifestyle interactions in the development of these diseases. In addition, we point out specific research gaps that still need to be addressed to better understand the complex genetic and metabolic crosstalk within the mother-placenta-fetus triad that contributes to hyperglycemia in pregnancy.

Late-Pregnancy Fetal Hypoxia Is Associated With Altered Glucose Metabolism and Adiposity in Young Adult Offspring of Women With Type 1 Diabetes.

Objective: To investigate associations between exposure to fetal hypoxia and indicators of metabolic health in young adult offspring of women with type 1 diabetes (OT1D). Methods: 156 OT1D born between 7/1995 and 12/2000 at Helsinki University Hospital, Finland, were invited for follow-up between 3/2019 and 11/2019. A control group of 442 adults born from non-diabetic pregnancies, matched for date and place of birth, was obtained from the Finnish Medical Birth Register. In total, 58 OT1D and 86 controls agreed to participate. All OT1D had amniotic fluid (AF) sampled for erythropoietin (EPO) measurement within two days before delivery in order to diagnose fetal hypoxia. In total, 29 OTID had an AF EPO concentration <14.0 mU/l, defined as normal, and were categorized into the low EPO (L-EPO) group. The remaining 29 OT1D had AF EPO ≥14.0 mU/ml, defined as fetal hypoxia, and were categorized into the high EPO (H-EPO) group. At the age of 18-23 years, participants underwent a 2-h 75g oral glucose tolerance test (OGTT) in addition to height, weight, waist circumference, body composition, blood pressure, HbA1c, cholesterol, triglyceride, high-sensitivity CRP and leisure-time physical activity measurements. Results: Two OT1D were diagnosed with diabetes and excluded from further analyses. At young adult age, OT1D in the H-EPO group had a higher BMI than those in the L-EPO group. In addition, among female participants, waist circumference and body fat percentage were highest in the H-EPO group. In the OGTTs, the mean (SD) 2-h post-load plasma glucose (mmol/L) was higher in the H-EPO [6.50 (2.11)] than in the L-EPO [5.21 (1.10)] or control [5.67 (1.48)] offspring (p=0.009). AF EPO concentrations correlated positively with 2-h post-load plasma glucose [r=0.35 (95% CI: 0.07 to 0.62)] and serum insulin [r=0.44 (95% CI: 0.14 to 0.69)] concentrations, even after adjusting for maternal BMI, birth weight z-score, gestational age at birth and adult BMI. Control, L-EPO and H-EPO groups did not differ with regards to other assessed parameters. Conclusions: High AF EPO concentrations in late pregnancy, indicating fetal hypoxia, are associated with increased adiposity and elevated post-load glucose and insulin concentrations in young adult OT1D.

Skin Autofluorescence in Young Adult Offspring of Women with Type 1 Diabetes: A Cross-Sectional Case-Control Study.

INTRODUCTION: Offspring born to women with type 1 diabetes pregnancies have an elevated risk for early-onset obesity and type 2 diabetes compared with offspring born to women without diabetes. Skin autofluorescence (SAF) is a marker of accumulated advanced glycation end products (AGEs) and it has been shown to predict type 2 diabetes, cardiovascular disease, and mortality in the general population. The aim of this study was to evaluate whether maternal type 1 diabetes influences the SAF value in young adult offspring. METHODS: This cross-sectional case-control study included 78 offspring of women with type 1 diabetes (cases) and 85 control participants (controls). All study participants, aged 18-23 years, were invited to participate in a clinical assessment including laboratory tests and questionnaires. SAF was assessed using the AGE reader from the dominant forearm of each participant. RESULTS: The mean SAF value did not differ between the cases (1.61 [standard deviation (SD) 0.37]) arbitrary units [AU]) and the controls (1.64 [SD 0.41] AU) (p = 0.69). After adjusting for glycated hemoglobin A1c, body fat percentage, smoking, and season the mean SAF value did not differ between the cases and the controls (p = 0.49) but differed between men and women (p = 0.008), without any interaction observed (p = 0.78). CONCLUSION: SAF values did not differ between the young adult offspring of women with type 1 diabetes and offspring born to mothers without diabetes. Surprisingly, young adult women showed higher SAF values than men in both case and control groups.

Oral glucose tolerance test results in early pregnancy: A Finnish population-based cohort study.

AIMS: To analyze early-pregnancy oral glucose tolerance test (OGTT) results and differences between early- and late-pregnancy OGTT results in a population-based cohort. METHODS: From 3/2013 to 12/2016, pregnant women in South Karelia, Finland, were invited to undergo a 2-hour 75 g OGTT at 12-16 weeks' gestation (OGTT1) and, if normal, repeat testing at 24-28 weeks (OGTT2). Early and late gestational diabetes (GDM) were diagnosed using the same nationally endorsed criteria (fasting [FPG], 1- or 2-hour plasma glucose ≥5.3, ≥10.0 or ≥8.6 mmol/L, respectively). RESULTS: In OGTT1 (n = 1401), the mean (SD) FPG, 1- and 2-hour values were 4.85 (0.34), 6.63 (1.73) and 5.60 (1.28) mmol/L, respectively. Early GDM was diagnosed in 209 (14.9%). In OGTT2 (n = 1067), late GDM was diagnosed in 114 (10.6%). In women without GDM (n = 953), the mean FPG values were higher and post-load values lower in OGTT1 vs. OGTT2. No interaction effects of gestational timepoint and maternal BMI on OGTT results were detected, except for the 2-hour value. In women with late GDM, both mean FPG and post-load values were lower in OGTT1 vs. OGTT2. Results were similar employing the IADPSG GDM criteria. CONCLUSIONS: Our findings suggest that gestational-age specific OGTT thresholds for early GDM diagnosis need to be generated.

Fetal Microsatellite in the Heme Oxygenase 1 Promoter Is Associated With Severe and Early-Onset Preeclampsia.

Preeclampsia is a vascular pregnancy disorder that often involves impaired placental development. HO-1 (heme oxygenase 1, encoded by HMOX1) is a stress response enzyme crucial for endothelial and placental function. Long version of the guanine-thymine (GTn) microsatellite in the HMOX1 promoter decreases HO-1 expression, and the long maternal repeat is associated with late-onset preeclampsia. Our aim was to study whether the length of fetal repeat is associated with mother's preeclampsia, whether the length of fetal and maternal repeats affect HO-1 levels in placenta and maternal serum, and whether HO-1 levels are altered in preeclampsia. We genotyped the repeat in the cord blood of 609 preeclamptic and 745 nonpreeclamptic neonates. HO-1 levels were measured in 36 placental samples, and in the first (222 cases/243 controls) and third (176 cases/53 controls) pregnancy trimester serum samples using enzyme-linked immunosorbent assay. The long fetal GTn repeat was associated with preeclampsia and its severe and early-onset subtypes. Interaction analysis suggested the maternal and fetal effects to be independent. Placental or serum HO-1 levels were not altered in preeclamptics, possibly reflecting heterogeneity of preeclampsia. Carriers of the long fetal and maternal repeats had lower placental and serum HO-1 levels, respectively, providing functional evidence for the association. We conclude that the long fetal GTn repeat may increase mother's risk for especially severe and early-onset preeclampsia. The fetal and maternal risk alleles likely predispose to different disease subtypes.