Gestational diabetes mellitus (GDM) is an obstetric complication that affects approximately 5-10% of all pregnancies worldwide. GDM is defined as any degree of glucose intolerance with onset or first ...recognition during pregnancy, and is characterized by exaggerated insulin resistance, a condition which is already pronounced in healthy pregnancies. Maternal hyperglycaemia ensues, instigating a 'glucose stress' response and concurrent systemic inflammation. Previous findings have proposed that both placental and visceral adipose tissue play a part in instigating and mediating this low-grade inflammatory response which involves altered infiltration, differentiation and activation of maternal innate and adaptive immune cells. The resulting maternal immune dysregulation is responsible for exacerbation of the condition and a further reduction in maternal insulin sensitivity. GDM pathology results in maternal and foetal adverse outcomes such as increased susceptibility to diabetes mellitus development and foetal neurological conditions. A clearer understanding of how these pathways originate and evolve will improve therapeutic targeting. In this review, we will explore the existing findings describing maternal immunological adaption in GDM in an attempt to highlight our current understanding of GDM-mediated immune dysregulation and identify areas where further research is required.
The associations between pregnancy hypertensive disorders and common cardiovascular disorders have not been investigated at scale in a contemporaneous population. We aimed to investigate the ...association between preeclampsia, hypertensive disorders of pregnancy, and subsequent diagnosis of 12 different cardiovascular disorders.
We used linked electronic health records from 1997 to 2016 to recreate a UK population-based cohort of 1.3 million women, mean age at delivery 28 years, with nearly 1.9 million completed pregnancies. We used multivariable Cox models to determine the associations between hypertensive disorders of pregnancy, and preeclampsia alone (term and preterm), with 12 cardiovascular disorders in addition to chronic hypertension. We estimated the cumulative incidence of a composite end point of any cardiovascular disorder according to preeclampsia exposure.
During the 20-year study period, 18 624 incident cardiovascular disorders were observed, 65% of which had occurred in women under 40 years. Compared to women without hypertension in pregnancy, women who had 1 or more pregnancies affected by preeclampsia had a hazard ratio of 1.9 (95% confidence interval 1.53-2.35) for any stroke, 1.67 (1.54-1.81) for cardiac atherosclerotic events, 1.82 (1.34-2.46) for peripheral events, 2.13 (1.64-2.76) for heart failure, 1.73 (1.38-2.16) for atrial fibrillation, 2.12 (1.49-2.99) for cardiovascular deaths, and 4.47 (4.32-4.62) for chronic hypertension. Differences in cumulative incidence curves, according to preeclampsia status, were apparent within 1 year of the first index pregnancy. Similar patterns of association were observed for hypertensive disorders of pregnancy, while preterm preeclampsia conferred slightly further elevated risks.
Hypertensive disorders of pregnancy, including preeclampsia, have a similar pattern of increased risk across all 12 cardiovascular disorders and chronic hypertension, and the impact was evident soon after pregnancy. Hypertensive disorders of pregnancy should be considered as a natural screening tool for cardiovascular events, enabling cardiovascular risk prevention through national initiatives.
Placental insufficiency and adipose tissue dysregulation are postulated to play key roles in the pathophysiology of both pre-eclampsia (PE) and gestational diabetes mellitus (GDM). A dysfunctional ...release of deleterious signaling motifs can offset an increase in circulating oxidative stressors, pro-inflammatory factors and various cytokines. It has been previously postulated that endothelial dysfunction, instigated by signaling from endocrine organs such as the placenta and adipose tissue, may be a key mediator of the vasculopathy that is evident in both adverse obstetric complications. These signaling pathways also have significant effects on long term maternal cardiometabolic health outcomes, specifically cardiovascular disease, hypertension, and type II diabetes. Recent studies have noted that both PE and GDM are strongly associated with lower maternal flow-mediated dilation, however the exact pathways which link endothelial dysfunction to clinical outcomes in these complications remains in question. The current diagnostic regimen for both PE and GDM lacks specificity and consistency in relation to clinical guidelines. Furthermore, current therapeutic options rely largely on clinical symptom control such as antihypertensives and insulin therapy, rather than that of early intervention or prophylaxis. A better understanding of the pathogenic origin of these obstetric complications will allow for more targeted therapeutic interventions. In this review we will explore the complex signaling relationship between the placenta and adipose tissue in PE and GDM and investigate how these intricate pathways affect maternal endothelial function and, hence, play a role in acute pathophysiology and the development of future chronic maternal health outcomes.
Preeclampsia has been suggested to increase the risk of end-stage kidney disease (ESKD); however, most studies were unable to adjust for potential confounders including pre-existing comorbidities ...such as renal disease and cardiovascular disease (CVD). We aimed to examine the association between preeclampsia and the risk of ESKD in healthy women, while taking into account pre-existing comorbidity and potential confounders.
Using data from the Swedish Medical Birth Register (MBR), women who had singleton live births in Sweden between 1982 and 2012, including those who had preeclampsia, were identified. Women with a diagnosis of chronic kidney disease (CKD), CVD, hypertension, or diabetes prior to the first pregnancy were excluded. The outcome was a diagnosis of ESKD, identified from the Swedish Renal Registry (SRR) from January 1, 1991, onwards along with the specified cause of renal disease. We conducted Cox proportional hazards regression analysis to examine the association between preeclampsia and ESKD adjusting for several potential confounders: maternal age, body mass index (BMI), education, native country, and smoking. This analysis accounts for differential follow-up among women because women had different lengths of follow-up time. We performed subgroup analyses according to preterm preeclampsia, small for gestational age (SGA), and women who had 2 pregnancies with preeclampsia in both. The cohort consisted of 1,366,441 healthy women who had 2,665,320 singleton live births in Sweden between 1982 and 2012. At the first pregnancy, women's mean (SD) age and BMI were 27.8 (5.13) and 23.4 (4.03), respectively, 15.2% were smokers, and 80.7% were native Swedish. The overall median (interquartile range IQR) follow-up was 7.4 years (3.2-17.4) and 16.4 years (10.3-22.0) among women with ESKD diagnosis. During the study period, 67,273 (4.9%) women having 74,648 (2.8% of all pregnancies) singleton live births had preeclampsia, and 410 women developed ESKD with an incidence rate of 1.85 per 100,000 person-years. There was an association between preeclampsia and ESKD in the unadjusted analysis (hazard ratio HR = 4.99, 95% confidence interval CI 3.93-6.33; p < 0.001), which remained in the extensively adjusted (HR = 4.96, 95% CI 3.89-6.32, p < 0.001) models. Women who had preterm preeclampsia (adjusted HR = 9.19; 95% CI 5.16-15.61, p < 0.001) and women who had preeclampsia in 2 pregnancies (adjusted HR = 7.13, 95% CI 3.12-16.31, p < 0.001) had the highest risk of ESKD compared with women with no preeclampsia. Considering this was an observational cohort study, and although we accounted for several potential confounders, residual confounding cannot be ruled out.
The present findings suggest that women with preeclampsia and no major comorbidities before their first pregnancy are at a 5-fold increased risk of ESKD compared with parous women with no preeclampsia; however, the absolute risk of ESKD among women with preeclampsia remains small. Preeclampsia should be considered as an important risk factor for subsequent ESKD. Whether screening and/or preventive strategies will reduce the risk of ESKD in women with adverse pregnancy outcomes is worthy of further investigation.
Preeclampsia is a multisystemic pregnancy disorder and a major cause of maternal and neonatal morbidity and mortality worldwide. The exact pathophysiology of preeclampsia remains unclear; however, it ...is speculated that the various pathologies can be attributed to impaired vascular remodelling and elevated oxidative stress within the placenta. Oxidative stress plays a key role in cell ageing, and the persistent presence of elevated oxidative stress precipitates cellular senescence and mitochondrial dysfunction, resulting in premature ageing of the placenta. Premature ageing of the placenta is associated with placental insufficiency, which reduces the functional capacity of this critical organ and leads to abnormal pregnancy outcomes. The changes brought about by oxidative insults are irreversible and often lead to deleterious modifications in macromolecules such as lipids and proteins, DNA mutations, and alteration of mitochondrial functioning and dynamics. In this review, we have summarized the current knowledge of placental ageing in the aetiology of adverse pregnancy outcomes and discussed the hallmarks of ageing which could be potential markers for preeclampsia and fetal growth restriction.
Hypertensive disorders of pregnancy (HDP) (preeclampsia, gestational hypertension) are associated with an increased risk of end-stage kidney disease (ESKD). Evidence for associations between HDP and ...chronic kidney disease (CKD) is more limited and inconsistent. The underlying causes of CKD are wide-ranging, and HDP may have differential associations with various aetiologies of CKD. We aimed to measure associations between HDP and maternal CKD in women who have had at least one live birth and to identify whether the risk differs by CKD aetiology.
Using data from the Swedish Medical Birth Register (MBR), singleton live births from 1973 to 2012 were identified and linked to data from the Swedish Renal Register (SRR) and National Patient Register (NPR; up to 2013). Preeclampsia was the main exposure of interest and was treated as a time-dependent variable. Gestational hypertension was also investigated as a secondary exposure. The primary outcome was maternal CKD, and this was classified into 5 subtypes: hypertensive, diabetic, glomerular/proteinuric, tubulointerstitial, and other/nonspecific CKD. Cox proportional hazard regression models were used, adjusting for maternal age, country of origin, education level, antenatal BMI, smoking during pregnancy, gestational diabetes, and parity. Women with pre-pregnancy comorbidities were excluded. The final sample consisted of 1,924,409 women who had 3,726,554 singleton live births. The mean (±SD) age of women at first delivery was 27.0 (±5.1) years. Median follow-up was 20.7 (interquartile range IQR 9.9-30.0) years. A total of 90,917 women (4.7%) were diagnosed with preeclampsia, 43,964 (2.3%) had gestational hypertension, and 18,477 (0.9%) developed CKD. Preeclampsia was associated with a higher risk of developing CKD during follow-up (adjusted hazard ratio aHR 1.92, 95% CI 1.83-2.03, p < 0.001). This risk differed by CKD subtype and was higher for hypertensive CKD (aHR 3.72, 95% CI 3.05-4.53, p < 0.001), diabetic CKD (aHR 3.94, 95% CI 3.38-4.60, p < 0.001), and glomerular/proteinuric CKD (aHR 2.06, 95% CI 1.88-2.26, p < 0.001). More modest associations were observed between preeclampsia and tubulointerstitial CKD (aHR 1.44, 95% CI 1.24-1.68, p < 0.001) or other/nonspecific CKD (aHR 1.51, 95% CI 1.38-1.65, p < 0.001). The risk of CKD was increased after preterm preeclampsia, recurrent preeclampsia, or preeclampsia complicated by pre-pregnancy obesity. Women who had gestational hypertension also had increased risk of developing CKD (aHR 1.49, 95% CI 1.38-1.61, p < 0.001). This association was strongest for hypertensive CKD (aHR 3.13, 95% CI 2.47-3.97, p < 0.001). Limitations of the study are the possibility that cases of CKD were underdiagnosed in the national registers, and some women may have been too young to have developed symptomatic CKD despite the long follow-up time. Underreporting of postpartum hypertension is also possible.
In this study, we found that HDP are associated with increased risk of maternal CKD, particularly hypertensive or diabetic forms of CKD. The risk is higher after preterm preeclampsia, recurrent preeclampsia, or preeclampsia complicated by pre-pregnancy obesity. Women who experience HDP may benefit from future systematic renal monitoring.
Premature ageing of the placenta in pregnancy outcomes is associated with the persistent presence of oxidative stress and placental insufficiency reducing its functional capacity. In this study, we ...investigated cellular senescence phenotypes of pre-eclampsia and IUGR pregnancies by simultaneously measuring several biomarkers of senescence. Maternal plasma and placental samples were collected at term gestation from nulliparous women undergoing pre-labour elective caesarean section with pre-eclampsia without intrauterine growth restriction (PE;
= 5), pre-eclampsia associated with intrauterine growth restriction (n = 8), intrauterine growth restriction (IUGR < 10th centile;
= 6), and age-matched controls (
= 20). Placental absolute telomere length and senescence gene analysis was performed by RTqPCR. The expression of cyclin-dependent kinase inhibitors (p21 and p16) was determined by Western blot. Senescence-associated secretory phenotypes (SASPs) were evaluated in maternal plasma by multiplex ELISA assay. Placental expression of senescence-associated genes showed significant increases in CHEK1, PCNA, PTEN, CDKN2A, and CCNB-1 (
< 0.05) in pre-eclampsia, while TBX-2, PCNA, ATM, and CCNB-1 expression were evident (
< 0.05) and were significantly decreased in IUGR compared with controls. Placental p16 protein expression was significantly decreased in pre-eclampsia only compared with controls (
= 0.028). IL-6 was significantly increased in pre-eclampsia (0.54 pg/mL ± 0.271 vs. 0.3 pg/mL ± 0.102;
= 0.017) while IFN-γ was significantly increased in IUGR (4.6 pg/mL ± 2.2 vs. 2.17 pg/mL ± 0.8;
= 0.002) compared with controls. These results provide evidence of premature senescence in IUGR pregnancies, and while cell cycle checkpoint regulators are activated in pre-eclampsia, the cellular phenotype is one of cell repair and subsequent proliferation rather than progression to senescence. The heterogeneity of these cellular phenotypes highlights the complexity of characterising cellular senescence and may equally be indicative of the differing pathophysiological insults unique to each obstetric complication.
Gestational diabetes mellitus (GDM) is a complex obstetric condition affecting localized glucose metabolism, resulting in systemic metabolic dysfunction.
This cross-sectional study aimed to explore ...visceral adipose tissue (VAT) as an integral contributor to GDM, focusing on elucidating the specific contribution of obesity and GDM pathology to maternal outcomes.
Fifty-six nulliparous pregnant women were recruited, including normal glucose tolerant (NGT) (n = 30) and GDM (n = 26) participants. Participants were subgrouped as nonobese (BMI <30 kg/m2) or obese (BMI ≥30 kg/m2). Metabolic markers in circulation, VAT, and placenta were determined. Morphological analysis of VAT and immunoblotting of the insulin signaling cascade were performed.
GDM participants demonstrated hyperinsulinemia and elevated homeostatic model assessment for insulin resistance (HOMA-IR) scores relative to NGT participants. The GDM-obese subgroup had significant VAT adipocyte hypoplasia relative to NGT-nonobese tissue. GDM-obese VAT had significantly lower insulin receptor substrate (IRS)-2 expression, with elevated ser312 phosphorylation of IRS-1, relative to NGT-nonobese. GDM-obese participants had significantly elevated circulating leptin levels and placental adipsin secretion, while GDM-nonobese participants had elevated circulating adipsin levels with reduced placental adiponectin secretion.
These findings suggest that GDM-obese pregnancy is specifically characterized by inadequate VAT remodeling and dysfunctional molecular signaling, which contribute to insulin resistance and hinder metabolic health.
PDF
