Normotensive Pregnancies Research Articles

Placental lesions and differential expression of pro-and anti-angiogenic growth mediators and oxidative DNA damage marker in placentae of Ghanaian suboptimal and optimal health status pregnant women who later developed preeclampsia.

BackgroundAngiogenic growth mediators (AGMs) and oxidative stress (OS) both play essential roles in normal placental vascular development and as such, placental alterations in these factors contribute to pre-eclampsia (PE). Suboptimal health status (SHS), an intermediate between health and disease, has been associated with imbalanced AGMs and OS biomarkers. Thus, SHS pregnant women may be at increased risk of developing PE and may present abnormal placental alteration and expression of AGMs and OS compared to optimal health status (OHS) pregnant women. We examined the histopathological morphology, immunohistochemical expression of AGMs antibodies and oxidative DNA damage marker in the placentae of SHS and OHS pregnant women who developed early-onset PE (EO-PE) and late-onset (LO-PE) compared to normotensive pregnancy (NTN-P).MethodsThis nested case-control study recruited 593 singleton normotensive pregnant women at baseline (10–20 weeks gestation) from the Ghanaian Suboptimal Health Status Cohort Study (GHOACS) undertaken at the Komfo Anokye Teaching Hospital, Ghana. Socio-demographic, clinical and obstetrics data were collected, and a validated SHS questionnaire-25 (SHSQ-25) was used in classifying participants into SHS (n = 297) and OHS (n = 296). Participants were followed until the time of PE diagnosis and delivery (32–42 weeks gestation). Blood samples were collected at the two-time points and were assayed for AGMs; soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PIGF), vascular endothelial growth factor-A (VEGF-A), and soluble endoglin (sEng), and OS biomarkers; 8-hydroxydeoxyguanosine (8-OHdG), 8-epiprostaglandinF2-alpha (8- epi-PGF2α) and total antioxidant capacity (TAC) using ELISA. Placental samples were collected for histopathological and immunohistochemical analysis.ResultsOf the 593 pregnant women, 498 comprising 248 SHS and 250 OHS women returned for delivery and were included in the final analysis. Of the 248 SHS women, 56, 97 and 95 developed EO-PE, LO-PE and NTN-P, respectively, whereas 14, 30 and 206 of the 250 OHS mothers developed EO-PE, LO-PE and NTN-P, respectively. At baseline, SHS_NTN pregnant women had a significant imbalance in AGMs and OS biomarkers compared to OHS_NTN pregnant women (p<0.0001). At the time of PE diagnosis, SHS_NTN-P women who developed EO-PE, LO-PE, and NTN-P had lower serum levels of P1GF, VEGF-A and TAC and correspondingly higher levels of sEng, sFlt-1, 8-epiPGF2α, and 8-OHdG than OHS-NTN-P women who developed EO-PE and LO-PE, NTN-P (p<0.0001). A reduced placental size, increased foetal/placental weight ratio, and a significantly higher proportion of fibrinoid necrosis, infarction, villous fibrin, syncytial knots, calcification, chorangiosis, tunica media/vascular wall hypertrophy and chorioamnionitis was associated with the SHS group who developed PE (EO-PE>LO-PE) more than OHS groups who developed PE (EO-PE>LO-PE) when all were compared to NTN-P (p<0.0001). The intensity of antibody expression of PIGF and VEGF-A were significantly reduced, whereas Flt-1, Eng and 8-OHdG were significantly increased in placentae from SHS-pregnant women who developed EO-PE>LO-PE more than OHS- pregnant women who developed EO-PE>LO-PE when all were compared to NTN-P (p<0.0001).ConclusionIncreased lesions, oxidative DNA damage, and imbalanced expression between pro-and anti-AGMs are associated more with SHS-embodied PE placentae rather than OHS-embodied PE subtypes, thus potentially allowing differential evaluation of PE.

Vitamin D stimulates placental L-type amino acid transporter 1 (LAT1) in preeclampsia

Vitamin D insufficiency/deficiency has been linked to an increased risk of preeclampsia. Impaired placental amino acid transport is suggested to contribute to abnormal fetal intrauterine growth in pregnancies complicated by preeclampsia. However, if vitamin D-regulated amino acid transporter is involved in the pathophysiologic mechanism of preeclampsia has not been clarified yet. The aberrant expression of key isoform of L-type amino acid transporter LAT1 was determined by western blot and immunohistochemistry in the placenta from normotensive and preeclamptic pregnancies. The role for vitamin D on placental LAT1 expression was investigated through the exposure of HTR-8/SVneo human trophoblast cells to the biologically active 1,25(OH)2D3 and the oxidative stress-inducer cobalt chloride (CoCl2). Our results showed that placental LAT1 expression was reduced in women with preeclampsia compared to normotensive pregnancies, which was associated with decreased expression of vitamin D receptor (VDR). 1,25(OH)2D3 significantly upregulated LAT1 expression in placental trophoblasts, and also prevented the decrease of mTOR activity under CoCl2-induced oxidative stress. siRNA targeting VDR significantly attenuated 1,25(OH)2D3-stimulated LAT1 expression and mTOR signaling activity. Moreover, treatment of rapamycin specifically inhibited the activity of mTOR signaling and resulted in decrease of LAT1 expression. In conclusion, LAT1 expression was downregulated in the placenta from women with preeclampsia. 1,25(OH)2D3/VDR could stimulate LAT1 expression, which was likely mediated by mTOR signaling in placental trophoblasts. Regulation on placental amino acid transport may be one of the mechanisms by which vitamin D affects fetal growth in preeclampsia.

Biochemical markers in the pathogenesis of preeclampsia: novel link between placental growth factor and interleukin-6.

Preeclampsia (PE) is a multisystem disorder of pregnancy characterized by sudden onset of hypertension and proteinuria. The appearance and diagnosis of the disease remain elusive and the only treatment is the termination of pregnancy. The onset of the disease is preceded by a shift in the balance of the angiogenic and antiangiogenic proteins in the maternal circulation. We surmised that the assessment of the levels of these proteins during pregnancy could lead to a proper diagnosis of the disease. In this study, we determined the levels of angiogenic and antiangiogenic proteins and IL-6 in maternal circulation during normotensive and hypertensive pregnancy, including PE. Serum isolated from pregnant women during antenatal visits was used to determine the concentrations of these proteins. The levels of antiangiogenic proteins, sFlt-1 and sEng, were higher in hypertensive disorders [gestational hypertension (GH), mild PE, and PE] of pregnancy and were significantly higher for PE than for GH. The levels of sFlt-1 and sEng were higher in PE samples compared to those in GH and NT samples. These proteins may have contributed to increased blood pressure. The levels of PlGF were decreased in pregnant women having GH, mild PE, and PE. The levels of the inflammatory intermediate, IL-6, were increased in PE samples compared to those in the GH and normotensive samples. The evaluation of the altered levels of antiangiogenic and angiogenic proteins can be useful for diagnosis of PE.

Cardiac magnetic resonance imaging in preeclampsia complicated by pulmonary edema shows myocardial edema with normal left ventricular systolic function

Preeclampsia complicates approximately 5% of all pregnancies. When pulmonary edema occurs, it accounts for 50% of preeclampsia-related mortality. Currently, there is no consensus on the degree to which left ventricular systolic dysfunction contributes to the development of pulmonary edema. This study aimed to use cardiac magnetic resonance imaging to detect subtle changes in left ventricular systolic function and evidence of acute left ventricular dysfunction (through tissue characterization) in women with preeclampsia complicated by pulmonary edema compared with both preeclamptic and normotensive controls. Cases were postpartum women aged ≥18 years presenting with preeclampsia complicated by pulmonary edema. Of note, 2 control groups were recruited: women with preeclampsia without pulmonary edema and women with normotensive pregnancies. All women underwent echocardiography and 1.5T cardiac magnetic resonance imaging with native T1 and T2 mapping. Gadolinium contrast was administered to cases only. Because of small sample sizes, a nonparametric test (Kruskal-Wallis) with pairwise posthoc analysis using Bonferroni correction was used to compare the differences between the groups. Cardiac magnetic resonance images were interpreted by 2 independent reporters. The intraclass correlation coefficient was calculated to assess interobserver reliability. Here, 20 women with preeclampsia complicated by pulmonary edema, 13 women with preeclampsia (5 with severe features and 8 without severe features), and 6 normotensive controls were recruited. There was no difference in the baseline characteristics between groups apart from the expected differences in blood pressure. Left atrial sizes were similar across all groups. Women with preeclampsia complicated by pulmonary edema had increased left ventricular mass (P=.01) but had normal systolic function compared with the normotensive controls. Furthermore, they had elevated native T1 values (P=.025) and a trend toward elevated T2 values (P=.07) in the absence of late gadolinium enhancement consistent with myocardial edema. Moreover, myocardial edema was present in all women with eclampsia or hemolysis, elevated liver enzymes, and low platelet count. Women with preeclampsia without severe features had similar findings to the normotensive controls. All cardiac magnetic resonance imaging measurements showed a very high level of interobserver correlation. This study focused on cardiac magnetic resonance imaging in women with preeclampsia complicated by pulmonary edema, eclampsia, and hemolysis, elevated liver enzymes, and low platelet count. We have demonstrated normal systolic function with myocardial edema in women with preeclampsia with these severe features. These findings implicate an acute myocardial process as part of this clinical syndrome. The pathogenesis of myocardial edema and its relationship to pulmonary edema require further elucidation. With normal left atrial sizes, any hemodynamic component must be acute.

Cerebral biomarkers in neurologic complications of preeclampsia

There is no tool to accurately predict who is at risk of developing neurologic complications of preeclampsia, and there is no objective method to determine disease severity. We assessed whether plasma concentrations of the cerebral biomarkers neurofilament light, tau, and glial fibrillary acidic protein could reflect disease severity in several phenotypes of preeclampsia. Furthermore, we compared the cerebral biomarkers with the angiogenic biomarkers soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin. In this observational study, we included women from the South African Preeclampsia Obstetric Adverse Events biobank. Plasma samples taken at diagnosis (preeclampsia cases) or admission for delivery (normotensive controls) were analyzed for concentrations of neurofilament light, tau, glial fibrillary acidic protein, placental growth factor, soluble fms-like tyrosine kinase 1, and soluble endoglin. The cerebrospinal fluid concentrations of inflammatory markers and albumin were analyzed in a subgroup of 15 women. Analyses were adjusted for gestational age, time from seizures and delivery to sampling, maternal age, and parity. Compared with 28 women with normotensive pregnancies, 146 women with preeclampsia demonstrated 2.18-fold higher plasma concentrations of neurofilament light (95% confidence interval, 1.64-2.88), 2.17-fold higher tau (95% confidence interval, 1.49-3.16), and 2.77-fold higher glial fibrillary acidic protein (95% confidence interval, 2.06-3.72). Overall, 72 women with neurologic complications (eclampsia, cortical blindness, and stroke) demonstrated increased plasma concentrations of tau (2.99-fold higher; 95% confidence interval, 1.92-4.65) and glial fibrillary acidic protein (3.22-fold higher; 95% confidence interval, 2.06-5.02) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications (n=31). Moreover, angiogenic markers were higher, but to a lesser extent. Women with hemolysis, elevated liver enzymes, and low platelet count (n=20) demonstrated increased plasma concentrations of neurofilament light (1.64-fold higher; 95% confidence interval, 1.06-2.55), tau (4.44-fold higher; 95% confidence interval, 1.85-10.66), and glial fibrillary acidic protein (1.82-fold higher; 95% confidence interval, 1.32-2.50) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications. There was no difference shown in the angiogenic biomarkers. There was no difference between 23 women with preeclampsia complicated by pulmonary edema and women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications for any of the biomarkers. Plasma concentrations of tau and glial fibrillary acidic protein were increased in women with several neurologic complications compared with women with eclampsia only. Plasma neurofilament light, glial fibrillary acidic, and tau were candidate biomarkers for the diagnosis and possibly prediction of cerebral complications of preeclampsia.

Blood pressure adjustments throughout healthy and hypertensive pregnancy: A systematic review and meta-analysis.

Gestational hypertensive complications are preceded by deviant hemodynamic adjustments affecting blood pressure. Our objective was to determine the timing and magnitude of changes in blood pressure during singleton normotensive and hypertensive pregnancies. PubMed (NCBI) and Embase (Ovid) databases were searched for relevant studies up to November 2019. Studies reporting original blood pressure measurements during pregnancy together with a non-pregnant reference measurement were included. Studies including women with a history of cardiovascular or metabolic disease, or women using antihypertensive drugs were excluded. Pooled mean differences between pregnant and non-pregnant women, and absolute blood pressure values were calculated for predefined gestational intervals in normotensive and hypertensive pregnancy, using a random-effects model. Meta-regression analysis was used to analyze group differences in adjustments. In early normotensive pregnancy, both systolic and diastolic blood pressure decreased, reaching their maximum reduction of -4 mmHg (95%CI -6 to -1 mmHg) and -4 mmHg (95%CI, -5 to -3 mmHg), respectively in the second trimester. Thereafter, blood pressure gradually increased towards non-pregnant values. All absolute blood pressure measurements throughout normotensive pregnancy were below 130/80mmHg. In hypertensive pregnancies, only diastolic blood pressure decreased early in pregnancy. In conclusion, this meta-analysis showed a clinically moderate, but significant mid-pregnancy drop in blood pressure during normotensive pregnancy. Reference curves with absolute values underscore the current liberal cut-off limit for gestational hypertension. A lack of a mid-pregnancy systolic blood pressure drop might reflect increased vascular resistance in women destined to develop hypertensive pregnancy complications.

The P4 study: Subsequent pregnancy maternal physiology after hypertensive and normotensive pregnancies.

Hypertensive disorders of pregnancy are associated with subsequent increased risk of cardiometabolic disease. Adverse cardiometabolic measures are noted soon after hypertensive versus normotensive pregnancy (NP); to what degree these persist into a subsequent pregnancy (SP) is unknown. This study aimed to assess women's physiology early in SP after hypertensive pregnancy (HP: preeclampsia or gestational hypertension) or NP and compare SP to 6 months postpartum findings from the index pregnancy. Prospective sub-study of the P4 (Postpartum, Physiology, Psychology and Paediatric) observational cohort. Measurements six months after NP versus HP, and the SP at 11-13 weeks gestation. Blood pressure (BP), blood and urine tests (urine ACR, HOMA-IR, LDL cholesterol), body composition, and contribution of maternal characteristics and inter-pregnancy factors to BP and body fat (FM%) in SP. 49 women (34 NP, 15 HP). In the SP, post-HP women had higher BP (112/70 mmHg HP vs 102/64 mmHg NP; p < .001), with no significant drop from six months postpartum to early SP. On regression analysis, systolic and diastolic BP at 6-months were the major predictors for SP systolic (p < 0.001) and diastolic (p = 0.009) BP respectively in the SP. Longer interpregnancy interval and increased FM% 6-months postpartum were associated with higher SP FM% (p < 0.001). BP and body fat six months postpartum were similar early in the SP for HP group, and postpartum BP and FM% were major predictors of their corresponding SP measurements. Postpartum/inter-pregnancy intervention programs to improve these cardiometabolic risk markers might help improve women's long-term health and require investigation.

Association between brain natriuretic peptide and cardiac dysfunction in hypertensive pregnancy disorders.

The aim of this work is to identify the correlation between serum brain natriuretic peptide (BNP) and left ventricle (LV) systolic and diastolic function in hypertensive pregnancy disorders (HPD) through echocardiographic parameters. Eighty-seven pregnant patients were included, 23 with normotensive pregnancy (NP), 28 with gestational hypertension (GH) and 36 with preeclampsia (PE). Conventional 2D echocardiography was used to evaluate systolic and diastolic function such as E/a, E/e', LV mass index, LV ejection fraction, as well as left atria (LA) diameters, LA indexed volume, LV strain and LA strain (LAS). Brain natriuretic levels (BNP) blood levels were also determined. The serum levels of BNP were higher in patients with PE [median (interquartile range, IQR)] 189 (142-215) pg/ml and GH 105 (46-162) pg/ml compared to NP 23 (9-33) pg/ml, (p=0.001). BNP levels had a negative correlation with LAS (Rho=-0.79, p<0.001). Preeclampsia patients had lower LAS [median (IQR)] 22% (20%-24%) compared to the GH group 23% (20%-24%) and NP 35% (34% -35%), p=0.001. Classification and Regression Trees multivariate analysis found patterns that define trends to form mutually excluding homogeneous groups such as: a) First parameter that separates 2 groups is septal e>8.2 or<8.2b), BNP serum levels above 89pg/ml, and c) LAS increases the discriminatory performance to detect and define the diastolic dysfunction or not. At least one third of women with HPD had moderate diastolic dysfunction. The degree of diastolic dysfunction was negatively correlated with serum BNP levels and severity of HPD. LAS increase discriminatory performance to identify diastolic dysfunction in HPD.

Correlation between N-terminal pro-atrial natriuretic peptide, corin, and target organ damage in hypertensive disorders of pregnancy.

The objective was to evaluate the correlation between N‐terminal pro‐atrial natriuretic peptide (NT‐proANP), corin and the severity of target organ injury in hypertensive disorders of pregnancy. A total of 78 women with hypertensive disorders of pregnancy and 49 normotensive pregnancies were enrolled. The clinical characteristics, laboratory index and echocardiogram results were collected. NT‐proANP, corin, sFlt‐1 and PlGF levels were measured. A receiver's operating characteristics (ROC) curve was performed to evaluate the efficacy of predicting target organ injury in the HDP group. The NT‐proANP, corin, and sFlt‐1/PlGF ratio were increased in the HDP group (p < .05). The area under the curve (AUC) predicted by NT‐proANP and corin were larger than sFlt‐1/PlGF ratio (0.779, 0.867, and 0.766, respectively). The creatinine and urine protein were significantly increased, while the estimated glomerular filtration rate (eGFR) was dramatically decreased in the HDP group (p < .05 each). The left atrial diameter (LAD), left atrial volume index (LAVI), left ventricular posterior wall thickness (LVPWT), and left ventricular septal thickness (LVST) were larger in the HDP group (p < .001 each). The NT‐proANP/corin levels were positively correlated with LAD, creatinine, and urine protein, and negatively correlated with eGFR in HDP group (p < .05 each). Multiple regressions demonstrated that NT‐proANP was an independent risk factor of LAD and urine protein, and corin was an independent risk factor of creatinine and eGFR in HDP group. NT‐proANP and corin may be reliable biomarkers for evaluating the severity of target organ damage in the hypertensive disorders of pregnant patients.

Depression, anxiety and posttraumatic stress disorder six months following preeclampsia and normotensive pregnancy: a P4 study

BackgroundMental health is an integral part of overall health. Mental health disorders following childbirth are common and poor maternal mental health has consequences for both the mother and her infant. Preeclampsia is also relatively common in pregnancy but there is little known about the intersection between these two important conditions. Gaining a better understanding of the psychological consequences following preeclampsia is important, especially the link with depression, anxiety and posttraumatic stress disorder. If women who experience preeclampsia are recognised as being at increased risk of poor mental health, targeted screening in the postpartum period should be implemented.AimsTo describe the prevalence and symptom severity of depression, anxiety and posttraumatic stress disorder at six months postpartum in women, who had a diagnosis of preeclampsia, compared to those who had normal blood pressure in pregnancy.MethodsThe mental health component of the prospective cohort study, the Postpartum, Physiology, Psychology and Paediatric follow-up study (P4 Study) was used. Women diagnosed with preeclampsia (n = 90) and those who were normotensive during pregnancy (n = 302) completed the Edinburgh Postnatal Depression Scale, General Anxiety Disorder Scale, and the Posttraumatic Stress Diagnostic Scale or Posttraumatic Stress Diagnostic Sclae-5 at six months postpartum.ResultsAt six months postpartum, depressive scores were similar in both groups but a higher proportion of women from the preeclampsia group scored above the threshold for depression (2% v 7% p = 0.04). There were no differences between the groups in the prevalence or severity of anxiety or PTSD. However, more women in the preeclampsia group reported their birth experience as a traumatic event (1% vs 7%, p = 0.01). On correlation testing and modelling, booking Edinburgh Postnatal Depression Scale score, any mental health history, experiencing birth as traumatic and the General Anxiety Disorder Scale score were independent predictors of postpartum Edinburgh Postnatal Depression Scale scores.ConclusionThe postpartum clinical care of women with preeclampsia often focusses on the immediate physical health issues, but these women may also benefit from mental health screening. Targeted screening of preeclamptic women in the postpartum period may lead to more timely referral and initiation of treatment.Trial registrationRetrospectively registered on 18/11/2013 with the Australian and New Zealand Clinical Trials Registry. Registration Number: ACTRN12613001260718.

Postpartum blood pressure self-management following hypertensive pregnancy: protocol of the Physician Optimised Post-partum Hypertension Treatment (POP-HT) trial

IntroductionNew-onset hypertension affects approximately 10% of pregnancies and is associated with a significant increase in risk of cardiovascular disease in later life, with blood pressure measured 6 weeks postpartum predictive...

Effects of pre-eclampsia on HDL-mediated cholesterol efflux capacity after pregnancy

Background and aimsPreeclampsia (PE) is associated with life-long increased risk of cardiovascular disease. One of the main protective functions of high-density lipoprotein (HDL) is its role in reverse cholesterol transport. HDL-mediated cholesterol efflux capacity (CEC) is decreased during pregnancy in women with PE. Whether this persists postpartum is unknown. MethodsBasal and transporter-specific CEC were determined 6 months postpartum in women who had a normotensive (n = 44) or a PE (n = 42) pregnancy. CEC was also measured in 23 normotensive and 20 PE women for whom samples were collected 24 months postpartum. Basal, ATP-binding cassette transporter-A1 (ABCA1)- and -G1 (ABCG1)-specific CEC were primarily determined using Chinese hamster ovary cells stably expressing human ABCA1 or ABCG1, and were also assessed using a J774 mouse macrophage cell line. ResultsABCA1-specific CEC was significantly lower in women who had PE 6 months postpartum (0.57 ± 0.1 vs 0.53 ± 0.08; p < 0.05), whilst basal and ABCG1-specific efflux were not significantly different. cAMP-specific CEC in J774 cells was also lower 6 months after PE (0.85 ± 0.21 vs 0.75 ± 0.25, p < 0.05). Although apoA-I, apoE, plasminogen and PON-1 levels were not significantly different in women who had PE compared with controls, ABCA1 efflux did correlate with apoA-l, HDL-C and apoE levels after a normal, and with apoA-l and HDL-C levels after a PE pregnancy. ABCA1-specific efflux decreased in all women between 6 and 24 months postpartum, by 11 ± 1.6% in women who had a normotensive pregnancy and 9 ± 1.3% in women who had PE. After adjustment for apoA-I levels, there was no significant difference in ABCA1-specific efflux between the groups at 6 months postpartum and in normotensive women over time, but remained significantly different between 6 and 24 months in women who had PE. ConclusionsABCA1-mediated CEC is impaired 6 months postpartum after a PE pregnancy and decreases thereafter in both normotensive and PE pregnancies. ABCA1-mediated efflux is dynamic after pregnancy but is unlikely to explain the long-term increased CVD risk in women with PE.

Evaluation of epigenetic age calculators between preeclampsia and normotensive pregnancies in an Australian cohort

Advanced biological aging, as assessed through DNA methylation markers, is associated with several complex diseases. The associations between maternal DNA methylation age and preeclampsia (PE) have not been fully assessed. The aim of this study was to examine if increased maternal DNA methylation age (DNAmAge) was shown to be accelerated in women with PE when compared to women who had normotensive pregnancies. The case/control cohort available for study consisted of 166 women (89 with normotensive pregnancy, 77 with PE) recruited previously at the Royal Women’s Hospital in Melbourne, Australia. DNA methylation profiles were obtained using the Illumina EPIC Infinium array for analysis of genomic DNA isolated from whole blood. These profiles were used to calculate seven estimates of DNAmAge and included (1) Horvath, (2) Hannum, (3) Horvath Skin and Blood, (4) Wu, (5) PhenoAge, (6) telomere length and (7) GrimAge and its surrogate measures. Three measures of DNA methylation age acceleration were calculated for all seven measures using linear regression. Pearson's correlation was performed to investigate associations between chronological age and DNAmAge. Differences between chronological age and DNAmAge and epigenetic age acceleration were investigated using t-tests. No significant difference was observed for chronological age between women with PE (age = 30.53 ± 5.68) and women who had normotensive pregnancies (age = 31.76 ± 4.76). All seven DNAmAge measures were significantly correlated (p < 0.001) with chronological age. After accounting for multiple testing and investigating differences in DNAmAge between normotensive women and women with PE, only Wu DNAmAge was significant (p = 0.001). When examining differences for epigenetic age acceleration between PE and normotensive women Hannum, Wu, and PhenoAge DNAmAge estimates (p < 0.001) were significant for both epigenetic age acceleration and intrinsic acceleration models. We found that accelerated maternal DNAmAge is increased in women with PE in some models of epigenetic aging. This research underlines the importance for further investigation into the potential changes of differential DNA methylation in PE.

The P4 Study: Postpartum Maternal and Infant Faecal Microbiome 6 Months After Hypertensive Versus Normotensive Pregnancy.

Objective/HypothesisTo explore potential differences in faecal microbiome between women, and their infants, who had normotensive pregnancies (NP) and those who had a hypertensive pregnancy (HP), either gestational hypertension (GH) or preeclampsia (PE).MethodsThis is a sub study of P4 (Postpartum Physiology, Psychology, and Paediatrics Study) and includes 18 mother-infant pairs: 10 NP and 8 HP (HP as defined by blood pressure > 140/90mmHg; of which 6 had PE, and 2 GH), six months postpartum. The participating mothers collected stool samples from themselves and their infants. 16S rRNA V3-V4 amplicons were used to study the faecal microbiome.ResultsThe sample of women and their infants were mostly primiparous (n =16) with vaginal birth (n = 14). At the time of faecal sampling 8 women were using hormonal contraception, and one HP woman remained on an antihypertensive. All women had blood pressure < 130/80mmHg, and 10 had high BMI (> 30). All infants had started solids, 8 were exclusively breastfed, 1 exclusively formula fed and 9 both. Three infants had been exposed to a course of antibiotics. Six months postpartum, there were no significant differences in alpha or beta diversity between the gut microbiota of HP and NP women (P > 0.05). However, a statistically significant difference was detected in alpha diversity between infants following HP and NP, with lower diversity levels in HP infants (P < 0.05). It was also found that at a genus and species level, the gut microbiota of HP women was enriched with Bifidobacterium and Bifidobacterium sp. and depleted in Barnesiella and Barnesiella intestinihominis when compared to NP women (P < 0.05). Similarly, the gut microbiota of infants born from HP was enriched in Streptococcus infantis and depleted in Sutterella, Sutterella sp., Bacteroides sp. and Clostridium aldenense compared to infants born from NP (P < 0.05).DiscussionWhile our findings are at best preliminary, due to the very small sample size, they do suggest that the presence of hypertension in pregnancy may adversely affect the maternal microbiota postpartum, and that of their infants. Further analysis of postpartum microbiome data from future studies will be important to validate these early findings and provide further evidence about the changes in the microbiota in the offspring of women following hypertensive disorders of pregnancy (HDP), including possible links to the causes of long-term cardiovascular disease, the prevalence of which is increased in women who have experienced HDP.

Increased Cardiac Arrhythmia After Pregnancy-Induced Hypertension: A South Korean Nationwide Database Study.

BackgroundAlthough pregnancy‐induced hypertension (PIH) is associated with an elevated cardiovascular risk, long‐term studies or prepregnancy baseline data are scarce. Therefore, using a large nationwide cohort with prepregnancy periodic health screening data, we investigated whether clinically significant arrhythmia incidence increases after PIH.Methods and ResultsData were extracted from the Korea National Health Insurance database and combined with the National Health Screening Examination database; women who gave birth between 2007 and 2015 and underwent the national health screening test within a year before pregnancy were followed up until 2016. We excluded women who had a diagnosis of arrhythmia within 1 year before pregnancy. The primary outcome was significant arrhythmia during the year after delivery. Secondary analysis included only specific diagnostic codes of arrhythmia with clinical significance. Additionally, the risk of arrhythmia was stratified by the use of magnesium sulfate. Of 2 035 684 women (PIH; n=37 297 versus normotensive pregnancy; n=1 998 387), the PIH group had a higher prepregnancy risk profile and showed a higher incidence of arrhythmia than women with normotensive pregnancies within 1 year. Women with PIH had a significantly higher risk of atrial flutter/fibrillation and atrioventricular block, but not lethal arrhythmias. Other predictors of arrhythmia development included advanced maternal age and cesarean section. Stratified analysis showed a higher risk of arrhythmia with magnesium sulfate use.ConclusionsPIH was significantly associated with the development of arrhythmia within 1 year after delivery. Nevertheless, the incidence of lethal arrhythmias was not increased by PIH. Arrhythmia, especially atrial fibrillation, may largely contribute to increasing the future cardiovascular risk in women with a PIH history.

Women with a history of preeclampsia have preserved sensory nerve-mediated dilatation in the cutaneous microvasculature.

What is the central question of this study? Are sensory nerve-mediated vasodilatation and the NO-dependent contribution to that response attenuated in the cutaneous microvasculature of women who have had preeclampsia? What is the main finding and its importance? Women who have had preeclampsia demonstrate attenuated microvascular endothelium-dependent dilatation compared to women with a history of uncomplicated pregnancy. However, there are no differences in sensory nerve-mediated vasodilatation between groups. This suggests that the neurogenic response is not altered following preeclampsia, and that the NO-dependent vasodilatation of the neurogenic response is not related to endothelium-dependent NO-mediated dilatation in these women. Women who have had preeclampsia (PE) demonstrate microvascular endothelial dysfunction, mediated in part by reduced nitric oxide (NO)-dependent mechanisms. Localized heating of the skin induces a biphasic vasodilatation response: a sensory nerve-mediated initial peak, followed by a sustained endothelium-dependent plateau. We have previously shown that the endothelium-dependent plateau is attenuated in PE. However, it is unknown if the sensory nerve-mediated initial peak is similarly attenuated. Therefore, the purpose of this study was to examine the effect of PE history on sensory nerve-mediated vasodilatation and the NO-dependent contribution to that response. We hypothesized that PE would have an attenuated initial peak and a reduced NO-dependent contribution to that response compared to women with a history of normotensive pregnancy (healthy controls, HC). Nine HC (31±4years) and nine PE (28±6years) underwent a standard local heating protocol (42°C; 0.1°Cs-1 ). Two intradermal microdialysis fibres were placed in the skin of the ventral forearm for the continuous local delivery of lactated Ringer solution alone (control) or 15-mM NG -nitro-l-arginine methyl ester for nitric oxide synthase (NOS) inhibition. Red blood cell flux was measured at each site by laser Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC=LDF/mean arterial pressure) and normalized to maximum (%CVCmax ; 28-mM SNP + local heat 43°C). There were no differences in the initial peak between groups (HC: 79±8 vs. PE: 80±10%CVCmax ; P=0.936). NOS inhibition attenuated the initial peak in both HC (57±18% CVCmax ; P=0.003) and PE (54±10%CVCmax ; P=0.002). However, there were no differences in the NO-dependent portion of the initial peak (HC: 23±16 vs. PE: 24±9%; P=0.777). The local heating plateau (HC: 99±4 vs. PE: 88±7%CVCmax ; P=0.001) and NO contribution to the plateau (HC: 31±9 vs. PE: 17±14%; P=0.02) were attenuated in PE. There was no relation between NO-dependent dilatation in the initial peak and NO-dependent dilatation in the plateau across groups (R2 =0.005; P=0.943). Women who have had PE demonstrate attenuated microvascular endothelium-dependent dilatation. However, there are no differences in sensory nerve-mediated vasodilatation following PE, suggesting that the NO-dependent vasodilatation of the neurogenic response is not related to endothelium-dependent NO-mediated dilatation in these women.

Study on the Correlation between the Levels of HtrA3 and TGF-β2 in Late Pregnancy and Preeclampsia.

Preeclampsia (PE) is a common and proprietary complication during pregnancy. The correlation was found between the levels of HtrA3 and TGF-β 2 and preeclampsia (PE). This study aimed to detect the HtrA3 and TGF-β2 in different parts of the third trimester (maternal serum, placenta). The 102 pregnant women who were eligible for enrollment in the obstetric examination at Tengzhou Maternity and Child Health Hospital from June 2020 to December 2020 were selected as the research objects. 28 cases diagnosed with PE were set up as the observation group 1, and 24 cases diagnosed with severe PE were set up as the observation group 2. Select 50 normal pregnant women as the control group and research the expressions of HtrA3 and TGF-β2 in maternal blood and placental tissues of patients with PE. ELISA was used to measure the concentration of HtrA3 and TGF-β2 in maternal blood. The distribution of HtrA3 and TGF-β2 in the placenta was observed by immunohistochemical techniques (IHC) and mean optical density value (MOD). S/D was measured by using color Doppler ultrasonic. The concentration of HtrA3 and TGF-β2 in the maternal blood and placenta tissue was higher in severe PE compared with PE and normotensive pregnancy, respectively (P < 0.05). There is a negative correlation between the level of HtrA3 and TGF-β2 and the birthweight of newborns both in maternal plasma and placenta tissue in preeclampsia and positive correlation between HtrA3 and TGF-β2 levels and S/D. HtrA3 and TGF-β2 may correlate with severity of PE and their neonatal adverse outcomes.

Comprehensive fatty acid fractionation profilling in preeclampsia: a case control study with multivariable analysis.

BackgroundPreeclampsia is a complication during pregnancy characterised by new-onset hypertension and proteinuria that develops after 20 weeks of gestation. Dyslipidemia in pregnancy is correlated with an increased risk of preeclampsia. However, the dynamic changes in lipid metabolic product, particularly fatty acid fraction, in preeclampsia maternal circulation, are not well understood. This study aimed to investigate fatty acid fraction in preeclampsia maternal blood compared with normotensive normal pregnancy.MethodsA total of 34 women who developed preeclampsia and 32 women with normotensive normal pregnancy were included in our case-control study. Maternal blood samples were collected for serum fatty acid fractions analysis and other biochemical parameters. Serum fatty acid fractions included long-chain polyunsaturated fatty acid (LCPUFA), monounsaturated fatty acid (MUFA), saturated fatty acid, and total fatty acid, measured with gas chromatography-mass spectrometry (GC-MS). The mean difference of fatty acid level was analysed using parametric and non-parametric bivariate analysis based on normality distributed data, while the risk of preeclampsia based on fatty acid fraction was analysed using a logistic regression model.ResultsWomen with preeclampsia have lower high-density lipoprotein (53.97 ± 12.82 mg/dL vs. 63.71 ± 15.20 mg/dL, p = 0.006), higher triglyceride (284.91 ± 97.68 mg/dL vs. 232.84 ± 73.69 mg/dL, p = 0.018) than that in the normotensive group. Higher palmitoleic acid was found in women with preeclampsia compared to normotensive normal pregnancy (422.94 ± 195.99 vs. 325.71 ± 111.03 μmol/L, p = 0.037). The binary logistic regression model showed that pregnant women who had total omega-3 levels within the reference values had a higher risk of suffering preeclampsia than those with the higher reference value (odds ratio OR (95% CI): 8,5 (1.51–48.07), p = 0.015). Pregnant women who have saturated fatty acid within reference values had a lower risk for suffering preeclampsia than those in upper reference value (OR (95% CI): 0.21 (0.52–0.88), p = 0.032).ConclusionOverall, palmitoleic acid was higher in women with preeclampsia. Further analysis indicated that reference omega-3 in and high saturated fatty acid serum levels are characteristics of women with preeclampsia.

Arterial Stiffness as a Cardiovascular Risk Factor for the Development of Preeclampsia and Pharmacopreventive Options

Arterial Stiffness (AS) describes the rigidity of the arterial walls. Epidemiological studies have shown that increased AS is an independent predictive marker of Cardiovascular (CV) morbidity and mortality in both pregnant and non-pregnant women. Preeclampsia (PE), a form of pregnancy-induced hypertension, affects approximately 5% of pregnancies worldwide. Preeclamptic women have a higher risk of CV Disease (CVD), mainly because PE damages the heart's ability to relax between contractions. Different pharmacological approaches for the prevention of PE have been tested in clinical trials (e.g., aspirin, enoxaparin, metformin, pravastatin, and sildenafil citrate). In current clinical practice, only low-dose aspirin is used for PE pharmacoprevention. However, low-dose aspirin does not prevent term PE, which is the most common form of PE. Compromised vascular integrity precedes the onset of PE and therefore, AS assessment may constitute a promising predictive marker of PE. Several non-invasive techniques have been developed to assess AS. Compared with normotensive pregnancies, both Carotid-Femoral Pulse Wave Velocity (cfPWV) and Augmentation Index (AIx) are increased in PE. In view of simplicity, reliability, and reproducibility, there is an interest in oscillometric AS measurements in pregnancies complicated by PE.

Association of SNP rs163550 in IL5RA Gene with Risk of Preeclampsia

Background: Several research have looked at the significance of SNPs in inflammatory mediator genes and their link to preeclamptic pregnancies, but the results have not been conclusive enough to explain why SNPs in inflammatory mediator genes may increase the risk of preeclampsia. The goal of this study is to analyze the IL5RA SNPs in order to learn more about the possible link between preeclampsia and inflammatory genes. Materials and Methods: A total of 304 pregnant participants were a part of this prospective observational case-control study, out of which 152 had preeclampsia, and the other 152 participants had normotensive pregnancies. The “polymerase chain reaction-restriction fragment length polymorphism” method was used to genotype SNP rs163550. Results: The commonness of the IL5RA rs163550G allele has been linked to an increased risk for preeclampsia with P value: 0.0230 and odds ratio: 0.6818 (95% confidence interval: 0.489–0.9505). Conclusion: A prominent association among the IL5RA rs163550 SNP and preeclampsia in comparison to nonpreeclampsia has been observed in the study. The study stands first to report IL5RA Polymorphism association with the pathogenesis of preeclampsia's among the Indian population.