Alternative pathway activation in pregnancy, a measured amount "complements" a successful pregnancy, too much results in adverse events.

During pregnancy, the maternal host must adapt in order to enable growth of the fetus. These changes affect all organ systems and are designed both to protect the fetus and to minimize risk to the mother. One of the most prominent adaptations involves the immune system. The semi-allogenic fetoplacental unit has non-self components and must be protected against attack from the host. This requires both attenuation of adaptive immunity and protection from innate immune defense mechanisms. One of the key innate immune players is complement, and it is important that the fetoplacental unit is not identified as non-self and subjected to complement attack. Adaptation of the complement response must, however, be managed in such a way that maternal protection against infection is not compromised. As the complement system also plays a significant facilitating role in many of the stages of a normal pregnancy, it is also important that any necessary adaptation to accommodate the semi-allogenic aspects of the fetoplacental unit does not compromise this. In this review, both the physiological role of the alternative pathway of complement in facilitating a normal pregnancy, and its detrimental participation in pregnancy-specific disorders, are discussed.

Hypertension Related Co-Morbidities and Complications in Women of Sub-Saharan Africa: A Brief Review.

Hypertension is the leading cause of cardiovascular disease in women, and sub-Saharan African (SSA) countries have some of the highest rates of hypertension in the world. Expanding knowledge of causes, management, and awareness of hypertension and its co-morbidities worldwide is an effective strategy to mitigate its harms, decrease morbidities and mortality, and improve individual quality of life. Hypertensive disorders of pregnancy (HDPs) are a particularly important subset of hypertension, as pregnancy is a major stress test of the cardiovascular system and can be the first instance in which cardiovascular disease is clinically apparent. In SSA, women experience a higher incidence of HDP compared with other African regions. However, the region has yet to adopt treatment and preventative strategies for HDP. This delay stems from insufficient awareness, lack of clinical screening for hypertension, and lack of prevention programs. In this brief literature review, we will address the long-term consequences of hypertension and HDP in women. We evaluate the effects of uncontrolled hypertension in SSA by including research on heart disease, stroke, kidney disease, peripheral arterial disease, and HDP. Limitations exist in the number of studies from SSA; therefore, we will use data from countries across the globe, comparing and contrasting approaches in similar and dissimilar populations. Our review highlights an urgent need to prioritize public health, clinical, and bench research to discover cost-effective preventative and treatment strategies that will improve the lives of women living with hypertension in SSA.

Cardiac Remodeling After Hypertensive Pregnancy Following Physician-Optimized Blood Pressure Self-Management: The POP-HT Randomized Clinical Trial Imaging Substudy.

BACKGROUND: Hypertensive pregnancy disorders are associated with adverse cardiac remodeling, which can fail to reverse in the postpartum period in some women. The Physician-Optimized Postpartum Hypertension Treatment trial demonstrated that improved blood pressure control while the cardiovascular system recovers postpartum associates with persistently reduced blood pressure. We now report the effect on cardiac remodeling. METHODS: In this prospective, randomized, open-label, blinded end point trial, in a single UK hospital, 220 women were randomly assigned 1:1 to self-monitoring with research physician-optimized antihypertensive titration or usual postnatal care from a primary care physician and midwife. Participants were 18 years of age or older, with preeclampsia or gestational hypertension, requiring antihypertensives on hospital discharge postnatally. Prespecified secondary cardiac imaging outcomes were recorded by echocardiography around delivery, and again at blood pressure primary outcome assessment, around 9 months postpartum, when cardiovascular magnetic resonance was also performed. RESULTS: A total of 187 women (101 intervention; 86 usual care) underwent echocardiography at baseline and follow-up, at a mean 258±14.6 days postpartum, of which 174 (93 intervention; 81 usual care) also had cardiovascular magnetic resonance at follow-up. Relative wall thickness by echocardiography was 0.06 (95% CI, 0.07-0.05; P<0.001) lower in the intervention group between baseline and follow-up, and cardiovascular magnetic resonance at follow-up demonstrated a lower left ventricular mass (-6.37 g/m2; 95% CI, -7.99 to -4.74; P<0.001), end-diastolic volume (-3.87 mL/m2; 95% CI, -6.77 to -0.98; P=0.009), and end-systolic volume (-3.25 mL/m2; 95% CI, 4.87 to -1.63; P<0.001) and higher left and right ventricular ejection fraction by 2.6% (95% CI, 1.3-3.9; P<0.001) and 2.8% (95% CI, 1.4-4.1; P<0.001), respectively. Echocardiography-assessed left ventricular diastolic function demonstrated a mean difference in average E/E' of 0.52 (95% CI, -0.97 to -0.07; P=0.024) and a reduction in left atrial volumes of -4.33 mL/m2 (95% CI, -5.52 to -3.21; P<0.001) between baseline and follow-up when adjusted for baseline differences in measures. CONCLUSIONS: Short-term postnatal optimization of blood pressure control after hypertensive pregnancy, through self-monitoring and physician-guided antihypertensive titration, associates with long-term changes in cardiovascular structure and function, in a pattern associated with more favorable cardiovascular outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04273854.

Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia.

BACKGROUND: Preeclampsia is a syndrome of high blood pressure (BP) with end organ damage in late pregnancy that is associated with high circulating soluble VEGF receptor (sFlt1 [soluble Fms-like tyrosine kinase 1]). Women exposed to preeclampsia have a substantially increased risk of hypertension after pregnancy, but the mechanism remains unknown, leaving a missed interventional opportunity. After preeclampsia, women have enhanced sensitivity to hypertensive stress. Since smooth muscle cell mineralocorticoid receptors (SMC-MR) are activated by hypertensive stimuli, we hypothesized that high sFlt1 exposure in pregnancy induces a postpartum state of enhanced SMC-MR responsiveness. METHODS: Postpartum BP response to high salt intake was studied in women with prior preeclampsia. MR transcriptional activity was assessed in vitro in sFlt1-treated SMC by reporter assays and PCR. Preeclampsia was modeled by transient sFlt1 expression in pregnant mice. Two months post-partum, mice were exposed to high salt and then to AngII (angiotensin II) and BP and vasoconstriction were measured. RESULTS: Women exposed to preeclampsia had significantly enhanced salt sensitivity of BP verses those with a normotensive pregnancy. sFlt1 overexpression during pregnancy in mice induced elevated BP and glomerular endotheliosis, which resolved post-partum. The sFlt1 exposed post-partum mice had significantly increased BP response to 4% salt diet and to AngII infusion. In vitro, SMC-MR transcriptional activity in response to aldosterone or AngII was significantly increased after transient exposure to sFlt1 as was aldosterone-induced expression of AngII type 1 receptor. Post-partum, SMC-MR-KO mice were protected from the enhanced response to hypertensive stimuli after preeclampsia. Mechanistically, preeclampsia mice exposed to postpartum hypertensive stimuli develop enhanced aortic stiffness, microvascular myogenic tone, AngII constriction, and AngII type 1 receptor expression, all of which were prevented in SMC-MR-KO littermates. CONCLUSIONS: These data support that sFlt1-induced vascular injury during preeclampsia produces a persistent state of enhanced sensitivity of SMC-MR to activation. This contributes to postpartum hypertension in response to common stresses and supports testing of MR antagonism to mitigate the increased cardiovascular risk in women after PE.

High level 27-HC impairs trophoblast cell invasion and migration via LXR in pre-eclampsia.

INTRODUCTION: To explore the potential impact of 27-hydroxycholesterol (27-HC) on trophoblast cell function in pre-eclampsia. RESULTS: The levels of 27-HC and the expression of CYP27A1 are upregulated in clinical samples of PE. Furthermore, high concentrations of 27-HC can inhibit the invasion and migration ability of trophoblast cells in vitro, and this inhibitory effect is weakened after LXR silencing. In HTR8/SVneo cells treated with 27-HC, the expression of ABCA1/ABCG1 are increased. Finally, we established a mouse model of PE using l-NAME (N-Nitro-l-Arginine Methyl Ester). We found an increase in the levels of 27-HC in the peripheral blood serum of the PE mouse model, and an upregulation of CYP27A1 and LXR expressions in the placenta of the PE mouse model. CONCLUSION: 27-HC inhibits the invasion and migration ability of trophoblast cells by activating the LXR signaling pathway, which is involved in the pathogenesis of Pre-eclampsia(PE).

Dietary patterns during pregnancy and maternal and birth outcomes in women with type 1 diabetes: the Environmental Determinants of Islet Autoimmunity (ENDIA) study.

AIMS/HYPOTHESIS: Dietary patterns characterised by high intakes of vegetables may lower the risk of pre-eclampsia and premature birth in the general population. The effect of dietary patterns in women with type 1 diabetes, who have an increased risk of complications in pregnancy, is not known. The aim of this study was to investigate the relationship between dietary patterns and physical activity during pregnancy and maternal complications and birth outcomes in women with type 1 diabetes. We also compared dietary patterns in women with and without type 1 diabetes. METHODS: Diet was assessed in the third trimester using a validated food frequency questionnaire in participants followed prospectively in the multi-centre Environmental Determinants of Islet Autoimmunity (ENDIA) study. Dietary patterns were characterised by principal component analysis. The Pregnancy Physical Activity Questionnaire was completed in each trimester. Data for maternal and birth outcomes were collected prospectively. RESULTS: Questionnaires were completed by 973 participants during 1124 pregnancies. Women with type 1 diabetes (n=615 pregnancies with dietary data) were more likely to have a 'fresh food' dietary pattern than women without type 1 diabetes (OR 1.19, 95% CI 1.07, 1.31; p=0.001). In women with type 1 diabetes, an increase equivalent to a change from quartile 1 to 3 in 'fresh food' dietary pattern score was associated with a lower risk of pre-eclampsia (OR 0.37, 95% CI 0.17, 0.78; p=0.01) and premature birth (OR 0.35, 95% CI 0.20, 0.62, p<0.001). These associations were mediated in part by BMI and HbA1c. The 'processed food' dietary pattern was associated with an increased birthweight (ß coefficient 56.8 g, 95% CI 2.8, 110.8; p=0.04). Physical activity did not relate to outcomes. CONCLUSIONS/INTERPRETATION: A dietary pattern higher in fresh foods during pregnancy was associated with sizeable reductions in risk of pre-eclampsia and premature birth in women with type 1 diabetes.

In vivo mitochondria-targeted protection against uterine artery vascular dysfunction and remodelling in rodent hypoxic pregnancy.

Gestational hypoxia adversely affects uterine artery function, increasing complications. However, an effective therapy remains unidentified. Here, we show in rodent uterine arteries that hypoxic pregnancy promotes hypertrophic remodelling, increases constrictor reactivity via protein kinase C signalling, and triggers compensatory dilatation via nitric oxide-dependent mechanisms and stimulation of large conductance Ca2+ -activated K+ -channels. Maternal in vivo oral treatment with the mitochondria-targeted antioxidant MitoQ in hypoxic pregnancy normalises uterine artery reactivity and prevents vascular remodelling. From days 6-20 of gestation (term ∼22 days), female Wistar rats were randomly assigned to normoxic or hypoxic (13-14% O2 ) pregnancy ± daily maternal MitoQ treatment (500 µm in drinking water). At 20 days of gestation, maternal, placental and fetal tissue was frozen to determine MitoQ uptake. The uterine arteries were harvested and, in one segment, constrictor and dilator reactivity was determined by wire myography. Another segment was fixed for unbiased stereological analysis of vessel morphology. Maternal administration of MitoQ in both normoxic and hypoxic pregnancy crossed the placenta and was present in all tissues analysed. Hypoxia increased uterine artery constrictor responses to norepinephrine, angiotensin II and the protein kinase C activator, phorbol 12,13-dibutyrate. Hypoxia enhanced dilator reactivity to sodium nitroprusside, the large conductance Ca2+ -activated K+ -channel activator NS1619 and ACh via increased nitric oxide-dependent mechanisms. Uterine arteries from hypoxic pregnancy showed increased wall thickness and MitoQ treatment in hypoxic pregnancy prevented all effects on uterine artery reactivity and remodelling. The data support mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy. KEY POINTS: Dysfunction and remodelling of the uterine artery are strongly implicated in many pregnancy complications, including advanced maternal age, maternal hypertension of pregnancy, maternal obesity, gestational diabetes and pregnancy at high altitude. Such complications not only have immediate adverse effects on the growth of the fetus, but also they can also increase the risk of cardiovascular disease in the mother and offspring. Despite this, there is a significant unmet clinical need for therapeutics that treat uterine artery vascular dysfunction in adverse pregnancy. Here, we show in a rodent model of gestational hypoxia that in vivo oral treatment of the mitochondria-targeted antioxidant MitoQ protects against uterine artery vascular dysfunction and remodelling, supporting the use of mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy.

Pregnancy Complications and Long-Term Mortality in a Diverse Cohort.

BACKGROUND: Pregnancy complications are associated with increased risk of development of cardiometabolic diseases and earlier mortality. However, much of the previous research has been limited to White pregnant participants. We aimed to investigate pregnancy complications in association with total and cause-specific mortality in a racially diverse cohort and evaluate whether associations differ between Black and White pregnant participants. METHODS: The Collaborative Perinatal Project was a prospective cohort study of 48 197 pregnant participants at 12 US clinical centers (1959-1966). The Collaborative Perinatal Project Mortality Linkage Study ascertained participants' vital status through 2016 with linkage to the National Death Index and Social Security Death Master File. Adjusted hazard ratios (aHRs) for underlying all-cause and cause-specific mortality were estimated for preterm delivery (PTD), hypertensive disorders of pregnancy, and gestational diabetes/impaired glucose tolerance (GDM/IGT) using Cox models adjusted for age, prepregnancy body mass index, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions, site, and year. RESULTS: Among 46 551 participants, 45% (21 107 of 46 551) were Black, and 46% (21 502 of 46 551) were White. The median time between the index pregnancy and death/censoring was 52 years (interquartile range, 45-54). Mortality was higher among Black (8714 of 21 107 [41%]) compared with White (8019 of 21 502 [37%]) participants. Overall, 15% (6753 of 43 969) of participants had PTD, 5% (2155 of 45 897) had hypertensive disorders of pregnancy, and 1% (540 of 45 890) had GDM/IGT. PTD incidence was higher in Black (4145 of 20 288 [20%]) compared with White (1941 of 19 963 [10%]) participants. The following were associated with all-cause mortality: preterm spontaneous labor (aHR, 1.07 [95% CI, 1.03-1.1]); preterm premature rupture of membranes (aHR, 1.23 [1.05-1.44]); preterm induced labor (aHR, 1.31 [1.03-1.66]); preterm prelabor cesarean delivery (aHR, 2.09 [1.75-2.48]) compared with full-term delivery; gestational hypertension (aHR, 1.09 [0.97-1.22]); preeclampsia or eclampsia (aHR, 1.14 [0.99-1.32]) and superimposed preeclampsia or eclampsia (aHR, 1.32 [1.20-1.46]) compared with normotensive; and GDM/IGT (aHR, 1.14 [1.00-1.30]) compared with normoglycemic. P values for effect modification between Black and White participants for PTD, hypertensive disorders of pregnancy, and GDM/IGT were 0.009, 0.05, and 0.92, respectively. Preterm induced labor was associated with greater mortality risk among Black (aHR, 1.64 [1.10-2.46]) compared with White (aHR, 1.29 [0.97-1.73]) participants, while preterm prelabor cesarean delivery was higher in White (aHR, 2.34 [1.90-2.90]) compared with Black (aHR, 1.40 [1.00-1.96]) participants. CONCLUSIONS: In this large, diverse US cohort, pregnancy complications were associated with higher mortality nearly 50 years later. Higher incidence of some complications in Black individuals and differential associations with mortality risk suggest that disparities in pregnancy health may have life-long implications for earlier mortality.

Relationship between Androgens and Vascular and Placental Function during Pre-eclampsia.

Hypertensive disorders of pregnancy (HDP) represent a substantial risk to maternal and fetal health. Emerging evidence suggests an association between testosterone and pre-eclampsia (PE), potentially mediated through androgen receptors (AR). Nevertheless, the mechanism driving this association is yet to be elucidated. On the other hand, reports of transgender men's pregnancies offer a limited and insightful opportunity to understand the role of high androgen levels in the development of HDP. In this sense, a literature review was performed from a little over 2 decades (1998-2022) to address the association of testosterone levels with the development of HDP. Furthermore, this review addresses the case of transgender men for the first time. The main in vitro outcomes reveal placenta samples with greater AR mRNA expression. Moreover, ex vivo studies show that testosterone-induced vasorelaxation impairment promotes hypertension. Epidemiological data point to greater testosterone levels in blood samples during PE. Studies with transgender men allow us to infer that exogenous testosterone administration can be considered a risk factor for PE and that the administration of testosterone does not affect fetal development. Overall, all studies analyzed suggested that high testosterone levels are associated with PE.

AC092100.1 promotes angiogenesis in pre-eclampsia through YTHDC2/VEGFA signaling.

Aberrant long non-coding RNA (lncRNA) expression has been shown to be involved in the pathological process of pre-eclampsia (PE), yet only a small portion of lncRNAs has been characterized concerning the function and molecular mechanisms involved in PE. This study aimed to investigate the regulatory mechanism of the lncRNA AC092100.1 (AC092100.1) in angiogenesis in PE. In our study, bioinformatics analysis was performed to screen for differentially expressed lncRNAs between normal subjects and PE patients. The levels of AC092100.1 in placental tissues of patients with or without PE were validated using qRT-PCR. The effect of AC092100.1 overexpression on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) was investigated. The binding of AC092100.1 and YT521-B homology domain-containing 2 (YTHDC2) was predicted and verified. The effect of AC092100.1/YTHDC2 on the expression of vascular endothelial growth factor-A (VEGFA) in HUVECs was determined. Finally, a PE mice model was conducted. Fetal mouse growth, the abundance of mesenchymal morphology markers, including hypoxia-inducible factor 1-alpha (HIF-1α), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), Slug, and Vimentin, and endothelial markers, including placental growth factor (PLGF), CD31, and vascular endothelial (VE)-cadherin, in placental tissues were assessed. Here, we found that AC092100.1 was abnormally downregulated in placental tissues from PE patients. We established that AC092100.1 overexpression promoted HUVEC proliferation, migration, and tube formation in vitro. Mechanistically, AC092100.1 induced the accumulation of YTHDC2 and VEGFA through binding to YTHDC2 in HUVECs. Inhibition of YTHDC2 or VEGFA reversed AC092100.1-promoted tube formation. AC092100.1 overexpression contributed to alleviating fetal growth disorder, decreased levels of sEng, HIF-1α, sFlt-1, Slug, and Vimentin, and increased levels of VEGFA, PLGF, CD31, and VE-cadherin in PE mice. Our findings provided evidence supporting the role of the AC092100.1/YTHDC2/VEGFA axis in regulating angiogenesis, which demonstrated a therapeutic pathway for PE targeting angiogenesis.

Metformin use and preeclampsia risk in women with diabetes: a two-country cohort analysis.

BACKGROUND: Metformin is a hypoglycaemic medication that has been proposed to treat or prevent preeclampsia. Combining national birth data from Scotland and Sweden, we investigated whether metformin used during pregnancy was associated with an altered risk of developing a hypertensive disorder of pregnancy. METHODS: We utilised data from two population-based cohorts: Scotland (2012-2018) and Sweden (2007-2019). Nulliparous women with gestational diabetes or type 2 diabetes who had birth outcome data linked with medications prescribed during pregnancy were included. The association between metformin prescription and hypertensive disorders of pregnancy was characterised using inverse probability weighted regression analysis, adjusting for variables that predict metformin use and potential confounders. Adverse neonatal outcomes were included as secondary outcomes. Results from both countries were then combined in a meta-analysis using a random effects model. RESULTS: The Scottish cohort included 3859 women with gestational diabetes or type 2 diabetes. Of these women, 30.8% (n = 1187) received at least one metformin prescription during pregnancy. For Sweden, 7771 women with gestational diabetes were included where 19.3% (1498) used metformin during pregnancy. Metformin prescription was not associated with an altered risk of any hypertensive disorder of pregnancy (Scotland adjusted relative risk (aRR) 0.88 [95% confidence interval (CI) 0.66-1.19]; Sweden aRR 1.08 [95% CI 0.86-1.37]) or preeclampsia (Scotland aRR 1.02 [95% CI 0.66-1.60]; Sweden aRR 1.00 [95% CI 0.72-1.39]). Combining adjusted results in a meta-analysis produced similar findings, with a pooled RR of 0.98 (95% CI 0.79-1.18) for any hypertensive disorder and RR 1.01 ([95% CI 0.73-1.28]) for preeclampsia. For neonatal outcomes, metformin was associated with a reduced risk of birthweight > 4500 g in Scotland (aRR 0.39 [95% CI 0.21-0.71]) but not in Sweden. There was no association between metformin and preterm birth or birthweight < 3rd or < 10th percentiles. Pooling results from both countries, metformin was not associated with adverse neonatal outcomes, including preterm birth (RR 1.00 [95% CI 0.89-1.13]), and birthweight < 10th percentile (RR 0.82 [95% CI 0.60-1.13]) or < 3rd percentile (RR 0.78 [95% CI 0.41-1.48]). CONCLUSIONS: In this two-country analysis, metformin use in pregnancy among women with diabetes was not associated with an altered risk of developing any hypertensive disorder of pregnancy. In the combined meta-analysis, metformin was not associated with an altered risk of adverse neonatal outcomes.

The long non-coding RPPH1 is decreased in leukocytes and increased in plasma from women developing pre-eclampsia†.

Previous studies show differentially expressed long non-coding RNA present in the placenta from women with pre-eclampsia, potentially playing a vital role in the pathogenesis of the complication. In a published microarray study, Ribonuclease P RNA component H1 was decreased in leukocytes from women that later developed pre-eclampsia. We hypothesized that Ribonuclease P RNA component H1 decreased during pregnancy in women developing pre-eclampsia and important for the development of the complication. We isolated RNA from extracellular vesicles, leukocytes and plasma using blood samples taken at weeks 22-24 and 36-38 in women who subsequently developed pre-eclampsia and from healthy pregnancy. The expression of Ribonuclease P RNA component H1 was quantified using qPCR. Expression of Ribonuclease P RNA component H1 at 22-24 weeks was further examined to investigate its discriminatory potential of subsequent pre-eclampsia and association with clinical markers. We found lower expression of Ribonuclease P RNA component H1 in leukocytes at 22-24 and 36-38 weeks amongst women who subsequent developed pre-eclampsia compared with those who did not, while increased Ribonuclease P RNA component H1 expression was found in plasma at 36-38 weeks. Pre-eclampsia risk factors could not account for this difference in the Ribonuclease P RNA component H1 expression. Prediction of pre-eclampsia at 22-24 weeks using Ribonuclease P RNA component H1 expression in leukocytes in addition to the screening algorithm used today had a significantly better performance. In conclusion, Ribonuclease P RNA component H1 expression in leukocytes was significantly decreased in women with pre-eclampsia, and the expression at 22-24 weeks associated with the subsequent development of pre-eclampsia. Ribonuclease P RNA component H1 in leukocytes may be a useful biomarker for prediction and/or early detection of pre-eclampsia and an unknown regulator of the signaling affecting immune cells.

Adjusting methylation levels with nucleus proportions highlights functional significance of differentially methylated cytosines associated with pre-eclampsia.

Studies on DNA methylation alterations associated with pre-eclampsia (PE) have improved our understanding of the mechanisms underlying this disorder. However, differentially methylated cytosines (DMCs) have not been adjusted for cell-type heterogeneity, hampering the identification of alterations that drive disease risk. Using a reference-based, cell-type deconvolution approach, we estimated the nuclear proportions of 335 placental samples based on DNA methylation data. We found that the nuclei of total trophoblast lineages accounted for more than 80% of the placental samples, with a significant increase in PE placentas. The nuclear proportions of stromal and Hofbauer cells decreased in PE placentas. Our nuclear proportion estimation reflected previous histological knowledge on the changes in cell type proportions in PE placentas. We corrected 2125 DMCs associated with early-onset PE for cell-type heterogeneity by adjusting for the nuclear proportions and observed a notable reduction in the association signals, with 145 probes not reaching epigenome-wide significance. After correction, the top 200 significant DMCs were strongly enriched in active enhancers in trophoblast lineages, whereas 145 non-significant probes were enriched in regions with a quiescent state of chromatin. Our results suggest that future epigenetic studies of PE should focus on functional regulatory sequences.

Outcome-Based Risk Stratification Model for the Diagnosis of Placental Maternal Vascular Malperfusion.

The Amsterdam Consensus Statement introduced the term maternal vascular malperfusion (MVM) to group a constellation of findings associated with impaired maternal-placental circulation. In isolation, these findings are relatively common in placentas from normal gestations, and there is uncertainty on how many, and which, are required. We aimed to determine the criteria essential for MVM diagnosis in correlation with obstetrical outcomes. A total of 200 placentas (100 with a reported diagnosis of MVM and 100 controls matched by maternal age and gravida-para-abortus status) were reviewed to document MVM features. Obstetrical outcomes in the current pregnancy were recorded including hypertension, pre-eclampsia with or without severe features, gestational diabetes, prematurity, fetal growth restriction, and intrauterine fetal demise. On univariate logistic regression analysis, adverse outcome was associated with low placental weight (LPW, <10% percentile for gestational age), accelerated villous maturation (AVM), decidual arteriopathy (DA), infarcts (presence and volume), distal villous hypoplasia, and excess multinucleated trophoblast in basal plate ≥2 mm (all P < .01) but not with retroplacental hemorrhage. In a multivariable model DA, infarcts and AVM were significantly associated with adverse outcomes, whereas LPW showed a trend toward significance. A receiver-operating characteristic curve including these 4 parameters showed good predictive ability (area under the curve [AUC], 0.8256). Based on the probability of an adverse outcome, we recommend consistent reporting of DA, AVM, infarcts, and LPW, summarizing them as "diagnostic of MVM" (DA or AVM plus any other feature, yielding a probability of 65%-97% for adverse obstetrical outcomes) or "suggestive of MVM" (if only 1 feature is present, or only 2 features are infarcts plus LPW, yielding a probability of up to 52%). Other features such as distal villous hypoplasia, excess (≥2 mm) multinucleated trophoblast, and retroplacental hemorrhage can also be reported, and their role in MVM diagnosis should be further studied.

Placental neutrophil reverse trans-migration and maternal serum neutrophil extracellular trap expression in HIV infection co-morbid pre-eclampsia in women of African ancestry.

Neutrophil extracellular traps (NETs) and placental neutrophil reverse transmigration (r-TM) are implicated in the pathogenesis of pre-eclampsia (PE). However, the role of the comorbidity of PE and human immunodeficiency virus (HIV) infection in placental neutrophil r-TM and serum NETs remains unknown. Human placental tissue (n = 160) and serum (n = 80) samples were obtained post-ethical approval and divided by pregnancy type and HIV status and across the study population. Immunohistochemistry and morphometry were performed to localize and quantify junctional adhesion molecule-C (JAM-C) expression as an inverse marker of neutrophil r-TM within placental villi. An enzyme-linked immunosorbent assay (ELISA) was performed to quantify the concentration of citrullinated histone H3 (cit-H3) as a marker of NETs. GraphPad Prism (version 8.0.2) was used to compare the results, and a p value of p < 0.05 was considered statistically significant. The localization of JAM-C was observed on the syncytiotrophoblasts (STBs) and endothelial cells of placental villi. The immunoexpression of JAM-C was elevated in PE vs. normotensive (N) placentae. In the exchange villi, JAM-C immunoexpression was higher in the N+ve vs. N-ve group. However, in PE comorbid HIV infection, JAM-C expression was lower in the PE+ve vs. PE-ve group. Citrullinated histone-H3 concentration was lower in the N+ve vs. N-ve group but elevated in early-onset PE (EOPE)+ve vs. late-onset PE (LOPE)+ve group. These results indicate that PE and HIV-infected placentae individually express elevated JAM-C, manifesting in less neutrophil r-TM. However, in exchange villi of PE comorbid with HIV infection reduced JAM-C enhances neutrophil r-TM, thus supporting the synergistic effect of PE comorbid with HIV.

Oxidative stress biomarkers in pregnancy: a systematic review.

BACKGROUND: This systematic review explores the level of oxidative stress (OS) markers during pregnancy and their correlation with complications. Unlike previous studies, it refrains from directly investigating the role of OS but instead synthesises data on the levels of these markers and their implications for various pregnancy-related complications such as preeclampsia, intrauterine growth restrictions, preterm premature rupture of membranes, preterm labour, gestational diabetes mellitus and miscarriages. METHOD: STUDY DESIGN: Utilizing a systematic review approach, we conducted a comprehensive search across databases, including MEDLINE, CINAHL (EBSCOhost), ScienceDirect, Web of Science, and SCOPUS. Our search encompassed all publication years in English. RESULTS: After evaluating 54,173 records, 45 studies with a low risk of bias were selected for inclusion. This systematic review has underscored the importance of these markers in both physiological and pathological pregnancy states such as preeclampsia, intrauterine growth restrictions, preterm premature rupture of membranes, preterm labour, gestational diabetes mellitus and miscarriages. CONCLUSION: This systematic review provides valuable insights into the role of OS in pregnancy and their connection to complications. These selected studies delved deeply into OS markers during pregnancy and their implications for associated complications. The comprehensive findings highlighted the significance of OS markers in both normal and pathological pregnancy conditions, paving the way for further research in this field.

A comprehensive study of pre-eclampsia in IVF and natural conceptions: clinical phenotypes, perinatal outcomes and neonatal echocardiography.

RESEARCH QUESTION: What differences exist in the phenotypes of pre-eclampsia, perinatal outcomes and neonatal echocardiography between pregnancies conceived naturally and through IVF? DESIGN: Six hundred and ten women diagnosed with pre-eclampsia between January 2002 and December 2022 were included in this study. This research was conducted within the IVF and Maternal-Fetal Medicine Department of Kaohsiung Chang Gung Memorial Hospital, Taiwan. Participants were divided into two groups: those who achieved pregnancy through IVF, and those who conceived naturally. The phenotypes of pre-eclampsia and perinatal outcomes were assessed using a propensity-matched sample (n = 218), along with neonatal echocardiography. RESULTS: After conducting propensity score matching, the natural conception group had a higher prevalence of early-onset pre-eclampsia (53.9% versus 37.7%, P = 0.04) and exhibited more severe features of pre-eclampsia (89.1% versus 69.8%, P = 0.01) compared with the IVF group. Regarding perinatal outcomes, neonates in the IVF group had higher placental weights compared with the natural conception group (580 versus 480 g, P = 0.031). The prevalence of abnormal findings on neonatal echocardiography was similar between the groups. Multivariate analysis showed that greater gestational age at delivery reduced the likelihood of abnormal findings on echocardiography [adjusted risk ratio (aRR) 0.950, P = 0.001], while pregestational diabetes mellitus increased the likelihood of abnormal findings (aRR 1.451, P = 0.044). Septal defects were the most common type of defect, occurring in 16.1% of infants. CONCLUSION: The impact of IVF conception on the severity of pre-eclampsia is not as expected. Neonatal echocardiography revealed a higher prevalence of abnormalities in offspring of women with pre-eclampsia compared with the general population. However, these issues were not linked to the method of conception, suggesting the existence of undisclosed factors that could influence the clinical features and perinatal outcomes of pre-eclampsia.

Let's not abandon programmed frozen embryo transfers yet: a countercurrent perspective.

The countercurrent opinion given in this paper is that the optimal management of frozen embryo transfers (FET) is not a one-size-fits-all matter, but rather one that should be decided after considering all the various parameters and options. This choice should notably encompass patients' individual characteristics - including variable risks of obstetric complications - and weigh out the respective advantages of each FET option in each case. While there may be real advantages for natural-cycle FET in many cases, these need to be balanced against both practical and clinical issues. Contrary to several prevailing, sometimes loudly expressed suggestions, there is not a one single effective approach when it comes to choosing a mode of scheduling FET.

A randomised crossover design study comparing the pharmacokinetics and pharmacodynamics of two single Doses of ORal Aspirin (75 mg v 150mg) in pregnant women at risk of pre-eclampsia (DORA): implications on assessing aspirin response and patient adherence to therapy.

BACKGROUND: Pregnancy is associated with physiological changes that can alter the pharmacokinetic and pharmacodynamic profile of many drugs. Low-dose aspirin is used for pre-eclampsia (PE) prevention; however aspirin's pharmacokinetics and pharmacodynamics are poorly studied in pregnant women. OBJECTIVE: The aim of this study was to compare the pharmacodynamics of two common doses of aspirin (75 and 150 mg) used for PE prevention in high-risk women by examining their effect on thromboxane B2 (TbxB2) inhibition. A secondary objective sought to assess if salicylic acid could be used as means to evaluate adherence to aspirin. STUDY DESIGN: Fourteen pregnant women from a large maternity unit in England, eligible for prophylactic aspirin according to NICE guidance, were recruited into 2 x 2 randomised crossover trial. Blood samples were collected at baseline, 1, 2, 3, 4, 15, 16, 17, 18 and 19-hours post ingestion of either 75 or 150 mg of aspirin with a 7-day washout period. Plasma concentrations of salicylic acid (SA), the primary metabolite of aspirin, were determined using high performance liquid chromatography. Pharmacodynamic response to aspirin was assessed by measuring serum thromboxane B2 (TbxB2) concentrations by an enzyme-linked immunosorbent assay. Analyte data were compared using nonparametric test statistics for paired values (Wilcoxon Signed Rank Test) and areas under serum SA concentration versus time curve (AUC). Pharmacokinetic modelling was used to bridge the data arising from the overnight sampling break. The trial was registered with the ISRCTN (reg number ISRCTN14693054). RESULTS: A single dose of 150 mg of aspirin produced higher plasma exposure of SA in comparison to 75 mg (median SA AUC0-19 16.7 µg*h/ml (IQR 15.2-19.3) vs 6.8 µg*h/ml (IQR 6.1- 8.3), p<0.001). Pharmacokinetic models suggest that plasma SA concentrations could be detected above the maximum concentration recorded at baseline for the first 11 hours after 75 mg and for 12 hours after 150 mg aspirin dosing, providing a time frame to confirm recent aspirin ingestion. The 150 mg aspirin dose produced a greater normalised reduction in serum TbxB2 (median normalised reduction 95.7% (IQR 92.6%- 97.3%) than the 75 mg dose (median normalised reduction 84.6% (IQR 77.3-92.3%), p<0.007. CONCLUSION: Compared to the 75 mg dose, 150 mg of aspirin more effectively inhibits TbxB2, providing rationale for further investigation of effectiveness of higher doses for pre-eclampsia prevention. Despite limitations, measuring serum SA concentration could still be used in future models to test adherence if done within 11-12 hours after ingestion.

Expectant management of preeclampsia with severe features diagnosed at less than 24 weeks.

BACKGROUND: The recent American College of Obstetricians and Gynecologists Practice Bulletin offers no guidance on the management of preeclampsia with severe features at <24 weeks of gestation. Historically, immediate delivery was recommended because of poor perinatal outcomes and high maternal morbidity. Recently, advances in neonatal resuscitation have led to increased survival at periviable gestational ages. OBJECTIVE: This study aimed to report perinatal and maternal outcomes after expectant management of preeclampsia with severe features at <24 weeks of gestation. STUDY DESIGN: This was a retrospective case series of preeclampsia with severe features at <24 weeks of gestation at a level 4 center between 2017 and 2023. Individuals requiring delivery within 24 hours of diagnosis were excluded. Perinatal and maternal outcomes were analyzed. Categorical variables from our database were compared with previously published data using chi-square tests. RESULTS: A total of 41 individuals were diagnosed with preeclampsia with severe features at <24 weeks of gestation. After the exclusion of delivery within 24 hours, 30 individuals (73%) were evaluated. The median gestational age at diagnosis was 22 weeks (interquartile range, 22-23). Moreover, 16% of individuals had assisted reproductive technology, 27% of individuals had chronic hypertension, 13% of individuals had pregestational diabetes mellitus, 30% of individuals had previous preeclampsia, and 73% of individuals had a body mass index of >30 kg/m2. The median latency periods at 22 and 23 weeks of gestation were 7 days (interquartile range, 4-23) and 8 days (interquartile range, 4-13). In preeclampsia with severe features, neonatal survival rates were 44% (95% confidence interval, 3%-85%) at 22 weeks of gestation and 29% (95% confidence interval, 1%-56%) at 23 weeks of gestation. There were 2 cases of acute kidney injury (7%) and 2 cases of pericardial or pleural effusions (7%). Overall perinatal survival at <24 weeks of gestation was 30% in our current study vs 7% in previous reports (P=.02). CONCLUSION: For cases of expectant management of preeclampsia with severe features at <24 weeks of gestation, our findings showed an increased perinatal survival rate with decreased maternal morbidity compared with previously published data. This information may be used when counseling on expectant management of preeclampsia with severe features at <24 weeks of gestation.