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Preeclampsia is a human placental disorder affecting 2-8% of pregnancies worldwide annually, with hypertension and proteinuria appearing after 20 weeks of gestation. The underlying cause is believed to be incomplete trophoblast invasion of the maternal spiral arteries during placentation in the first trimester, resulting in oxidative and nitrative stress as well as maternal inflammation and organ alterations. In the Storkhead box 1 (STOX1) preeclampsia mouse model, pregnant females develop severe and early onset manifestations as seen in human preeclampsia e.g. gestational hypertension, proteinuria, and organ alterations. Here we aimed to evaluate the therapeutic potential of human recombinant alpha-1 microglobulin (rA1M) to alleviate the manifestations observed. Human rA1M significantly reduced the hypertension during gestation and significantly reduced the level of hypoxia and nitrative stress in the placenta. In addition, rA1M treatment reduced cellular damage in both placenta and kidneys, thereby protecting the tissue and improving their function. This study confirms that rA1M has the potential as a therapeutic drug in preeclampsia, and likely also in other pathological conditions associated with oxidative stress, by preserving normal organ function.

Background: Germinal matrix intraventricular hemorrhage (GM-IVH) is associated with cerebro-cerebellar damage in very preterm infants, leading to neurodevelopmental impairment. Penetration, from the intraventricular space, of extravasated red blood cells and extracellular hemoglobin (Hb), to the periventricular parenchyma and the cerebellum has been shown to be causal in the development of brain injury following GM-IVH. Furthermore, the damage has been described to be associated with the cytotoxic nature of extracellular Hb-metabolites. To date, there is no therapy available to prevent infants from developing either hydrocephalus or serious neurological disability. Mechanisms previously described to cause brain damage following GM-IVH, i.e., oxidative stress and Hb-metabolite toxicity, suggest that the free radical and heme scavenger α 1 -microglobulin (A1M) may constitute a potential neuroprotective intervention., Methods: Using a preterm rabbit pup model of IVH, where IVH was induced shortly after birth in pups delivered by cesarean section at E29 (3 days prior to term), we investigated the brain distribution of recombinant A1M (rA1M) following intracerebroventricular (i.c.v.) administration at 24 h post-IVH induction. Further, short-term functional protection of i.c.v.-administered human A1M (hA1M) following IVH in the preterm rabbit pup model was evaluated., Results: Following i.c.v. administration, rA1M was distributed in periventricular white matter regions, throughout the fore- and midbrain and extending to the cerebellum. The regional distribution of rA1M was accompanied by a high co-existence of positive staining for extracellular Hb. Administration of i.c.v.-injected hA1M was associated with decreased structural tissue and mitochondrial damage and with reduced mRNA expression for proinflammatory and inflammatory signaling-related genes induced by IVH in periventricular brain tissue., Conclusions: The results of this study indicate that rA1M/hA1M is a potential candidate for neuroprotective treatment following preterm IVH.

Objective: The aim of this study was to investigate how maternal cell-free fetal hemoglobin and heme impact the scavenger enzyme systems Hemopexin and Heme Oxygenase-1 in patients with preeclampsia (PE). The secondary aims were to evaluate these proteins as biomarkers for severity of the clinical manifestation i.e. hypertension, in early- and late onset PE., Material and Methods: Plasma samples taken within the last 24 h before delivery from 135 patients were analyzed, 89 PE and 46 normal pregnancies. All samples were analyzed for cell-free fetal hemoglobin (HbF), heme, hemopexin enzymatic activity (Hx activity), hemopexin concentration (Hx), and heme oxygenase 1 concentration (HO-1). Logistic regression analysis with ROC-curve analysis was performed to evaluate the possible use as biomarkers for preeclampsia., Results: There were significantly higher levels of HbF (p = 0.01) and heme (0.01) but significantly lower Hx activity (p = 0.02), Hx (p < 0.0001) and HO-1 (p = 0.03) in PE plasma as compared to plasma of normal pregnancies. The Hx activity was significantly inversely correlated (p = 0.04) to the diastolic blood pressure. The HO-1 concentration was significantly inversely correlated to both the systolic and diastolic blood pressure (p = 0.01 and p = 0.003). ROC-curve analysis showed a combined detection rate for these biomarkers of 84% at 10% false positive rate., Conclusions: Increased maternal plasma levels of heme and HbF in PE are associated with decreased HO-1 and hemopexin protein levels as well as reduced hemopexin activity. By measuring the consumption of the scavenger protein Hx, and the proteins in the Hb degradation system, clinical information about the dynamics of the disease can be obtained., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Fetal growth may be impaired by poor placental function or maternal conditions, each of which can influence the transfer of nutrients and oxygen from the mother to the developing fetus. Large-scale studies of metabolites (metabolomics) are key to understand cellular metabolism and pathophysiology of human conditions. Herein, maternal and cord blood plasma samples were used for NMR-based metabolic fingerprinting and profiling, including analysis of the enrichment of circulating lipid classes and subclasses, as well as the number of sub-fraction particles and their size. Changes in phosphatidylcholines and glycoproteins were prominent in growth-restricted fetuses indicating significant alterations in their abundance and biophysical properties. Lipoprotein profiles showed significantly lower plasma concentrations of cholesterol-intermediate density lipoprotein (IDL), triglycerides-IDL and high-density lipoprotein (HDL) in mothers of growth-restricted fetuses compared to controls (p < 0.05). In contrast, growth-restricted fetuses had significantly higher plasma concentrations of cholesterol and triglycerides transporting lipoproteins [LDL, IDL, and VLDL, (p < 0.005; all)], as well as increased VLDL particle types (large, medium and small). Significant changes in plasma concentrations of formate, histidine, isoleucine and citrate in growth-restricted fetuses were also observed. Comprehensive metabolic profiling reveals that both, mother and fetuses of pregnancies complicated with fetal growth restriction have a substantial disruption in lipid metabolism.

Renal histologic expression of the podocyte-specific protein, nephrin, but not podocin, is reduced in preeclamptic compared with normotensive pregnancies. We hypothesized that renal expression of podocyte-specific proteins would be reflected in urinary extracellular vesicles (EVs) of podocyte origin and accompanied by increased urinary soluble nephrin levels (nephrinuria) in preeclampsia. We further postulated that podocyte injury and attendant formation of EVs are related mechanistically to cellfree fetal hemoglobin (HbF) in maternal plasma. Our study population included preeclamptic ( n =49) and normotensive ( n =42) pregnant women recruited at delivery. Plasma measurements included HbF concentrations and concentrations of the endogenous chelators haptoglobin, hemopexin, and α 1- microglobulin. We assessed concentrations of urinary EVs containing immunologically detectable podocyte-specific proteins by digital flow cytometry and measured nephrinuria by ELISA. The mechanistic role of HbF in podocyte injury was studied in pregnant rabbits. Compared with urine from women with normotensive pregnancies, urine from women with preeclamptic pregnancies contained a high ratio of podocin-positive to nephrin-positive urinary EVs (podocin + EVs-to-nephrin + EVs ratio) and increased nephrinuria, both of which correlated with proteinuria. Plasma levels of hemopexin, which were decreased in women with preeclampsia, negatively correlated with proteinuria, urinary podocin + EVs-to-nephrin + EVs ratio, and nephrinuria. Administration of HbF to pregnant rabbits increased the number of urinary EVs of podocyte origin. These findings provide evidence that urinary EVs are reflective of preeclampsia-related altered podocyte protein expression. Furthermore, renal injury in preeclampsia associated with an elevated urinary podocin + EVs-to-nephrin + EVs ratio and may be mediated by prolonged exposure to cellfree HbF., (Copyright © 2017 by the American Society of Nephrology.)

Preeclampsia is a serious pregnancy-specific condition, affecting 10 million women annually worldwide. No specific treatment is currently available. Recent studies have demonstrated abnormal production and accumulation of free fetal hemoglobin in the preeclamptic placenta, and identified subsequent leakage into the maternal circulation as an important factor in the development of preeclampsia. A recombinant version of alpha-1-microglobulin, an endogenous well-characterized heme and radical scavenger, has been developed. Intravenous administration of recombinant alpha-1-microglobulin in animal models has been proved to eliminate or significantly reduce the manifestations of preeclampsia. Recombinant alpha-1-microglobulin has the potential to become the first specific therapy for preeclampsia., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To investigate the cerebrospinal fluid (CSF) proteome of patients with preeclampsia (PE) and normotensive pregnant women, in order to provide a better understanding of brain involvement in PE., Experimental Design: Ninety-eight CSF samples (43 women with PE and 55 normotensive controls) were analyzed by LC-MS/MS proteome profiling. CSF was obtained during the spinal puncture before caesarean delivery., Results: Eight proteins were higher abundant and 17 proteins were lower abundant in patients with PE. The most significantly differentially abundant protein was protein AMBP (alpha-1-microglobulin/bikunin precursor). This finding was validated by performing an ELISA experiment (p = 0.002)., Conclusions and Clinical Relevance: The current study showed a clear difference between the protein profiles of CSF from patients with PE and normotensive pregnant women. Protein AMBP is a precursor of a heme-binding protein that counteracts the damaging effects of free hemoglobin, which may be related to the presence of free hemoglobin in CSF. Protein levels showed correlations with clinical symptoms during pregnancy and postpartum. To our knowledge, this is the first LC-MS/MS proteome profiling study on a unique set of CSF samples from (severe) preeclamptic patients and normotensive pregnant women., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Overproduction of cell-free fetal hemoglobin (HbF) in the preeclamptic placenta has been recently implicated as a new etiological factor of preeclampsia. In this study, maternal serum levels of HbF and the endogenous hemoglobin/heme scavenging systems were evaluated as predictive biomarkers for preeclampsia in combination with uterine artery Doppler ultrasound., Study Design: Case-control study including 433 women in early pregnancy (mean 13.7weeks of gestation) of which 86 subsequently developed preeclampsia. The serum concentrations of HbF, total cell-free hemoglobin, hemopexin, haptoglobin and α1-microglobulin were measured in maternal serum. All patients were examined with uterine artery Doppler ultrasound. Logistic regression models were developed, which included the biomarkers, ultrasound indices, and maternal risk factors., Results: There were significantly higher serum concentrations of HbF and α1-microglobulin and significantly lower serum concentrations of hemopexin in patients who later developed preeclampsia. The uterine artery Doppler ultrasound results showed significantly higher pulsatility index values in the preeclampsia group. The optimal prediction model was obtained by combining HbF, α1-microglobulin and hemopexin in combination with the maternal characteristics parity, diabetes and pre-pregnancy hypertension. The optimal sensitivity for all preeclampsia was 60% at 95% specificity., Conclusions: Overproduction of placentally derived HbF and depletion of hemoglobin/heme scavenging mechanisms are involved in the pathogenesis of preeclampsia. The combination of HbF and α1-microglobulin and/or hemopexin may serve as a prediction model for preeclampsia in combination with maternal risk factors and/or uterine artery Doppler ultrasound., (Copyright © 2016 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Preeclampsia is a pregnancy-related disease afflicting 3-7% of pregnancies worldwide and leads to maternal and infant morbidity and mortality. The disease is of placental origin and is commonly described as a disease of two stages. A variety of preeclampsia animal models have been proposed, but all of them have limitations in fully recapitulating the human disease. Based on the research question at hand, different or multiple models might be suitable. Multiple animal models in combination with in vitro or ex vivo studies on human placenta together offer a synergistic platform to further our understanding of the etiology of preeclampsia and potential therapeutic interventions. The described animal models of preeclampsia divide into four categories (i) spontaneous, (ii) surgically induced, (iii) pharmacologically/substance induced, and (iv) transgenic. This review aims at providing an inventory of novel models addressing etiology of the disease and or therapeutic/intervention opportunities., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Preeclampsia (PE) is a serious pregnancy-related condition that causes severe maternal and fetal morbidity and mortality. Within the recent years, there has been an increasing focus in predicting PE at the end of the first trimester of pregnancy. In this review, literature published between 2011 and 2015 was evaluated. In a total of six biomarker algorithms, for first and early second trimester, the prediction of preeclampsia is discussed. In addition, one randomized clinical trial was included. Several algorithms were based on placental biomarkers such as pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PLGF), and soluble FMS-like tyrosine kinase 1 (s-FLT-1). The algorithms containing these biomarkers showed a high prediction rate (PR) for early onset PE, ranging from 44 to 92 % at 5 % false positive rate (FPR). New biomarkers suggest an alternative model based on free HbF and the heme scavenger alpha-1-microglobulin (A1M) with a prediction rate of 69 % at an FPR of 5 %. Interestingly, this model performs well without uterine artery Doppler pulsatility index (UtAD-PI), which is an advantage particularly if the screening method were to be implemented in developing countries. The randomized clinical trial showed a clear reduction in early onset PE as well as reducing preterm PE if identified high-risk pregnancies were treated with low-dose aspirin. In conclusion, PE prediction is now possible through several prediction algorithms and prophylaxis is beneficial in high-risk cases.

Extracellular fetal hemoglobin (HbF) and adult hemoglobin (HbA) are proinflammatory and generate ROS. Increased plasma levels of extracellular HbF have recently been reported to occur in early preeclampsia. α1-Microglobulin (A1M) is a physiological heme-binding protein and radical scavenger that has been shown to counteract vascular permeability increases induced by HbA in the perfused placenta. The present study was performed to investigate whether HbF and HbA will increase glomerular permeability in vivo and to test whether A1M and tempol, a ROS scavenger, can prevent their effects. Anesthetized Wistar rats were continuously infused intravenously with either HbA, HbF, or cyano-inactivated HbF together with FITC-Ficoll-70/400, inulin, and (51)Cr-labeled EDTA for 2 h. Plasma samples and urine samples (left ureter) were taken repeatedly and analyzed by high-performance size exclusion chromatography to assess glomerular sieving coefficients for Ficoll of radius 10-80 Å. In separate experiments, A1M or tempol was given before and during Hb infusions. Extracellular HbF caused rapid, transient increases in glomerular permeability to large Ficoll molecules (50-80Å), contrary to the effects of HbA and cyano-inactivated HbF. For HbF, glomerular sieving coefficients for Ficoll of radius 60Å increased from 3.85 ± 0.85 × 10(-5) to 2.60 ± 0.96 × 10(-4) at 15 min, changes that were abrogated by tempol and reduced by A1M. In conclusion, our data demonstrate that extracellular HbF, infused systemically, can acutely increase glomerular permeability through inducing oxidative stress.

Purpose of Review: Preeclampsia, one of the leading causes of pregnancy complications, affects 3-7% of pregnant women. This review summarizes the present knowledge of a new potential cause of the disease and suggests a method for its prediction/diagnosis and a possible treatment, both based on the recent findings on the involvement of fetal hemoglobin (HbF) and the heme and radical scavenging protein A1M (alpha-1-microglobulin)., Recent Findings: Gene and protein profiling studies have independently shown that increased amount of free HbF is accumulated in the preeclampsia placenta. As a result of a predominantly oxidative damage to the blood-placenta barrier, HbF leaks over to the maternal blood circulation. Elevated levels can be measured already in the first trimester, and later in pregnancy, the levels correlate with the blood pressure in women with preeclampsia. Ex-vivo data show that the human protein A1M, an endogeneous antioxidation protection protein, can prevent Hb-induced damage to the placenta, restore the blood-placental barrier and prevent maternal tissue damage., Summary: Free HbF may provide both a predictive and a diagnostic clinical biomarker from the first trimester. A1M has the potential as a future pharmacological treatment for preeclampsia.

Objective: The aim of this study was to evaluate fetal hemoglobin (HbF) and α(1)-microglobulin (A1M) in maternal serum as first-trimester biomarkers for preeclampsia (PE)., Study Design: The design was a case-control study. We included 96 patients in the first trimester of pregnancy (60 with PE and 36 controls). Venous serum samples were analyzed for HbF and total hemoglobin (Hb) by enzyme-linked immunosorbent assay and for A1M by radioimmunoassay. Sensitivity and specificity was calculated by logistic regression and receiver operating characteristic curve analysis., Results: The HbF/Hb ratio and A1M concentration were significantly elevated in serum from women with subsequent development of PE (P < .0001). The optimal sensitivity and specificity was obtained using the biomarkers in combination; 69% sensitivity for a 5% screen positive rate and 90% sensitivity for a 23% screen positive rate., Conclusion: The study suggests that HbF/Hb ratio in combination with A1M is predictive biomarkers for PE., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Purpose: preeclampsia (PE) is a severe, multi-system pregnancy disorder of yet unknown cause, missing means of treatment, and our fundamental understanding of the disease is still impaired. The purpose of this discovery study was to define candidate placenta tissue protein biomarker signatures to further decipher the molecular features of PE., Experimental Design: we used recombinant antibody microarrays for multiplexed protein expression profiling of preeclamptic placenta tissue (n=25) versus normal placenta (n=11) targeting mainly immunoregulatory water-soluble proteins and membrane proteins. Furthermore, the three known subgroups of PE were profiled, including women with early onset preeclampsia and late onset preeclampsia, as well as women with PE and bilateral notching and intrauterine growth restrictions., Results: the data showed that the first generation of candidate PE-associated placenta tissue protein signatures were delineated, indicating that PE (receiver operating characteristics (ROC) AUC value of 0.83) and the subgroups thereof (ROC AUC values ≤ 0.91) could be distinguished. Notably, the data implied that all subgroups, but preeclampsia with bilateral notching and IUGR, could be further classified into novel subsets (ROC AUC values of 1.0) displaying different inflammatory signatures., Conclusions and Clinical Relevance: we have taken one step further toward de-convoluting the complex features of PE at the molecular level using affinity proteomics.

Preeclampsia is a major cause of morbidity and mortality during pregnancy. To date, the pathogenesis of the disease is not fully understood. Recent studies show that preeclampsia is associated with overexpression of the hemoglobin genes alpha2 and gamma and accumulation of the protein in the vascular lumen of the placenta. Hypothesizing that cell-free hemoglobin leaks from the placenta into the maternal circulation and contributes to the endothelial damage and symptoms by inducing oxidative stress, we analyzed fetal and adult hemoglobin (HbF, HbA), haptoglobin, oxidation markers, and the heme scavenger and antioxidant alpha(1)-microglobulin in plasma, urine, and placenta in preeclamptic women (n=28) and women with normal pregnancy (n=27). The mean plasma concentrations of HbF, HbA, protein carbonyl groups, membrane peroxidation capacity, and alpha(1)-microglobulin were significantly increased in preeclamptic women. The levels of total plasma Hb correlated strongly with the systolic blood pressure. The plasma haptoglobin concentrations of women with preeclampsia were significantly depressed. Increased amounts of alpha(1)-microglobulin mRNA and protein were found in placenta from preeclamptic women, and the levels of plasma and placenta alpha(1)-microglobulin correlated with the plasma Hb concentrations. The heme-degrading form t-alpha(1)-microglobulin was significantly increased in urine in preeclampsia. These results support the idea that hemoglobin-induced oxidative stress is a pathogenic factor in preeclampsia., (Copyright 2009. Published by Elsevier Inc.)

Objective: To investigate gene expressions for neurohypophyseal and ovarian hormones as well as their receptors in the endometrium of women with primary dysmenorrhoea and healthy subjects at ovulation., Study Design: A group of eight women with moderate to severe dysmenorrhoea and eight healthy subjects were compared in parallel between 18 and 35 years of age, regularly menstruating, non-overweight and nulliparous. The study was performed at The Department of Obstetrics and Gynecology, University Hospital of Lund, Sweden. Endometrial biopsies were taken around the time of ovulation, which was determined by repeated ultrasound examinations. Receptor and gene expressions for oxytocin and vasopressin in the tissue were measured., Results: The gene expression for oxytocin receptor was significantly lower in dysmenorrhoic than in healthy women, in median 1.21 and 3.44 oxytocin-receptor/actin, respectively (p=0.048). The expressions for oxytocin peptide, vasopressin V1a receptor, oestrogen receptor alpha, beta and progesterone receptor did not differ between the two groups. Expression of vasopressin peptide was not detectable., Conclusion: A lower oxytocin receptor gene expression at mid-cycle could be involved in the aetiology of primary dysmenorrhoea. However, the importance of a paracrine effect of oxytocin and its receptor at ovulation warrants further investigation.