Pregnancy Outcomes in Women Screened for Tuberculosis Infection in Swedish Antenatal Care.

BACKGROUND: Tuberculosis (TB) disease has been associated with pregnancy complications. However, the potential impact of TB infection (TBI) on pregnancy outcome is unknown. To investigate this, we conducted a register-based study in immigrant women screened with QuantiFERON assays for TBI in antenatal care in Sweden. METHODS: Women with history of immigration from TB-endemic countries were eligible for inclusion if national identification numbers and available QuantiFERON results obtained during pregnancy from 2014 to 2018 were available. QuantiFERON results were linked to data on maternal characteristics and pregnancy outcomes from the national Pregnancy and Patient Registers. TBI was defined as nil-corrected QuantiFERON result ≥0.35 IU/mL, in the absence of TB disease. Pregnancies in women with TB disease or human immunodeficiency virus were excluded, as were multiplex pregnancies, pregnancies resulting in miscarriage, and pregnancies occurring >10 years after immigration. Odds of defined adverse pregnancy outcomes were compared by maternal TBI status using mixed effects logistic regression with adjustment for maternal age and region of origin. RESULTS: In total, 7408 women with 12 443 pregnancies were included. In multivariable analysis, stillbirth (adjusted odds ratio [AOR], 1.90; 95% confidence interval [CI], 1.13-3.21; P = .016), severe preeclampsia (AOR, 1.62; 95% CI, 1.03-2.56; P = .036), low birthweight (<2500 g; AOR, 1.38; 95% CI, 1.01-1.88; P = .041), and emergency cesarean section (AOR, 1.28; 95% CI, 1.02-1.63; P = .033) were significantly associated with TBI. CONCLUSIONS: Among immigrant women seeking antenatal care in Sweden, TBI was independently associated with adverse pregnancy outcomes. Further studies are needed to corroborate these findings and to explore mechanisms involved.

Childhood atopic disorders in relation to placental changes-A systematic review and meta-analysis.

Fetal programming may arise from prenatal exposure and increase the risk of diseases later in life, potentially mediated by the placenta. The objective of this systematic review was to summarize and critically evaluate publications describing associations between human placental changes and risk of atopic disorders during childhood. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. The inclusion criteria were original research articles or case reports written in English describing a human placental change in relation to disease occurring in offspring during childhood. The MEDLINE and EMBASE databases were searched for eligible studies. Risk of bias (RoB) was assessed using the ROBINS-I tool. The results were pooled both in a narrative way and by a meta-analysis. Nineteen studies were included (n = 12,997 participants). All studies had an overall serious RoB, and publication bias could not be completely ruled out. However, five studies showed that histological chorioamnionitis in preterm-born children was associated with asthma-related problems (pooled odds ratio = 3.25 (95% confidence interval = 2.22-4.75)). In term-born children, a large placenta (≥750 g) increased the risk of being prescribed anti-asthma medications during the first year of life. Placental histone acetylation, DNA methylation, and gene expression differences were found to be associated with different atopic disorders in term-born children. There is some evidence supporting the idea that the placenta can mediate an increased risk of atopic disorders in children. However, further studies are needed to validate the findings, properly control for confounders, and examine potential mechanisms.

Correlation of adenomyosis features to live birth rates after the first IVF/ICSI treatment, when using the revised Morphological Uterus Sonographic Assessment group definitions.

INTRODUCTION: Data regarding the impact of adenomyosis on the outcomes after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment are conflicting. Standardized diagnostic criteria are prerequisites for studying a potential association between adenomyosis and IVF/ICSI treatment outcomes. This study aims to examine the cumulative live birth rate (CLBR) after the first IVF/ICSI treatment in women with or without direct or indirect features of adenomyosis, using the revised Morphological Uterus Sonographic Assessment (MUSA) group definitions. MATERIAL AND METHODS: This was a prospective cohort study of 1037 women aged 25-≤39 years, undergoing their first IVF/ICSI treatment between January 2019 and October 2022. The presence of MUSA features of adenomyosis was assessed prior to treatment start. RESULTS: The CLBR after the first IVF/ICSI treatment was 424/1037 (40.9%, 95% CI, 37.9-43.8) in the total cohort. Women with direct features of adenomyosis had lower CLBR, 25/102 (24.5%; 95% CI, 17.5-31.5) than women without, 399/935 (42.7%; 95% CI, 39.5-45.8), p < 0.001. The adjusted relative risk (aRR) for live birth for women with direct features of adenomyosis compared to women without was 0.62 (95% CI, 0.43-0.88), p = 0.007. Direct features were associated with a higher risk of miscarriage after frozen embryo transfer, aRR 2.88 (95% CI, 1.49-5.57), p = 0.002. Women with indirect features had a lower CLBR [50/188 (26.6%, 95% CI, 20.3-32.9)] than women without [399/935, (42.7%, 95% CI, 39.5-45.8)], aRR 0.58 (95% CI, 0.45-0.75), p < 0.001. For features located in the inner myometrium, the aRR for live birth was 0.29 (95% CI 0.11-0.74), p = 0.010 and for the outer myometrium 2.61 (95% CI 1.42-4.8), p = 0.002. An interrupted junctional zone was the single feature that impacted CLBR the most. CONCLUSIONS: The presence of direct or indirect MUSA features of adenomyosis correlates to reduced live birth rates in women undergoing their first IVF/ICSI treatment. Features located in the inner myometrium, particularly an interrupted junctional zone, reduced the chance of live birth the most, whereas location in the outer myometrium was associated with higher chances of live birth. Systematic ultrasound examinations should be considered for women scheduled for IVF/ICSI treatment, for adequate counseling on the chances of successful treatment.

Placenta-associated adverse pregnancy outcomes in women experiencing mild or severe hyperemesis gravidarum - a systematic review and meta-analysis.

BACKGROUND: Nausea and vomiting in pregnancy (NVP) affects 50-80% of pregnant women and is correlated to the level of human chorionic gonadotropin (hCG). Hyperemesis gravidarum (HG) is a severe condition, with an incidence of 0.2-1.5%, characterized by consistent nausea, vomiting, weight loss and dehydration continuing after the second trimester. AIM: The aim of this systematic review was to investigate a potential correlation between NVP or HG with adverse pregnancy outcomes and hCG levels. METHOD: A systematic search in PubMed, Embase and CINAHL Complete was conducted. Studies on pregnant women with nausea in the first or second trimester, reporting either pregnancy outcomes or levels of hCG were included. The primary outcomes were preterm delivery (PTD), preeclampsia, miscarriage, and fetal growth restriction. Risk of bias was assessed using ROBINS-I. The overall certainty of evidence was assessed using GRADE. RESULTS: The search resulted in 2023 potentially relevant studies; 23 were included. The evidence was uncertain for all outcomes, however women with HG had a tendency to have an increased risk for preeclampsia [odds ratio (OR) 1.18, 95% confidence of interval (CI) 1.03 to 1.35], PTD [OR 1.35, 95% CI 1.13 to 1.61], small for gestational age (SGA) [OR 1.24, 95% CI 1.13 to 1.35], and low birth weight (LBW) [OR 1.35, 95% CI 1.26 to 1.44]. Further, a higher fetal female/male ratio was observed [OR 1.36, 95% CI 1.15 to 1.60]. Meta-analyses were not performed for women with NVP; however, most of these studies indicated that women with NVP have a lower risk for PTD and LBW and a higher risk for SGA, and a higher fetal female/male ratio. CONCLUSION: There may be an increased risk in women with HG and a decreased risk in women with NVP for adverse placenta-associated pregnancy outcomes, however the evidence is very uncertain. TRIAL REGISTRATION: PROSPERO: CRD42021281218.

Maternal and fetal haemopexin and α1-microglobulin concentrations in pre-eclamptic IVF pregnancies according to presence of corpus luteum at embryo transfer.

RESEARCH QUESTION: Do pregnancies with corpus luteum show different maternal and fetal plasma concentrations of the scavenger proteins haemopexin and α1-microglobulin compared with pregnancies without corpus luteum in preeclampsia? DESIGN: Case-control study of 160 singleton pregnancies: 54 naturally conceived, 50 by IVF after fresh embryo transfer or frozen embryo transfer (FET) in natural cycle (presence of corpus luteum) and 56 after fresh oocyte donation or FET in programmed cycles (absence of corpus luteum). Pregnancies were subclassified into normotensive, preeclampsia and severe preeclampsia cases. Heme-scavenger concentrations were measured by ELISA in maternal and cord plasma collected at delivery. RESULTS: After adjustment, maternal haemopexin was higher in IVF with corpus luteum than in naturally conceived pregnancies in normotensive (P = 0.038) and preeclampsia (P = 0.011) populations, and lower in preeclampsia for IVF pregnancies lacking corpus luteum compared with IVF with corpus luteum (P = 0.002). Maternal α1-microglobulin levels were higher in the absence of corpus luteum only in severe cases of preeclampsia compared with naturally conceived pregnancies (P = 0.014) and IVF with corpus luteum pregnancies (P = 0.041). In cord blood, haemopexin was higher in IVF with corpus luteum compared with naturally conceived pregnancies in preeclampsia (P = 0.039) and α1-microglobulin was higher in the group lacking corpus luteum compared with IVF with corpus luteum in the normotensive population (P < 0.001). CONCLUSIONS: The physiological differences shown for these heme-scavengers between pregnancies after embryo transfer in the presence or absence of corpus luteum support the hypothesis that corpus luteum activity could influence perinatal outcomes. Future research is needed on whether applying potential strategies to develop a corpus luteum might reduce the perinatal complications associated with programmed cycles of IVF.

Women´s experiences of preeclampsia as a condition of uncertainty: a qualitative study.

BACKGROUND: Preeclampsia is a severe condition that annually affects about 3-8% of pregnancies worldwide. Preeclampsia is thereby one of the most common pregnancy complications for both mother and child. Despite that, there is limited research exploring the women´s perspective of experiencing preeclampsia. AIM: The aim of this study was to describe women´s experiences of preeclampsia to improve the support and care given during and after pregnancy. METHODS: A qualitative descriptive interview study was undertaken. Nine women, diagnosed with preeclampsia, were recruited from a maternity unit in southern Sweden. The descriptive phenomenological method according to Amadeo Giorgi was used to analyse the data. RESULTS: The women´s experiences of PE were expressed as A condition of uncertainty, meaning that it was an unexpected and unknown situation. This main result consisted of 1) incomprehensible diagnosis message, 2) ambivalent feeling when the unexpected happens, 3) confusing contradictory messages, 4) appreciated support from the midwife, 5) need for continuous information. The nature of preeclampsia can sometimes deteriorate rapidly both for the mother and/or the child, often resulting in conversion from a planned vaginal spontaneous delivery to an emergency Caesarean section. The women narrated diffuse symptoms, and they experienced that they got contradictory information from different health care professionals regarding the severity of their disease. Detailed and continuous information is requested throughout the course of the disease, and the postpartum period. CONCLUSION: This qualitative study reveal a need for improved clinical management. Health care professionals must be aware that women and their partners need detailed, consistent and repeated information about severity and prognosis to diminish the condition of uncertainty, confusion and fearful experience. The clinical implication would be a standardized preeclampsia education for pregnant women early on in the pregnancy, to raise awareness of preeclamptic symptoms. Furthermore, there is a need for harmonized guidelines and individualized support to the woman and her partner both at the antenatal care and the maternity ward and inpatient care at the hospital.

Tuberculosis Infection in Women of Reproductive Age: A Cross-sectional Study at Antenatal Care Clinics in an Ethiopian City.

BACKGROUND: Knowledge on tuberculosis (TB) infection epidemiology in women of reproductive age living in TB-endemic areas is limited. We used a composite definition of TB infection in a cohort of pregnant women recruited in an Ethiopian city as a model for TB exposure patterns, and to identify factors associated with TB infection. METHODS: Women seeking antenatal care at public health facilities underwent structured interviews, physical examination, and QuantiFERON-TB Gold-Plus (QFT) testing. Women with symptoms compatible with TB disease, and all human immunodeficiency virus (HIV)-positive women, were investigated for active TB by sputum bacteriological testing. TB infection (TB+) was defined as either positive QFT (≥ 0.35 IU/mL), self-reported previous active TB, or current active TB. Associations between TB infection and clinical, demographic, and socioeconomic characteristics were tested in multiple logistic regression analysis. RESULTS: Among 1834 participants, 679 (37.0%) met criteria for TB+ (80 [4.4%] previous active TB, 5 [0.3%] current active TB, and 594 [32.4%] QFT-positive without previous or current active TB). Age (annual adjusted odds ratio [AOR], 1.069 [95% confidence interval {CI}, 1.045-1.093]) and HIV infection (AOR, 1.43 [95% CI, 1.033-1.988]) were independently associated with TB+. The relationship with increasing age was only observed in HIV-negative women, and translated to an estimated annual risk of TB infection of 2.1% in HIV-negative women. CONCLUSIONS: TB infection in women of reproductive age in Ethiopia was independently associated with HIV infection and increasing age, suggesting exposure to contagious TB and continuous acquisition of TB infection in this population.

The roles of free iron, heme, haemoglobin, and the scavenger proteins haemopexin and alpha-1-microglobulin in preeclampsia and fetal growth restriction.

BACKGROUND: Preeclampsia (PE) is a complex pregnancy syndrome characterised by maternal hypertension and organ damage after 20 weeks of gestation and is associated with an increased risk of cardiovascular disease later in life. Extracellular haemoglobin (Hb) and its metabolites heme and iron are highly toxic molecules and several defence mechanisms have evolved to protect the tissue. OBJECTIVES: We will discuss the roles of free iron, heme, Hb, and the scavenger proteins haemopexin and alpha-1-microglobulin in pregnancies complicated by PE and fetal growth restriction (FGR). CONCLUSION: In PE, oxidative stress causes syncytiotrophoblast (STB) stress and increased shedding of placental STB-derived extracellular vesicles (STBEV). The level in maternal circulation correlates with the severity of hypertension and supports the involvement of STBEVs in causing maternal symptoms in PE. In PE and FGR, iron homeostasis is changed, and iron levels significantly correlate with the severity of the disease. The normal increase in plasma volume taking place during pregnancy is less for PE and FGR and therefore have a different impact on, for example, iron concentration, compared to normal pregnancy. Excess iron promotes ferroptosis is suggested to play a role in trophoblast stress and lipotoxicity. Non-erythroid α-globin regulates vasodilation through the endothelial nitric oxide synthase pathway, and hypoxia-induced α-globin expression in STBs in PE placentas is suggested to contribute to hypertension in PE. Underlying placental pathology in PE with and without FGR might be amplified by iron and heme overload causing oxidative stress and ferroptosis. As the placenta becomes stressed, the release of STBEVs increases and affects the maternal vasculature.

The effect of Lactiplantibacillus plantarum 299v together with a low dose of iron on iron status in healthy pregnant women: A randomized clinical trial.

INTRODUCTION: Iron deficiency during pregnancy is a global health problem and is associated with adverse pregnancy outcomes. The aim of this randomized, double-blind, placebo-controlled study was to evaluate the effect of Lactiplantibacillus plantarum 299v (Lp299v, 1010 colony forming units), 4.2 mg iron, 12 mg ascorbic acid and 30 µg folic acid (Lp) on iron status in healthy, non-anemic, pregnant Swedish women. MATERIAL AND METHODS: A total of 326 women were randomized to receive Lp (n = 161) or placebo (n = 165) twice daily from gestational week 10-12 until end of pregnancy or until the potential start of iron therapy. The primary endpoint was serum ferritin at week 28. RESULTS: Intake of Lp attenuated the decrease in serum ferritin from baseline to week 28 (p = 0.003) and week 35 (p Ë‚ 0.001) and resulted in reduced prevalence of iron deficiency (59% vs 78%, p = 0.017) and iron deficiency anemia (7.4% vs 21%, p = 0.023) at week 35. Intake of Lp also resulted in beneficial effects on the soluble transferrin receptor (p = 0.011) and total body iron (p Ë‚ 0.001) at week 35. Gestational length and birthweight were comparable between groups. The proportion of women reporting adverse events during the study was comparable between groups. CONCLUSIONS: Intake of Lp from early pregnancy was safe, attenuated the loss of iron stores and improved iron status in healthy pregnant women.

Hypoxia-Induced Alpha-Globin Expression in Syncytiotrophoblasts Mimics the Pattern Observed in Preeclamptic Placentas.

Preeclampsia (PE) is a pregnancy disorder associated with placental dysfunction and elevated fetal hemoglobin (HbF). Early in pregnancy the placenta harbors hematopoietic stem and progenitor cells (HSPCs) and is an extramedullary source of erythropoiesis. However, globin expression is not unique to erythroid cells and can be triggered by hypoxia. To investigate the role of the placenta in increasing globin levels previously reported in PE, flow cytometry, histological and immunostaining and in situ analyses were used on placenta samples and ex vivo explant cultures. Our results indicated that in PE pregnancies, placental HSPC homing and erythropoiesis were not affected. Non-erythroid alpha-globin mRNA and protein, but not gamma-globin, were detected in syncytiotrophoblasts and stroma of PE placenta samples. Similarly, alpha-globin protein and mRNA were upregulated in normal placenta explants cultured in hypoxia. The upregulation was independent of HIF1 and NRF2, the two main candidates of globin transcription in non-erythroid cells. Our study is the first to demonstrate alpha-globin mRNA expression in syncytiotrophoblasts in PE, induced by hypoxia. However, gamma-globin was only expressed in erythrocytes. We conclude that alpha-globin, but not HbF, is expressed in placental syncytiotrophoblasts in PE and may contribute to the pathology of the disease.

Complicated COVID-19 in pregnancy: a case report with severe liver and coagulation dysfunction promptly improved by delivery.

BACKGROUND: It has been proposed that pregnant women and their fetuses may be particularly at risk for poor outcomes due to the coronavirus (COVID-19) pandemic. From the few case series that are available in the literature, women with high risk pregnancies have been associated with higher morbidity. It has been suggested that pregnancy induced immune responses and cardio-vascular changes can exaggerate the course of the COVID-19 infection. CASE PRESENTATION: A 26-year old Somalian woman (G2P1) presented with a nine-day history of shortness of breath, dry cough, myalgia, nausea, abdominal pain and fever. A nasopharyngeal swab returned positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Her condition rapidly worsened leading to severe liver and coagulation impairment. An emergency Caesarean section was performed at gestational week 32 + 6 after which the patient made a rapid recovery. Severe COVID-19 promptly improved by the termination of the pregnancy or atypical HELLP (Hemolysis, Elevated Liver Enzymes and Low Platelet Count) exacerbated by concomitant COVID-19 infection could not be ruled out. There was no evidence of vertical transmission. CONCLUSIONS: This case adds to the growing body of evidence which raises concerns about the possible negative maternal outcomes of COVID-19 infection during pregnancy and advocates for pregnant women to be recognized as a vulnerable group during the current pandemic.

Non-immune hydrops fetalis was rare in Sweden during 1997-2015, but cases were associated with complications and poor prognosis.

AIM: The study was designed to document the incidence of non-immune hydrops fetalis (NIHF) at birth and characterise associated outcomes and obstetric complications. METHODS: Data on more than 1.9 million births were extracted from the Swedish Birth Register for 1997-2015. Pregnancies not affected by NIHF served as controls. National registers on mortality and hospitalisations provided follow-up information. RESULTS: There were 309 cases of NIHF at birth corresponding to an incidence of 1.6 per 10 000, lower than in previous studies. NIHF was more frequent in mothers aged ≥35 years and with a history of stillbirth. Preterm delivery occurred in 77.7% in the NIHF group, including 31.7% before 32 weeks of gestation. Multiple births and Caesarean sections were reported more frequent in the NIHF group. NIHF was associated with poor outcome with 14.6% stillbirths and in 26.5% early neonatal death. Overall, 58.7% of live-born children with NIHF were alive at 12 months compared with 99.7% of controls. The most common causes of death were cardiovascular diseases and thoracic abnormalities. CONCLUSION: NIHF at birth is associated with obstetric complications and poor prognosis for the neonate related to underlying disease. The low incidence of NIHF observed in this study may reflect well-developed antenatal care.

Association of Maternal Regulatory Single Nucleotide Polymorphic CD99 Genotype with Preeclampsia in Pregnancies Carrying Male Fetuses in Ethiopian Women.

Preeclampsia (PE) is a human specific syndrome with unknown etiology causing maternal and fetal morbidities and mortalities. In PE, maternal inflammatory responses are more exaggerated if the fetus is male than female. Other pregnancy complications such as spontaneous abortions are also more common if the fetus is male. Recent transcriptome findings showed an increased expression of CD99 in erythroid cells from male cord blood in PE. The single nucleotide polymorphism (SNP) rs311103, located in a GATA-binding site in a regulatory region on the X/Y chromosomes, governs a coordinated expression of the Xg blood group members CD99 and Xga in hematopoietic cells in a sex-dependent fashion. The rs311103C disrupts the GATA-binding site, resulting in decreased CD99 expression. We aimed to investigate the association between PE and the allele frequency of rs311103 in pregnancies in a fetal sex-dependent fashion. In a case-controlled study, we included 241 pregnant women, i.e., 105 PE cases and 136 normotensive controls. A SNP allelic discrimination analysis was performed on DNA from maternal venous blood and fetal cord blood by qPCR. A statistically significant association was observed between rs311103 allele frequency and PE in mothers carrying male fetuses. Therefore, the rs311103 genotype may play a role in the pathogenesis of PE in a fetal sex-specific manner.

The Role of α1-Microglobulin (A1M) in Erythropoiesis and Erythrocyte Homeostasis-Therapeutic Opportunities in Hemolytic Conditions.

α1-microglobulin (A1M) is a small protein present in vertebrates including humans. It has several physiologically relevant properties, including binding of heme and radicals as well as enzymatic reduction, that are used in the protection of cells and tissue. Research has revealed that A1M can ameliorate heme and ROS-induced injuries in cell cultures, organs, explants and animal models. Recently, it was shown that A1M could reduce hemolysis in vitro, observed with several different types of insults and sources of RBCs. In addition, in a recently published study, it was observed that mice lacking A1M (A1M-KO) developed a macrocytic anemia phenotype. Altogether, this suggests that A1M may have a role in RBC development, stability and turnover. This opens up the possibility of utilizing A1M for therapeutic purposes in pathological conditions involving erythropoietic and hemolytic abnormalities. Here, we provide an overview of A1M and its potential therapeutic effect in the context of the following erythropoietic and hemolytic conditions: Diamond-Blackfan anemia (DBA), 5q-minus myelodysplastic syndrome (5q-MDS), blood transfusions (including storage), intraventricular hemorrhage (IVH), preeclampsia (PE) and atherosclerosis.

The heme and radical scavenger α1-microglobulin (A1M) confers early protection of the immature brain following preterm intraventricular hemorrhage.

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 α1-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.

Cell free hemoglobin in the fetoplacental circulation: a novel cause of fetal growth restriction?

Cell free hemoglobin impairs vascular function and blood flow in adult cardiovascular disease. In this study, we investigated the hypothesis that free fetal hemoglobin (fHbF) compromises vascular integrity and function in the fetoplacental circulation, contributing to the increased vascular resistance associated with fetal growth restriction (FGR). Women with normal and FGR pregnancies were recruited and their placentas collected freshly postpartum. FGR fetal capillaries showed evidence of erythrocyte vascular packing and extravasation. Fetal cord blood fHbF levels were higher in FGR than in normal pregnancies ( P < 0.05) and the elevation of fHbF in relation to heme oxygenase-1 suggests a failure of expected catabolic compensation, which occurs in adults. During ex vivo placental perfusion, pathophysiological fHbF concentrations significantly increased fetal-side microcirculatory resistance ( P < 0.05). fHbF sequestered NO in acute and chronic exposure models ( P < 0.001), and fHbF-primed placental endothelial cells developed a proinflammatory phenotype, demonstrated by activation of NF-κB pathway, generation of IL-1α and TNF-α (both P < 0.05), uncontrolled angiogenesis, and disruption of endothelial cell flow alignment. Elevated fHbF contributes to increased fetoplacental vascular resistance and impaired endothelial protection. This unrecognized mechanism for fetal compromise offers a novel insight into FGR as well as a potential explanation for associated poor fetal outcomes such as fetal demise and stillbirth.-Brook, A., Hoaksey, A., Gurung, R., Yoong, E. E. C., Sneyd, R., Baynes, G. C., Bischof, H., Jones, S., Higgins, L. E., Jones, C., Greenwood, S. L., Jones, R. L., Gram, M., Lang, I., Desoye, G., Myers, J., Schneider, H., Hansson, S. R., Crocker, I. P., Brownbill, P. Cell free hemoglobin in the fetoplacental circulation: a novel cause of fetal growth restriction?

Preeclampsia is Associated with Sex-Specific Transcriptional and Proteomic Changes in Fetal Erythroid Cells.

Preeclampsia (PE) has been associated with placental dysfunction, resulting in fetal hypoxia, accelerated erythropoiesis, and increased erythroblast count in the umbilical cord blood (UCB). Although the detailed effects remain unknown, placental dysfunction can also cause inflammation, nutritional, and oxidative stress in the fetus that can affect erythropoiesis. Here, we compared the expression of surface adhesion molecules and the erythroid differentiation capacity of UCB hematopoietic stem/progenitor cells (HSPCs), UCB erythroid profiles along with the transcriptome and proteome of these cells between male and female fetuses from PE and normotensive pregnancies. While no significant differences were observed in UCB HSPC migration/homing and in vitro erythroid colony differentiation, the UCB HSPC transcriptome and the proteomic profile of the in vitro differentiated erythroid cells differed between PE vs. normotensive samples. Accordingly, despite the absence of significant differences in the UCB erythroid populations in male or female fetuses from PE or normotensive pregnancies, transcriptional changes were observed during erythropoiesis, particularly affecting male fetuses. Pathway analysis suggested deregulation in the mammalian target of rapamycin complex 1/AMP-activated protein kinase (mTORC1/AMPK) signaling pathways controlling cell cycle, differentiation, and protein synthesis. These results associate PE with transcriptional and proteomic changes in fetal HSPCs and erythroid cells that may underlie the higher erythroblast count in the UCB in PE.

Neuroprotective dobutamine treatment upregulates superoxide dismutase 3, anti-oxidant and survival genes and attenuates genes mediating inflammation.

BACKGROUND: Labor subjects the fetus to an hypoxic episode and concomitant adrenomodullary catecholamine surge that may provide protection against the hypoxic insult. The beta1-adrenergic agonist dobutamine protects against hypoxia/aglycemia induced neuronal damage. We aimed to identify the associated protective biological processes involved. RESULTS: Hippocampal slices from 6 days old mice showed significant changes of gene expression comparing slices with or without dobutamine (50 mM) in the following two experimental paradigms: (1) control conditions versus lipopolysacharide (LPS) stimulation and (2) oxygen-glucose deprivation (OGD), versus combined LPS/OGD. Dobutamine depressed the inflammatory response by modifying the toll-like receptor-4 signalling pathways, including interferon regulatory factors and nuclear factor κ B activation in experimental paradigm 1. The anti-oxidant defense genes superoxide dismutase 3 showed an upregulation in the OGD paradigm while thioredoxin reductase was upregulated in LPS paradigm. The survival genes Bag-3, Tinf2, and TMBIM-1, were up-regulated in paradigm 1. Moreover, increased levels of SOD3 were verified on the protein level 24 h after OGD and control stimulation in cultures with or without preconditioning with LPS and dobutamine, respectively. CONCLUSIONS: Neuroprotective treatment with dobutamine depresses expression of inflammatory mediators and promotes the defense against oxidative stress and depresses apoptotic genes in a model of neonatal brain hypoxia/ischemia interpreted as pharmacological preconditioning. We conclude that beta1-adrenoceptor activation might be an efficient strategy for identifying novel pharmacological targets for protection of the neonatal brain.

Urinary Extracellular Vesicles of Podocyte Origin and Renal Injury in Preeclampsia.

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 α1- 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.

Self-gated fetal cardiac MRI with tiny golden angle iGRASP: A feasibility study.

PURPOSE: To develop and assess a technique for self-gated fetal cardiac cine magnetic resonance imaging (MRI) using tiny golden angle radial sampling combined with iGRASP (iterative Golden-angle RAdial Sparse Parallel) for accelerated acquisition based on parallel imaging and compressed sensing. MATERIALS AND METHODS: Fetal cardiac data were acquired from five volunteers in gestational week 29-37 at 1.5T using tiny golden angles for eddy currents reduction. The acquired multicoil radial projections were input to a principal component analysis-based compression stage. The cardiac self-gating (CSG) signal for cardiac gating was extracted from the acquired radial projections and the iGRASP reconstruction procedure was applied. In all acquisitions, a total of 4000 radial spokes were acquired within a breath-hold of less than 15 seconds using a balanced steady-state free precession pulse sequence. The images were qualitatively compared by two independent observers (on a scale of 1-4) to a single midventricular cine image from metric optimized gating (MOG) and real-time acquisitions. RESULTS: For iGRASP and MOG images, good overall image quality (2.8 ± 0.4 and 2.6 ± 1.3, respectively, for observer 1; 3.6 ± 0.5 and 3.4 ± 0.9, respectively, for observer 2) and cardiac diagnostic quality (3.8 ± 0.4 and 3.4 ± 0.9, respectively, for observer 1; 3.6 ± 0.5 and 3.6 ± 0.9, respectively, for observer 2) were obtained, with visualized myocardial thickening over the cardiac cycle and well-defined myocardial borders to ventricular lumen and liver/lung tissue. For iGRASP, MOG, and real time, left ventricular lumen diameter (14.1 ± 2.2 mm, 14.2 ± 1.9 mm, 14.7 ± 1.1 mm, respectively) and wall thickness (2.7 ± 0.3 mm, 2.6 ± 0.3 mm, 3.0 ± 0.4, respectively) showed agreement and no statistically significant difference was found (all P > 0.05). Images with iGRASP tended to have higher overall image quality scores compared with MOG and particularly real-time images, albeit not statistically significant in this feasibility study (P > 0.99 and P = 0.12, respectively). CONCLUSION: Fetal cardiac cine MRI can be performed with iGRASP using tiny golden angles and CSG. Comparison with other fetal cardiac cine MRI methods showed that the proposed method produces high-quality fetal cardiac reconstructions. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:207-217.