Fetal cord plasma herpesviruses and preeclampsia: an observational cohort study.

A previous study suggested that fetal inheritance of chromosomally integrated human herpesvirus 6 (ici-HHV6) is associated with the hypertensive pregnancy disorder preeclampsia (PE). We aimed to study this question utilizing cord plasma samples (n = 1276) of the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort: 539 from a pregnancy with PE and 737 without. We studied these samples and 30 placentas from PE pregnancies by a multiplex qPCR for the DNAs of all nine human herpesviruses. To assess the population prevalence of iciHHV-6, we studied whole-genome sequencing data from blood-derived DNA of 3421 biobank subjects. Any herpes viral DNA was detected in only two (0.37%) PE and one (0.14%) control sample (OR 2.74, 95% CI 0.25-30.4). One PE sample contained iciHHV-6B and another HHV-7 DNA. The control's DNA was of iciHHV-6B; the fetus having growth restriction and preterm birth without PE diagnosis. Placentas showed no herpesviruses. In the biobank data, 3 of 3421 subjects (0.08%) had low level HHV-6B but no iciHHV-6. While iciHHV-6 proved extremely rare, both fetuses with iciHHV-6B were growth-restricted, preterm, and from a pregnancy with maternal hypertension. Our findings suggest that human herpesviruses are not a significant cause of PE, whereas iciHHV-6 may pose some fetal risk.

Deep metagenomic characterization of the gut virome in pregnant women with preeclampsia.

Preeclampsia (PE), a pregnancy-specific syndrome, has been associated with the gut bacteriome. Here, to investigate the impact of the gut virome on the development of PE, we identified over 8,000 nonredundant viruses from the fecal metagenomes of 40 early-onset PE and 37 healthy pregnant women and profiled their abundances. Comparison and correlation analysis showed that PE-enriched viruses frequently connected to Blautia species enriched in PE. By contrast, bacteria linked to PE-depleted viruses were often the Bacteroidaceae members such as Bacteroides spp., Phocaeicola spp., Parabacteroides spp., and Alistipes shahii. In terms of viral function, PE-depleted viruses had auxiliary metabolic genes that participated in the metabolism of simple and complex polysaccharides, sulfur metabolism, lipopolysaccharide biosynthesis, and peptidoglycan biosynthesis, while PE-enriched viruses had a gene encoding cyclic pyranopterin monophosphate synthase, which seemed to be special, that participates in the biosynthesis of the molybdenum cofactor. Furthermore, the classification model based on gut viral signatures was developed to discriminate PE patients from healthy controls and showed an area under the receiver operating characteristic curve of 0.922 that was better than that of the bacterium-based model. This study opens up new avenues for further research, providing valuable insights into the PE gut virome and offering potential directions for future mechanistic and therapeutic investigations, with the ultimate goal of improving the diagnosis and management of PE.IMPORTANCEThe importance of this study lies in its exploration of the previously overlooked but potentially critical role of the gut virome in preeclampsia (PE). While the association between PE and the gut bacteriome has been recognized, this research takes a pioneering step into understanding how the gut virome, represented by over 8,000 nonredundant viruses, contributes to this condition. The findings reveal intriguing connections between PE-enriched viruses and specific gut bacteria, such as the prevalence of Blautia species in individuals with PE, contrasting with bacteria linked to PE-depleted viruses, including members of the Bacteroidaceae family. These viral interactions and associations provide a deeper understanding of the complex dynamics at play in PE.

SARS- CoV-2 infection and oxidative stress in early-onset preeclampsia.

SARS-CoV-2 causes coronavirus disease 2019 (COVID-19) also in pregnant women. Infection in pregnancy leads to maternal and placental functional alterations. Pregnant women with vascular defects such as preeclampsia show high susceptibility to SARS-CoV-2 infection by undefined mechanisms. Pregnant women infected with SARS-CoV-2 show higher rates of preterm birth and caesarean delivery, and their placentas show signs of vasculopathy and inflammation. It is still unclear whether the foetus is affected by the maternal infection with this virus and whether maternal infection associates with postnatal affections. The SARS-CoV-2 infection causes oxidative stress and activation of the immune system leading to cytokine storm and next tissue damage as seen in the lung. The angiotensin-converting-enzyme 2 expression is determinant for these alterations in the lung. Since this enzyme is expressed in the human placenta, SARS-CoV-2 could infect the placenta tissue, although reported to be of low frequency compared with maternal lung tissue. Early-onset preeclampsia (eoPE) shows higher expression of ADAM17 (a disintegrin and metalloproteinase 17) causing an imbalanced renin-angiotensin system and endothelial dysfunction. A similar mechanism seems to potentially account for SARS-CoV-2 infection. This review highlights the potentially common characteristics of pregnant women with eoPE with those with COVID-19. A better understanding of the mechanisms of SARS-CoV-2 infection and its impact on the placenta function is determinant since eoPE/COVID-19 association may result in maternal metabolic alterations that might lead to a potential worsening of the foetal programming of diseases in the neonate, young, and adult.

HIV Associated Preeclampsia: A Multifactorial Appraisal.

Introduction: This review explores angiogenesis, vascular dysfunction, the complement system, RAAS, apoptosis and NETosis as potential pathways that are dysregulated during preeclampsia, HIV infection and ART usage. Results: HIV-1 accessory and matrix proteins are protagonists for the elevation of oxidative stress, apoptosis, angiogenesis, and elevation of adhesion markers. Despite the immunodeficiency during HIV-1 infection, HIV-1 exploits our cellular defence arsenal by escaping cell-mediated lysis, yet HIV-1 infectivity is enhanced via C5a release of TNF-α and IL-6. This review demonstrates that PE is an oxidatively stressed microenvironment associated with increased apoptosis and NETosis, but with a decline in angiogenesis. Immune reconstitution in the duality of HIV-1 and PE by protease inhibitors, HAART and nucleoside reverse transcriptase, affect similar cellular pathways that eventuate in loss of endothelial cell integrity and, hence, its dysfunction. Conclusions: HIV-1 infection, preeclampsia and ARTs differentially affect endothelial cell function. In the synergy of both conditions, endothelial dysfunction predominates. This knowledge will help us to understand the effect of HIV infection and ART on immune reconstitution in preeclampsia.

Incidence de la COVID-19 sur les issues de grossesse: examen systématique et méta-analyse.

CONTEXTE: La nature exacte des répercussions de la maladie à coronavirus 2019 (COVID-19) sur la santé maternelle et néonatale reste à préciser. Nous avons cherché à évaluer l'association entre l'infection par le coronavirus du syndrome respiratoire aigu sévère 2 (SRAS-CoV-2) pendant la grossesse et les issues défavorables de la grossesse. MÉTHODES: Nous avons réalisé une revue systématique et une méta-analyse d'études observationnelles fournissant des données comparatives sur l'infection par le SRAS-CoV-2 et la gravité de la COVID-19 pendant la grossesse. Nous avons sélectionné les études admissibles à partir des bases de données MEDLINE, Embase, ClinicalTrials.gov, medRxiv et Cochrane au 29 janvier 2021, en utilisant les Medical Subject Headings (vedettes matière en médecine) et les expressions clés « severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2 OR coronavirus disease 2019 OR COVID-19 ¼ (coronavirus du syndrome respiratoire aigu sévère 2 ou SRAS-CoV-2 ou maladie à coronavirus 2019 ou COVID-19) AND « pregnancy ¼ (grossesse). Nous avons ensuite évalué la qualité méthodologique de toutes les études retenues avec l'échelle de Newcastle­Ottawa. Les issues primaires étaient la prééclampsie et la naissance prématurée. Les issues secondaires incluaient la mortinaissance et le diabète gestationnel, ainsi que d'autres issues de grossesse. Nous avons calculé des rapports de cotes (RC) sommaires ou des différences moyennes pondérées avec des intervalles de confiance (IC) à 95 % par méta-analyse à effets aléatoires. RÉSULTATS: Nous avons retenu 42 études portant sur 438 548 personnes enceintes. Comparativement à une absence d'infection par le SRAS-CoV-2 pendant la grossesse, le diagnostic de COVID-19 a été associé à la prééclampsie (RC 1,33; IC à 95 % 1,03­1,73), à la naissance prématurée (RC 1,82; IC à 95 % 1,38­2,39) et à la mortinaissance (RC 2,11; IC à 95 % 1,14­3,90). Par rapport à la COVID-19 légère, la COVID-19 grave était fortement associée à la prééclampsie (RC 4,16; IC à 95 % 1,55­11,15), à la naissance prématurée (RC 4,29; IC à 95 % 2,41­7,63), au diabète gestationnel (RC 1,99; IC à 95 % 1,09­3,64) et au faible poids à la naissance (RC 1,89; IC à 95 % 1,14­3,12). INTERPRÉTATION: La COVID-19 pourrait être associée à un risque accru de prééclampsie, de naissance prématurée et d'autres issues défavorables de la grossesse.

Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study.

BACKGROUND: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. OBJECTIVE: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. STUDY DESIGN: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. RESULTS: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32-2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25-2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17-3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99-2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99-5.49) and 6.26 (95% confidence interval, 4.35-9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63-2.86; risk ratio, 2.53; 95% confidence interval, 1.44-4.45; and risk ratio, 2.84; 95% confidence interval, 1.67-4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32-2.35), 2.07 (95% confidence interval, 1.20-3.57), and 2.77 (95% confidence interval, 1.66-4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. CONCLUSION: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.

Serum levels of vasoactive factors in HIV-infected pre-eclamptic women on HAART.

In South Africa, pre-eclampsia (PE) and human immunodeficiency virus (HIV) infection are major causes of pregnancy-related deaths. This study aimed to measure serum levels of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS), soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PlGF) in HIV-infected highly active antiretroviral therapy (HAART)-treated and HIV-uninfected PE and normotensive women to ascertain if HIV/HAART alters their concentrations. Mean sFlt-1 levels were significantly up-regulated in the PE (HIV-uninfected 4.39 ± 1.29; HIV-infected 5.10 ± 1.10 ng/ml) compared to normotensive women (HIV-uninfected 2.59 ± 0.83; HIV-infected 2.20 ± 0.85 ng/ml). Mean PlGF levels were significantly lower in HIV-uninfected PE vs. HIV-infected normotensive women (29.69 ± 4.47 pg/ml vs. 32.86 ± 6.46 pg/ml; p = .002). In conclusion, PE women with HIV exhibited significantly low serum PlGF, ET-1 and eNOS levels. Infection with HIV may have further increased the sFlt-1 levels.IMPACT STATEMENTWhat is already known on this subject? In PE, the numerous identified local and circulating bioactive factors differed in concentrations when compared to normal pregnancy.What do the results of this study add? PE women with HIV exhibited significantly low serum PlGF, ET-1 and eNOS levels as well as increased levels of sFlt-1.What are the implications of these findings for clinical practice and/or further research? Understanding the link between PE, HIV and HAART during pregnancy will improve prognosis, management and treatment strategies for women clinically.

COVID-19 and preeclampsia with severe features at 34-weeks gestation.

The evolving coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a rapid expansion of knowledge on the disease's clinical manifestations, laboratory and radiographic abnormalities, and patient trajectories. One area of particular focus is the effect that this illness may have on pregnancy and maternal-fetal disease. As of April 24, 2020, we identified 55 English language reports in the scientific literature summarizing data for 339 women and 258 fetuses and neonates. The majority of these data have focused on maternal-fetal transmission and neonatal outcomes. One systematic review and meta-analysis including the spectrum of coronaviruses [Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19] in pregnancy noted increased rates of adverse outcomes associated with this group of infections. Here, we report the case of a COVID-19 positive woman presenting to our emergency department (ED) at 34 weeks gestation with preeclampsia. This case highlights the unique diagnostic and therapeutic challenges associated with treating patients with these concomitant diseases.

Maternal HBsAg carriers and pregnancy outcomes: a retrospective cohort analysis of 85,190 pregnancies.

BACKGROUND: Nowadays, a positive HBV carrier status is common among pregnant women, especially in endemic areas (such as China), little is known about the impact of maternal HBV infection on the risk of adverse pregnancy outcomes. Pregnant women with HBV infection often develop obstetric complications, such as pregnancy-induced hypertension (PIH) syndrome, postpartum hemorrhage, and gestational diabetes mellitus (GDM), and their infants often exhibit neonatal complications. METHODS: This study undertook a retrospective cohort analysis to explore the association of HBV carrier status with adverse pregnancy outcomes. A cohort of 85,190 women including 9699 HBsAg-positive and 73,076 HBsAg-negative pregnancies was retrospectively analyzed. RESULTS: It's found that HBsAg-positive pregnancies may result in higher risk of various maternal outcomes such as ICP (OR 3.4,95%CI 2.80 to 4.13), postpartum hemorrhage (OR 1.16,95%CI 1.00 to 1.34). Interestingly, there was a decreased risk of Preeclampsia (OR 0.91,95%CI 0.87 to 0.96), premature rupture of membrane (OR 0.91,95%CI 0.87 to 0.96) and gestational hypertension (OR 0.828,95%CI 0.701 to 0.978). And in vaginal delivery subgroup analysis, It's found that the HBsAg-positive group had a higher risk of placental abruption (OR, 1.44; 95% CI, 1.16-1.79). CONCLUSIONS: The present results suggest that compared with HBV positive pregnancies were more likely to be ICP and postpartum hemorrhage. HBV-positive pregnant women underwent vaginal delivery were more likely to have placental abruption and premature birth compared with HBV-negative women. Obstetricians should be aware of ICP, postpartum hemorrhage, placental abruption and premature birth in HBV-positive pregnant women.

Placental 11ß-HSD2 downregulated in HIV associated preeclampsia.

Preeclampsia (PE) and human immunodeficiency virus (HIV) have been linked with marked increases in maternal stress, resulting in a significant change in placental function ranging from alterations in placental structure to the precise and delicate transformations in placental gene expression. Such changes may lead to altered transport of essential signals to the fetus, which can have long-term impacts on offspring health and consequently affect fetal neurodevelopment. Therefore, this work investigated the role of placental 11ß-hydroxysteroid dehydrogenase types 2 (11ß-HSD2) in HIV associated preeclampsia. The placenta were obtained from 76 pregnant women, which were stratified based on pregnancy type and HIV status into; Normotensive HIV negative, normotensive HIV positive, PE HIV negative and PE HIV positive. The placental tissue was processed for immunocytochemistry and stained with rabbit polyclonal to 11ß-HSD2 Our results showed significant downregulation in the placental expression of 11ß-HSD2 in both the conducting and exchange villi of PE and HIV-positive patients when compared with Normotensive and HIV-negative individuals, respectively. Our results provide inferential evidence for comorbidity of PE and HIV in the downregulation of placental 11ß-HSD2 enzyme function, which mediates the programmed outcomes of an adverse maternal environment during pregnancy and long-term impacts on offspring health and consequently affects fetal neurodevelopment.

Maternal COVID-19 infection, clinical characteristics, pregnancy, and neonatal outcome: A prospective cohort study.

OBJECTIVE: To study the effect of COVID-19 on pregnancy and neonatal outcomes. STUDY DESIGN: Prospective cohort study in a large tertiary maternity unit within a university hospital with an average annual birth of over 10,000 births. We prospectively collected and analysed data for a cohort of 23 pregnant patients including singleton and multiple pregnancies tested positive for COVID-19 between February 2020 and April 2020 inclusive to assess the effect of COVID-19 on pregnancy, and neonatal outcomes. RESULTS: Twenty-three pregnant patients tested positive for COVID-19, delivering 20 babies including a set of twins, with four ongoing pregnancies at the time of manuscript submission. 16/23 (70 %) whom tested positive were patients from Asian (Indian sub-continent) background. The severity of the symptoms ranged from mild in 13/23 (65.2 %) of the patients, moderate in 2/23 (8.7 %), and severe in 8/23 (34.8 %). Four out of total 23 COVID-19 pregnant patients (17.4 %) developed severe adult respiratory distress syndrome complications requiring ICU support, one of whom led to maternal death 1/23 (4.3 %). 11/23 (48 %) of the patients had pre-existing co-morbidities, with morbid obesity 5/23 (21.7 %) and diabetes 4/23 (17.4 %) being the more commonly represented. Of the 23 pregnant patients 19 were in their third trimester of pregnancy and delivered; 7/19 (36.8 %) had preterm birth, 3/19 (15.8 %) developed adult respiratory distress syndrome before delivery, and 2/19 (10.5 %) had pre-eclampsia. 16/19 (84 %) of patients delivered by C-section. Out of the 20 new-borns, 18 were singletons with a set of twin. CONCLUSION: COVID-19 is associated with high prevalence of preterm birth, preeclampsia, and caesarean section compared to non-COVID pregnancies. COVID-19 infection was not found in the newborns and none developed severe neonatal complications.

SARS-CoV-2 infection of the placenta.

BACKGROUNDThe effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.METHODSWe analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through molecular and immunohistochemical assays and by and electron microscopy and measured the maternal antibody response in the blood to this infection.RESULTSSARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the materno-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for the vasculopathy typically associated with preeclampsia.CONCLUSIONThis case demonstrates SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with COVID-19.FUNDINGBeatrice Kleinberg Neuwirth Fund and Fast Grant Emergent Ventures funding from the Mercatus Center at George Mason University. The funding bodies did not have roles in the design of the study or data collection, analysis, and interpretation and played no role in writing the manuscript.

Evaluation of placental chorionic villi histone 2A expression in HIV-infected women with pre-eclampsia.

OBJECTIVE: Chorionic syncytiotrophoblasts (STB) function as an essential regulator of feto-maternal exchange. Therefore, STB actively differentiate to maintain their continuity for barrier function. However, the placental pathology reported in disorders such as pre-eclampsia (PE) threaten the homeostatic differentiation of STB. Since, HIV-1 requires the expression of co-receptors on STB to undergo vertical transmission, the aim of this study was to determine the effect of PE and HIV infection on the different stages of STB maturation [mature (H2A+) versus differentiating (H2A-)] and to immuno-localize and quantify the expression of histone 2A (H2A) i.e., positive (H2A+) and H2A negative (H2A-) nuclei within placental conducting and exchange villi. We also compared the expression of H2A + and H2A- nuclei between normotensive versus PE groups, HIV status and across the study population. STUDY DESIGN: Placental tissue was obtained from pregnant normotensive (n = 30) and pre-eclamptic (n = 30) women after informed written consent. The study groups were further categorized by their HIV status. Immunohistochemistry using the anti-histone 2A (H2A) antibody to identify fully differentiated functional (mature) STB was performed using conventional techniques. Morphometric image analysis was utilized to quantify placental histone H2A immuno-expression in placental exchange and conducting villi. Statistical analysis was performed using GraphPad Prism software. RESULTS: H2A + and H2A- nuclei were immuno-localized within STB of the exchange and conducting villi with H2A- nuclei prominent on the periphery. In the exchange villi, the immuno-expression of H2A + and H2A- nuclei were lower in the PE group compared to the normotensive group (p = 0.0003 and p < 0.0001 respectively). A reduced immuno-expression of H2A+ and H2A- nuclei was lower in exchange villi of HIV+ compared to HIV- placentae (p = 0.0002 and p = 0.0276 respectively). CONCLUSIONS: PE and HIV reduces the percentage of H2A + and H2A- immuno-expression indicative of mature STB and actively differentiating STB respectively. We speculate that the different maturation states of STB and their orientation resultant of PE pathogenesis may be protective against the process of HIV-1 vertical transmission.

Exosomal Th1/Th2 cytokines in preeclampsia and HIV-positive preeclamptic women on highly active anti-retroviral therapy.

Preeclampsia (PE) is a hypertensive disorder of pregnancy which is a leading cause of maternal and foetal morbidity and mortality. Furthermore, HIV/Highly Active Anti-Retroviral Treatment has been associated with the increased risk of preeclampsia due to maternal immune reconstitution, which complicates the clinical diagnosis of PE in these patients. It is therefore necessary to identify biomarkers involved in the pathology of both disorders with the intent to diagnose. Exosomal cytokines represent ideal biomarkers of PE and inflammatory conditions due to their immunomodulatory role in pregnancy. We therefore quantified exosomal Th1 (IL-2 and TNF-α) and Th2 cytokines (IL-10) in maternal circulation. A significant dysregulation in total exosomes, placental-derived exosomes and exosomal cytokines in PE and HIV-positive PE pregnant woman on Highly Active Antiretroviral Treatment (HAART) was observed (p < 0.01). Additionally, we observed a significant shift towards Th1 immunity in PE which becomes amplified in HIV-positive PE pregnant woman on HAART (p < 0.01). Moreover, we show the potential application of exosomal Tumor necrosis factor alpha (TNF-α) as a biomarker of PE and PE in HIV-positive pregnant women on HAART (CI: 95%, LHR > 10, sensitivity of 100% and specificity of 90%). These findings are in support of exosome release and exosome cytokine encapsulation as a tightly regulated process in favour of maintaining the immune microenvironment, which can orchestrate either normal pregnancy, or the pathogenesis of preeclampsia and preeclampsia in HIV/HAART pregnancies.

Angiogenesis, Lymphangiogenesis, and the Immune Response in South African Preeclamptic Women Receiving HAART.

Purpose of the review: This review highlights the role of angiogenesis, lymphangiogenesis, and immune markers in human immunodeficiency virus (HIV)-associated preeclamptic (PE) pregnancies in an attempt to unravel the mysteries underlying the duality of both conditions in South Africa. Recent findings: Studies demonstrate that HIV-infected pregnant women develop PE at a lower frequency than uninfected women. In contrast, women receiving highly active anti-retroviral therapy (HAART) are more inclined to develop PE, stemming from an imbalance of angiogenesis, lymphangiogenesis, and immune response. Summary: In view of the paradoxical effect of HIV infection on PE development, this study examines angiogenesis, lymphangiogenesis, and immune markers in the highly HIV endemic area of KwaZulu-Natal. We believe that HAART re-constitutes the immune response in PE, thereby predisposing women to PE development. This susceptibility is due to an imbalance in the angiogenic/lymphangiogenic/immune response as compared to normotensive pregnant women. Further large-scale studies are urgently required to investigate the effect of the duration of HAART on PE development.

Dysregulation of circulating sTie2 and sHER2 in HIV-infected women with preeclampsia.

OBJECTIVE: This study assesses whether circulating sTie2 and sHER2 are altered in HIV-negative and HIV-positive pregnant normotensive and preeclamptic women. METHODS: Serum samples were obtained from 80 pregnant women, stratified into four groups, namely, HIV-negative normotensives (20); HIV-positive normotensives (20); HIV-negative preeclamptics (20); and HIV-positive preeclamptics (20). The concentration of sTie2 and sHER2 was analyzed by Bio-Plex multiplex immunoassay and generated from a standard curve. RESULTS: sTie2 differed significantly by pregnancy type (p = 0.0403) but not by HIV status (p = 0.5214). sHER2 did not show a significant difference between normotensive and preeclampsia (p = 0.3677) and by HIV status (p = 0.5249). CONCLUSION: Irrespective of HIV status, reduced concentrations of sTie2 were evident in preeclampsia (PE) reflecting a dysregulation of the angiogenic process. sHER2 was similar between pregnancy types, attributable to the oxidative stressed microenvironment which promotes dysregulation of the MAPK and P13K/Akt signaling. HIV status did not influence sTie2 and sHER2 expression, reflecting the immune reconstitution of highly active antiretroviral therapy. sTie2 and sHER2 were not influenced by PE comorbid with HIV infection.

Signalling of ERK1/2, P38MAPK and P90RSK in HIV-associated pre-eclampsia.

Due to their significance in trophoblast differentiation and survival, we evaluated the expression of the cell signalling molecules; Extracellular signal-regulated kinase 1/2 (ERK1/2), Mitogen Activated Protein Kinase 38 (MAPK38) and p90 ribosomal protein S6 kinase (p90 RSK) in buffy coat samples. Eighty pregnant women attending a large hospital in Durban, South Africa were assigned into normotensive and pre-eclamptic groups and further stratified by their HIV status. The degree of phosphorylation of the analytes was determined using the Bio-Plex ProTM Cell Signalling Immunoassay. There was a significantly lower protein concentration of the analytes in the pre-eclamptic versus the normotensive patients, irrespective of HIV status (p < .0001). Also, there was no significant difference in expression of ERK1/2 (p = .4369), p38MAPK (p = .4720) and p90 RSK (p = .0188), according to HIV status. This study demonstrates a down-regulation of ERK1/2, p38MAPK and p90RSK prosurvival markers in pre-eclampsia. This implicates the involvement of the MAPK pathway in the pathogenesis of preeclampsia. Activation of these pathways may prove useful in increasing the body of evidence on prevention of placenta dysfunction and apoptosis. Impact statement What is already known on this subject? Preeclampsia occurring in co-morbidity with HIV is a public health problem among pregnant, black South-African women. There have been conflicting theories regarding the predisposition to the development of preeclampsia as a result of compromised immune response due to HIV infection. In normal pregnancies, the MAPK pathway plays a significant role in molecular processes involved in the cells including survival and differentiation of the placental trophoblast. ERK1/2, p38MAPK and p90RSK are members of the MAPK family, which are pro-apoptotic. Inhibition in the signalling of MAPKs has been found to result in oxidative stress, a process which contributes to the defective trophoblast invasion seen in preeclampsia. What do the results of this study add? The results from this study showed that there is no relationship between HIV infection and an increased predisposition to the development of preeclampsia. In addition, this study highlights a downregulation in the expression of ERK1/2, p38 MAPK and p90RSK in preeclampsia. What are the implications of these findings for clinical practice and/or further research? These findings demonstrate the potential of these analytes as biomarkers for the diagnosis of preeclampsia. Also, this may serve as a framework for further research in the prevention of preeclampsia by elucidating more on the pathway.