Molecular Advances in Preeclampsia and HELLP Syndrome.

Preeclampsia (PE) constitutes one of the principal reasons for maternal and perinatal morbidity and mortality worldwide. The circumstance typically implicates formerly healthful normotensive women, after 20 weeks of gestation, typically withinside the third trimester, without regarded threat elements or past deliveries. PE can be further complicated with hemolysis and thrombocytopenia, leading to the emergence of HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low platelets). Both conditions are classified as hypertensive diseases of pregnancy (HDP), and their pathogenesis has been linked to an excessive maternal inflammatory response, accompanied by enhanced endothelial activation. Several studies have found that in pregnancies affected by PE/HELLP, von Willebrand factor (vWF) antigen levels (vWF:Ag) are significantly elevated, while its cleaving protease (ADAMTS-13, A Disintegrin-like and Metalloprotease with Thrombospondin type 1 motif, member 13) activity is normal to decreased. Furthermore, the higher urine excretion of the terminal complement complex C5b-9, as well as its greater deposition in the placental surface in preeclamptic women, imply that the utero-placental unit's distinctive deficits are intimately tied to disproportionate complement activation. The goal of this updated evaluation is to provide the most up-to-date molecular advances in the pathophysiology of PE/HELLP syndromes. Recent medical data on vWF:Ag levels in patients with PE, ADAMTS-13, and dysregulation of the complement system, are highlighted and evaluated. Furthermore, we discuss the relationship between those entities and the progression of the disease, as well as their significance in the diagnostic process. Finally, considering the difficulties in analyzing and controlling those symptoms in pregnant women, we can provide a current diagnostic and therapeutic algorithm.

Cerebral perfusion pressure and autoregulation in eclampsia-a case control study.

BACKGROUND: Dynamic cerebral autoregulation and cerebral perfusion pressure are altered in pregnancies complicated by preeclampsia compared with normotensive pregnancies, but the connections of dynamic cerebral autoregulation, cerebral perfusion pressure, and cerebral complications in preeclampsia remain unclear. OBJECTIVE: This study aimed to assess dynamic cerebral autoregulation and cerebral perfusion pressure after delivery in women with eclampsia, in women with preeclampsia both with and without severe features, and in normotensive women. STUDY DESIGN: This was a prospective case control study at a large referral hospital in Cape Town, South Africa. The recruitment of participants was done at diagnosis (cases) or at admission for delivery (controls). Transcranial Doppler examinations with continuous noninvasive blood pressure measurements and end-tidal CO2 monitoring were conducted for cases and controls after delivery. Cerebral perfusion pressure and dynamic cerebral autoregulation index were calculated, and values were compared among groups. RESULTS: We included 16 women with eclampsia, 18 women with preeclampsia with severe features, 32 women with preeclampsia without severe features, and 21 normotensive women with uncomplicated pregnancies. Dynamic cerebral autoregulation was depressed in pregnant women with eclampsia; (autoregulation index, 3.9; interquartile range, 3.1-5.2) compared with all other groups (those with preeclampsia with severe features, autoregulation index, 5.6 [interquartile range, 4.4-6.8]; those with preeclampsia without severe features, autoregulation index, 6.8 [interquartile range, 5.1-7.4]; and normotensive controls, autoregulation index, 7.1 [interquartile range, 6.1-7.9]). Pregnant women with eclampsia had increased cerebral perfusion pressure (109.5 mm Hg; interquartile range, 91.2-130.9) compared with those with preeclampsia without severe features and those with normal blood pressure (84 mm Hg [interquartile range, 73.0-122.0] and 80.0 mm Hg [interquartile range, 67.5-92.0], respectively); furthermore, there was no difference in cerebral perfusion pressure between pregnant women with eclampsia and pregnant women with preeclampsia with severe features (109.5 mm Hg [interquartile range, 91.2-130.9] vs 96.5 mm Hg [interquartile range, 75.8-110.5]). CONCLUSION: Cerebral perfusion pressure and dynamic cerebral autoregulation are altered in eclampsia and may be important in the pathophysiological pathway and constitute a therapeutic target in the prevention of cerebral complications in preeclampsia.

Renal capsular vein thrombosis.

A 30-year-old pregnant woman developed postpartum HELLP syndrome. Abdominal computed tomography revealed a high-density vessel structure in contact with the right kidney and connected to the right ovarian vein, suggesting thrombosis in the right inferior renal capsular vein (RCV). RCV thrombosis is a rare thrombotic disorder in postpartum women, and hypercoagulability related to the pregnancy complications may be the predisposing factor. The potential risk for pulmonary embolism in the rare pregnancy-related thrombosis should be recognized.

Síndrome HELLP: controversias y pronóstico / HELLP syndrome: controversies and prognosis

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Casting a Wider NET: An Unusual Cause of Acute Liver Failure in a Pregnant Patient.

We present a case patient in her second trimester of pregnancy who developed acute liver failure from metastatic neuroendocrine tumor (NET). Although she underwent prompt induction of a non-viable fetus due to initial concerns of hemolysis, elevated liver enzymes, and low platelet count syndrome, her liver function continued to deteriorate postpartum. She was subsequently transferred to our institution in order to undergo further evaluation that included a transjugular liver biopsy and subsequent diagnosis of high-grade NET. She was given salvage carboplatin-based chemotherapy, as she was not a liver transplant candidate. Unfortunately, the patient expired from cardiovascular collapse as a component of multiorgan failure.

Pre-eclampsia-like syndrome induced by severe COVID-19: a prospective observational study.

OBJECTIVES: To investigate the incidence of clinical, ultrasonographic and biochemical findings related to pre-eclampsia (PE) in pregnancies with COVID-19, and to assess their accuracy to differentiate between PE and the PE-like features associated with COVID-19. DESIGN: A prospective, observational study. SETTING: Tertiary referral hospital. PARTICIPANTS: Singleton pregnancies with COVID-19 at >20+0  weeks. METHODS: Forty-two consecutive pregnancies were recruited and classified into two groups: severe and non-severe COVID-19, according to the occurrence of severe pneumonia. Uterine artery pulsatility index (UtAPI) and angiogenic factors (soluble fms-like tyrosine kinase-1/placental growth factor [sFlt-1/PlGF]) were assessed in women with suspected PE. MAIN OUTCOME MEASURES: Incidence of signs and symptoms related to PE, such as hypertension, proteinuria, thrombocytopenia, elevated liver enzymes, abnormal UtAPI and increased sFlt-1/PlGF. RESULTS: Thirty-four cases were classified as non-severe and 8 as severe COVID-19. Five (11.9%) women presented signs and symptoms of PE, all five being among the severe COVID-19 cases (62.5%). However, abnormal sFlt-1/PlGF and UtAPI could only be demonstrated in one case. One case remained pregnant after recovery from severe pneumonia and had a spontaneous resolution of the PE-like syndrome. CONCLUSIONS: Pregnant women with severe COVID-19 can develop a PE-like syndrome that might be distinguished from actual PE by sFlt-1/PlGF, LDH and UtAPI assessment. Healthcare providers should be aware of its existence and monitor pregnancies with suspected pre-eclampsia with caution. TWEETABLE ABSTRACT: This study shows that a pre-eclampsia-like syndrome could be present in some pregnancies with severe COVID-19.

Pregnancy-specific liver diseases.

Liver disease presenting in pregnancy may be due to a pregnancy-specific liver disorder, due to previously unrecognised pre-existing liver disease, or de novo liver disorders coincidentally presenting in a pregnant woman. The pregnancy-specific liver diseases can span from mild disease with limited impact on maternal and foetal health to severe disorders that can result in significant morbidity and mortality for mother and foetus. Swift identification of these disorders is essential to allow timely and appropriate management via a multi-disciplinary approach. The pregnancy-specific conditions, including their presentation, investigations, and management are reviewed in this chapter in detail.

The Prognostic Value of Angiogenic Markers in Twin Pregnancies to Predict Delivery Due to Maternal Complications of Preeclampsia.

The sFlt-1 (soluble fms-like tyrosine kinase-1), PlGF (placental growth factor), and their ratio are useful for predicting delivery because of preeclampsia in singleton pregnancies. Evidence on the utility of sFlt-1/PlGF ratio in twin pregnancies is lacking. We aimed to evaluate the predictive value of sFlt-1/PlGF ratio for delivery because of preeclampsia in twins. A retrospective data analysis of 164 twin pregnancies with suspected preeclampsia was performed. The sFlt-1/PlGF ratio, which was known to clinicians, was significantly higher in women who delivered within 1 and 2 weeks compared with those who did not (median: 98.9 and 84.2 versus 23.5 pg/mL, respectively; P<0.001). The area under the curve values sFlt-1/PlGF ratio levels were 0.88 (95% CI, 0.83-0.84) and 0.88 (95% CI, 0.83-0.93) for predicting delivery because of preeclampsia within 1 and 2 weeks of blood sampling, respectively. The predictive accuracy of sFlt-1/PlGF was independent of gestational age at sampling and chorionicity (P>0.100 for interaction). The area under the curve values of sFlt-1/PlGF were significantly higher than for PlGF alone (mean 0.88 and 0.88 versus 0.81 and 0.80) for predicting delivery because of preeclampsia within 1 and 2 weeks of blood sampling (P=0.055 and 0.001, respectively). sFlt-1/PlGF ratio lower than 38 was able to rule-out delivery within 1 and 2 weeks with a negative predictive value of 98.8% and 96.4% for delivery because of preeclampsia within 1 and 2 weeks, respectively. A cutoff of 38 is applicable for ruling out delivery because of preeclampsia in twin pregnancies.

Eculizumab Treatment for Postpartum HELLP Syndrome and aHUS-Case Report.

Preeclampsia is a pregnancy-specific disorder affecting ca 3% of all pregnant women. Preeclampsia is the source of severe pregnancy complications. Later life consequences for mother and infant include increased risk of cardiovascular disease. Preeclampsia is caused by the dysfunction of the endothelium with subsequent activation of complement and coagulation systems. HELLP syndrome is considered to be an extreme complication of preeclampsia but it can also present independently. Diagnostic symptoms in HELLP syndrome are Hemolysis, Elevated Liver enzymes, and Low Platelets. Similar phenotype is present in thrombotic microangiopathies (TMAs) and HELLP syndrome is considered part of the TMA spectrum. Here, we present a case of severe preeclampsia and HELLP syndrome, which exacerbated rapidly and eventually led to need of intensive care, plasma exchange, and hemodialysis. The patient showed signs of hemolysis, disturbance in the coagulation, and organ damage in liver and kidneys. After comprehensive laboratory testing and supportive care, the symptoms did not subside and treatment with complement C5 inhibitor eculizumab was started. Thereafter, the patient started to recover. The patient had pregnancy-induced aHUS. Earlier initiation of eculizumab treatment may potentially shorten and mitigate the disease and hypothetically decrease future health risks of preeclamptic women.

Hematoma hepático subcapsular como complicación del síndrome de HELLP: reporte de caso / Subcapsular hepatic hematoma as a complication of the HELLP syndrome: Case report

Presentamos el caso de una paciente con diagnóstico de hematoma subcapsular hepático como complicación del síndrome de HELLP. Debido al bajo volumen de casos publicados, la conducta terapéutica en esta entidad no ha sido definida con claridad. En el caso presentado, la ejecución pronta de un estudio de imagen fue clave para el establecimiento del diagnóstico. En caso de tratarse de un hematoma sin compromiso hemodinámico, el tratamiento conservador puede ser exitoso, como se demostró en nuestro caso

A case is presented on a patient diagnosed with a hepatic subcapsular haematoma as a complication of the HELLP syndrome. Due to the low volume of published cases, the therapeutic behaviour of this condition has not been clearly defined. In the case presented, the early execution of an imaging study was a key factor in establishing the diagnosis. In the case of a haematoma without haemodynamic compromise, conservative treatment can be successful, as demonstrated in our case

Maternal and perinatal outcomes after caesarean delivery in early and late onset preeclampsia with HIV positive and HIV negative South African Women.

OBJECTIVE: We analyzed the maternal and perinatal outcomes in early onset preeclampsia (EOPE) and late onset preeclampsia (LOPE) pregnant women who had scheduled caesarean deliveries. We sub-analyzed the two categories into HIV positive and HIV negative. PATIENTS AND METHODS: This prospective study was conducted at a regional hospital in Durban, South Africa during 14 months. A total of 14304 deliveries were registered. Out of the 1759 preeclampsia, 351 (19.9%) were EOPE and 1408 (80.1%) were LOPE. Hundred and twenty preeclamptics (n = 120) scheduled for caesarean delivery were selected and divided into two categories namely EOPE (n = 60) and LOPE (n = 60). Each preeclampsia category was then further stratified into HIV positive (n = 30) and HIV negative (n = 30) groups. Maternal demographic, clinical details for preeclampsia, blood laboratory tests, maternal, and perinatal outcomes were recorded. RESULTS: Women with EOPE were older compared to those with LOPE (P = 0.0001). Also the HIV positive women were older compared to the HIV negative groups in both EOPE and LOPE categories (P = 0.03). However, multiparous and primiparous were predominant in EOPE and LOPE categories, respectively (P = 0.00 and P = 0.00). The severity of hypertension and the HIV status did not differentiate the 2 groups. Overall, maternal complications (eclampsia, persistent postpartum hypertension, HELLP syndrome, maternal death) and poor fetal outcomes occurred predominately in EOPE. CONCLUSION: This study confirms the heterogeneity of preeclampsia and shows that the timing of onset of this pregnancy disorder is important to disease severity. Further HIV status influences maternal and neonatal outcome.

[HELLP syndrome and hemolytic uremic syndrome during pregnancy: two disease entities, same causation. Case report and literature review].

Thrombotic microangiopathies (TMA) are a group of diseases that can complicate pregnancy and threaten the lives of both the mother and the fetus. Several conditions can lead to TMA, including thrombotic thrombocytopenic purpura (TTP), HELLP syndrome and hemolytic uremic syndrome (HUS). We describe the case of a 39-year-old woman who presented a HELLP syndrome in the immediate postpartum period. The patient had acute kidney injury (AKI), increased LDH, unmeasurable haptoglobin levels and hypocomplementemia. Her ADAMTS13 value was normal, thus ruling out TTP. Shiga toxin tests were negative, so HUS associated with E. coli was also ruled out. HELLP syndrome and atypical hemolytic-uremic syndrome (aHUS) remained the most probable diagnosis. In the days following childbirth, the patient's transaminase and bilirubin levels normalized while the anemia persisted, as did the AKI, resulting in the institution of dialysis treatment. A diagnosis of aHUS was made and therapy with eculizumab was started. The patient's blood counts progressively improved, urine output was restored, her indices of renal function also concomitantly improved and dialysis was interrupted. A rash appeared after the third administration of eculizumab and the treatment was suspended. The patient is currently being followed up and has not relapsed. At thirteen months after delivery her renal function is normal as are her platelet counts, LDH, haptoglobin levels and proteinuria. Tests for mutations in the genes that regulate complement activity were negative. We believe that childbirth triggered the HELLP syndrome, which in turn brought about and sustained the HUS. In fact, the patient's liver function improved right after delivery, while her kidney injury and hemolysis persisted, and she also had an excellent response to eculizumab. To our knowledge, no other cases of HELLP syndrome associated with haemolytic uremic syndrome during pregnancy have been reported in literature, nor have cases in which treatment with eculizumab was limited to only three administrations.

Risk of eclampsia or HELLP-syndrome by institution availability and place of delivery - A population-based cohort study.

OBJECTIVE: To examine the association between availability of obstetric institutions and risk of eclampsia, HELLP-syndrome, or delivery before 35 gestational weeks in preeclamptic pregnancies. STUDY DESIGN: National population-based retrospective cohort study of deliveries in Norway, 1999-2009 (n = 636738) using data from The Medical Birth Registry of Norway and Statistics Norway. Main exposures were institution availability, measured by travel time to the nearest obstetric institution, and place of delivery. We computed relative risks (RR) with 95% confidence intervals (CI) using travel time ≤1 h as reference. We stratified analyses by parity and preeclampsia, and adjusted for socio-demographic and medical risk factors. Successive deliveries were linked using the national identification number. RESULTS: We identified 1387 eclampsia/HELLP cases (0.2%) and 3004 (0.5%) deliveries before 35 weeks in preeclamptic pregnancies. Nulliparous women living >1 h from any obstetric institution had 50% increased risk of eclampsia/HELLP (0.50 versus 0.35%, adjusted RR 1.5; 95 %CI 1.1-1.9). Parous women living >1 h from emergency institutions had a doubled risk of eclampsia (0.6‰ versus 0.3‰, adjusted RR 2.0; 1.2-3.3). Women without preeclampsia in the present pregnancy or history of preeclampsia constituted all eclampsia/HELLP cases in midwife-led institutions, 39-50% of cases in emergency institutions, and 78% of cases (135/173) in subsequent deliveries. Women with risk factors delivered in the emergency institutions, indicating well-implemented selective referral. CONCLUSION: The study shows the importance of available obstetric institutions. Policymakers and clinicians should consider the distribution of potential benefits and burdens when planning and evaluating the obstetric health service structure.

Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial.

OBJECTIVE: To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35. DESIGN: Randomised, phase III, double blinded international, multicentre clinical trial. SETTING: 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). PARTICIPANTS: 2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses. INTERVENTION: Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation. MAIN OUTCOME MEASURE: The primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks' gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). RESULTS: Pre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes. CONCLUSION: Supplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.

Salvage therapy for acute severe ulcerative colitis during pregnancy.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with an age of onset that affects young people during the peak of their reproductive years. Management of flares of disease during pregnancy can be complex and there are few case reports of pregnant women with acute severe ulcerative colitis (ASUC). We present the case of a 31-year-old pregnant woman who at 16 weeks gestation developed ASUC in the context of primary non-response to infliximab therapy. She subsequently underwent an emergency laparoscopic colectomy after failing to respond to hydrocortisone and cyclosporine salvage therapy. Her pregnancy was further complicated by HELLP (Haemolysis, Elevated liver enzymes and Low Platelets) syndrome resulting in premature delivery at 27 weeks gestation. This case highlights the management issues involved in ASUC during pregnancy and the assessment of disease activity, use of salvage therapies, and provides a framework to approach this complex medical emergency.

Comparison of materno-fetal predictors and short-term outcomes between early and late onset pre-eclampsia in the low-income setting of Douala, Cameroon.

OBJECTIVE: To describe and compare materno-fetal predictors and short-term outcomes of early onset pre-eclampsia (EOPE) and late onset pre-eclampsia (LOPE) in Douala, Cameroon. METHODS: The present prospective hospital-based cross-sectional study included women with pre-eclampsia attending obstetric units at four hospitals in Douala between December 1, 2016, and April 30, 2017. To determine maternal predictors, sociodemographic and medical data were recorded using a pretested questionnaire. Pregnancy outcomes, and maternal and fetal adverse events were recorded. Univariate and multivariate logistic regression analyses were used to examine associations. RESULTS: Of 170 participants, 58 (34.1%) had EOPE and 112 (65.9%) had LOPE. EOPE was associated with higher incidences of chronic hypertension (P=0.027) and history of pre-eclampsia (P=0.003) compared with LOPE. Higher incidences of nulliparity and a different partner from prior pregnancy (P=0.024) were associated with LOPE. Women with EOPE had higher odds of acute kidney injury (odds ratio [OR] 6.67, 95% confidence interval [CI] 1.73-25.73) and HELLP (hemolysis, elevated liver enzyme, low platelets) syndrome (OR 10.47, 95% CI 1.19-91.9), and lower odds of deliveries without perinatal adverse events (OR 0.19, 95% CI 0.09-0.38), compared with patients with LOPE. CONCLUSION: In the low-income setting of Douala, there was a higher rate of LOPE than EOPE. Factors associated with EOPE and LOPE varied, and outcomes were worse for women with EOPE.

[HYPERTENSION OF PREGNANCY ASSOCIATED WITH HYPERGOMOCYSTEINEMIA OF THE FIRST TRIMESTER OF PREGNANCY].

In this study, the association of high homocysteine concentrations (>10 µmol/L) of pregnant women with hypertensive disorders during pregnancy was studied, as well as other complications of pregnancy, such as loss of pregnancy in the first half, premature birth, intrauterine growth retardation, congenital malformations development of the fetus. A single-center prospective cohort study was conducted. Depending on the concentration of homocysteine detected by the immunoenzyme assay with monoclonal antibodies Homocysteine EIA ELISA (Axis-Shield Diagnostics Ltd, Scotland), for a period of up to 14 weeks, the subjects were divided into 2 groups: with high concentrations (>10 µmol/L) and normal levels (<10 µmol/L). We controlled complications of pregnancy: loss of pregnancy in the first half, premature birth, delayed fetal growth, congenital malformations of the fetus, gestational hypertension, mild and severe preeclampsia, eclampsia and HELLP syndrome. The results of the study showed that at a level of homocysteine I trimester >10 µmol/l spontaneous abortion, premature birth, gestational hypertension, mild preeclampsia develop more often. There were no differences in the groups for delaying intrauterine growth of the fetus, congenital malformations, severe preeclampsia.

Germline mutations in the alternative pathway of complement predispose to HELLP syndrome.

BACKGROUND: HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is a severe variant of hypertensive disorders of pregnancy affecting approximately 1% of all pregnancies, and has significant maternal and fetal morbidity. Previously, we showed that upregulation of the alternative pathway of complement (APC) plays a role in HELLP syndrome. We hypothesize that HELLP syndrome follows a 2-hit disease model similar to atypical hemolytic uremic syndrome (aHUS), requiring both genetic susceptibility and an environmental risk factor. Our objective was to perform a comparative analysis of the frequency of APC activation and germline mutations in affected women and to create a predictive model for identifying HELLP syndrome. METHODS: Pregnant women with HELLP syndrome, and healthy controls after 23 weeks of gestation were recruited, along with aHUS and thrombotic thrombocytopenic purpura participants. We performed a functional assay, the mHam, and targeted genetic sequencing in all groups. RESULTS: Significantly more participants with rare germline mutations in APC genes were present in the HELLP cohort compared with controls (46% versus 8%, P = 0.01). In addition, significantly more HELLP participants were positive for the mHam when compared with controls (62% versus 16%, P = 0.009). Testing positive for both a germline mutation and the mHam was highly predictive for the diagnosis of HELLP syndrome. CONCLUSION: HELLP syndrome is characterized by both activation of the APC and frequent germline mutations in APC genes. Similar to aHUS, treatment via complement inhibition to mitigate maternal and fetal morbidity and mortality may be possible. FUNDING: National Heart Lung and Blood Institute grants T32HL007525 and R01HL133113.