Immunosuppressive therapy with tacrolimus is a potential drug candidate for the prevention of unexplained or preeclamptic stillbirths with Th1-dominant immune states: a case series of five patients.

Some of obstetrical complications such as unexplained pregnancy loss and preeclampsia (PE) are associated with maternal-fetal immune abnormalities, leading to uteroplacental dysfunction, insufficient fetal immune tolerance, or fetal rejection. Immunosuppressants with calcineurin inhibitors could be useful for the prevention of these complications by modulating the cellular immune balance by directly inhibiting activated T-helper (Th) 1 and natural killer (NK)/NKT cells. We present our experience with the immunosuppressant tacrolimus in five pregnant women who had a previous pregnancy history of unexplained or preeclamptic stillbirth. Th1 and Th2 cell populations and NK cell activities in peripheral blood were measured as clinical parameters during pregnancy. Case 1-3 achieved suppressions of predominant Th1 immunity and live births without pregnancy-related complications. In case 4, increased tacrolimus dose after a miscarriage resulted in her first live birth; however, she developed PE and severe fetal growth restriction with elevated Th1/Th2 cell ratios at 26 weeks of gestation. Case 5 had a previous history of early onset PE and the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and an emergency cesarean section was needed for maternal safety at 20 weeks of gestation. The course of the next pregnancy was stable under tacrolimus treatment; however, the HELLP syndrome recurred after PE at 33 weeks of gestation. Although an imbalance in the Th1/Th2 cell ratio was not observed during pregnancy, NK cell activity was markedly elevated before delivery. In conclusion, tacrolimus is a potential drug candidate for the prevention of unexplained or preeclamptic stillbirth with Th1-dominant immune states.

Complement-Mediated Disorders in Pregnancy.

Complement-mediated disorders in pregnancy span a large spectrum and have been implicated in all three complement pathways: classical, lectin, and alternative. Our understanding of these disorders in recent years has advanced due to a better understanding of complement regulatory proteins, such as complement factor H, complement factor I, membrane cofactor protein, and thrombomodulin that particularly affect the alternative complement pathway. Enthusiasm in genotyping for mutations that encode these proteins has allowed us to study the presence of genetic variants which may predispose women to develop conditions such as pregnancy-associated hemolytic uremic syndrome (P-aHUS), thrombotic thrombocytopenic purpura, preeclampsia/hemolysis, elevated liver enzymes, low platelets (HELLP), systemic lupus erythematosus/antiphospholipid syndrome, and peripartum cardiomyopathy. The advent of the anti-C5-antibody eculizumab to quench the complement cascade has already proven in small case series to improve maternal kidney outcomes in complement-mediated obstetric catastrophes such as P-aHUS and HELLP. In this review, we will detail the pathogenesis behind these complement-mediated pregnancy disorders, the role of complement variants in disease phenotype, and the most up-to-date experience with eculizumab in this population.

Delivery or expectant management for prevention of adverse maternal and neonatal outcomes in hypertensive disorders of pregnancy: an individual participant data meta-analysis.

OBJECTIVE: Hypertensive disorders affect 3-10% of pregnancies. Delayed delivery carries maternal risks, while early delivery increases fetal risk, so appropriate timing is important. The aim of this study was to compare immediate delivery with expectant management for prevention of adverse maternal and neonatal outcomes in women with hypertensive disease in pregnancy. METHODS: CENTRAL, PubMed, MEDLINE and ClinicalTrials.gov were searched for randomized controlled trials comparing immediate delivery to expectant management in women presenting with gestational hypertension or pre-eclampsia without severe features from 34 weeks of gestation. The primary neonatal outcome was respiratory distress syndrome (RDS) and the primary maternal outcome was a composite of HELLP syndrome and eclampsia. The PRISMA-IPD guideline was followed and a two-stage meta-analysis approach was used. Relative risks (RR) and numbers needed to treat or harm (NNT/NNH) with 95% CI were calculated to evaluate the effect of the intervention. RESULTS: Main outcomes were available for 1724 eligible women. Compared with expectant management, immediate delivery reduced the composite risk of HELLP syndrome and eclampsia in all women (0.8% vs 2.8%; RR, 0.33 (95% CI, 0.15-0.73); I2  = 0%; NNT, 51 (95% CI, 31.1-139.3)) as well as in the pre-eclampsia subgroup (1.1% vs 3.5%; RR, 0.39 (95% CI, 0.15-0.98); I2  = 0%). Immediate delivery increased RDS risk (3.4% vs 1.6%; RR, 1.94 (95% CI 1.05-3.6); I2  = 24%; NNH, 58 (95% CI, 31.1-363.1)), but depended upon gestational age. Immediate delivery in the 35th week of gestation increased RDS risk (5.1% vs 0.6%; RR, 5.5 (95% CI, 1.0-29.6); I2  = 0%), but immediate delivery in the 36th week did not (1.5% vs 0.4%; RR, 3.4 (95% CI, 0.4-30.3); I2 not applicable). CONCLUSION: In women with hypertension in pregnancy, immediate delivery reduces the risk of maternal complications, whilst the effect on the neonate depends on gestational age. Specifically, women with a-priori higher risk of progression to HELLP, such as those already presenting with pre-eclampsia instead of gestational hypertension, were shown to benefit from earlier delivery. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Delayed hemolysis, elevated liver enzymes, low platelet count syndrome in succession of switches of preventive anticoagulant treatment in a 41-year-old patient with a history of recurrent assisted implantation failures: a case report.

BACKGROUND: For the past decades the mean age of primiparae in Western societies is constantly increasing. At the same time, there is a growing demand for assisted reproductive technologies such as in vitro fertilization and intracytoplasmic sperm injection. Subsequently, a higher prevalence of pregnancy-associated diseases such as gestational hypertension and preeclampsia is observed. To improve pregnancy rates after in vitro fertilization/intracytoplasmic sperm injection and to reduce the risk of pregnancy-associated diseases with a cardiovascular pathophysiology, two anticoagulants are the focus of current research: low molecular weight heparin and acetylsalicylic acid (aspirin). CASE PRESENTATION: A 41-year-old white woman, gravida 3, para 0, received low molecular weight heparin to reduce the risk of abortion after five unsuccessful intracytoplasmic sperm injections and two miscarriages. She autonomously discontinued the medication with low molecular weight heparin at 12 weeks and 2 days of gestation and took aspirin instead until 24 weeks and 2 days of gestation as preeclampsia prophylaxis. However, the pregnancy ended with an urgent cesarean section at 27 weeks and 4 days of gestation due to a fast progressing hemolysis, elevated liver enzyme levels, and low blood platelet count syndrome, a potentially life-threatening variant of preeclampsia. CONCLUSION: Based on the current demographic trend toward late-in-life pregnancy it is mandatory to establish clear guidelines concerning preventive treatment options of preeclampsia for patients with risk factors. The establishment of a special first-trimester screening for these women should be discussed. Moreover, it is necessary to raise the awareness among physicians of these contemporary issues to guarantee the best possible medical care.

Pravastatin for prevention of HELLP syndrome: A case report.

RATIONALE: Pravastatin has emerged for prevention and treatment of preeclampsia; no reports are available on pravastatin and HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. PATIENT CONCERNS: The first pregnancy necessitated termination of pregnancy at gestational age (GA) 20+5 for HELLP. Intrauterine fetal death at GA 22+5 occurred in the second pregnancy, whilst on temporizing management of HELLP. DIAGNOSES: Severe, recurrent early-onset HELLP syndrome. INTERVENTIONS: In her fourth pregnancy, pravastatin was commenced at GA 13. OUTCOMES: The course of pregnancy was uncomplicated, and a healthy, appropriate for gestational age fetus was delivered at term. LESSONS: Pravastatin may be effective in prevention of HELLP. The hepatic uptake may be of particular advantage.

High-Dose Methylprednisolone to Prevent Platelet Decline in Preeclampsia: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether early administration of high-dose methylprednisolone limits the fall of platelets in preeclampsia. METHODS: A randomized trial of 180 mg methylprednisolone or placebo administered in divided doses over 36 hours was conducted in women admitted for preeclampsia and platelet counts below 150×10/L in four French academic centers. Patients were not included when platelet counts were below 50×10/L or when immediate delivery was required. The primary study outcome was the proportion of patients with platelet counts above 100×10/L 36 hours after the first dose of study medication. The total sample size needed to detect a 23% difference in the rate of this outcome between groups with a one-tailed α of 0.05 and 90% power was 94 patients. RESULTS: Thirty-six patients were randomly assigned to receive methylprednisolone and 34 placebo between October 2007 and May 2011. Platelet counts above 100×10/L at 36 hours after the first dose of study medication were recorded in 30 (83%) in the active group and 29 (85%) in the placebo group (relative risk 0.98, 95% confidence interval 0.80-1.20; P=.82). The only adverse potentially study-related event was hyperglycemia in one woman allocated to methylprednisolone. CONCLUSION: In women with preeclampsia and platelet counts under 150×10/L, methylprednisolone was not effective in maintaining platelet counts above 100×10/L. CLINICAL TRIAL REGISTRATION: EU Clinical Trials Register, http://clinicaltrialsregister.eu, EudraCT 2006-004881-15-FR.

Doppler hepático na pré-eclâmpsia e na síndrome HELLP / Doppler ultrasonography of the liver in pre-eclampsia and HELLP syndrome

O fígado está entre os múltiplos órgãos que podem ser afetados na pré-eclâmpsia, e a função hepática pode ser gravemente prejudicada na síndrome HELLP. A ultrassonografia com Doppler constitui um método não invasivo que pode ser usado para o estudo da circulação hepática durante a gravidez. Com o objetivo de apresentar as evidências científicas disponíveis sobre as alterações do fluxo hepático na gravidez, foi realizada pesquisa da literatura mundial por meio das bases de dados MEDLINE/PubMed e LILACS. Em estudos de Dopplerfluxometria e Dopplervelocimetria, isoladamente ou associados ao eletrocardiograma e cardiografia por impedância, foram observadas alterações na circulação hepática durante a gravidez complicada por pré?eclâmpsia e síndrome HELLP. Entre os desafios para a pesquisa nesse campo destacamos a necessidade de aperfeiçoamento da técnica de exame, o estabelecimento de curvas de normalidade para as gestantes brasileiras, de indicadores de agravamento da pré?eclâmpsia e a aplicação potencial do método para o estudo da hipertensão crônica na gravidez.(AU)

The liver is among multiple organs that may be affected in pre-eclampsia, and liver function can be impaired in HELLP syndrome. Doppler ultrasonography of the liver provides a noninvasive method to study liver circulation during pregnancy. This paper reviews scientific evidence available in MEDLINE/ Pubmed and LILACS databases. Doppler studies on hepatic blood flow, flow velocities and vascular resistance indices, isolated or combined with Doppler?electrocardiography and impedance cardiography, observed changes in pregnancies complicated by pre?eclampsia and HELLP syndrome. Challenges to this research topic include improvements in Doppler examination techniques, establishment of normal values for Brazilian pregnant women, predictors for severe pre?eclampsia and potential use of hepatic Doppler use in chronic hypertension as well.(AU)

Rheological, hemostaseological changes during immunetherapy for prevention of HELLP-syndrome in a patient with elevated phospholipid antibodies.

OBJECTIVE: Patients with a history of severe obstetric complications in the presence of elevated phospholipid antibodies are at high risk for recurrent obstetric debacle. We report a successful immunologic treatment for prevention of HELLP-Syndrome in subsequent pregnancy in a patient with elevated Phospholipid antibodies, while under rheological and hemostaseological monitoring. METHODS: The patient with prior severe HELLP-Syndrome at term in the presence of reconfirmed elevated phospholipid antibodies in her first pregnancy received pooled immunoglobulins (Sandoglobulin 3 g - Novartis) intravenously for immunological treatment every three weeks in addition to low molecular weight heparin (Clexane 40 mg/d s.c.) and Aspirin (100 mg/d from 2nd trimester) during her subsequent pregnancy. Before each of 10 treatment cycles blood rheological parameters (Red Blood cell {RBC} aggregation stasis E0, low shear E1, RBC - deformability low-, moderate-, and high shear force, plasma viscosity {Pv}), as well as thrombelastometry (ROTEM) and in vitro platelet function (PFA-100) for hemostaseological evaluation was performed. At the same times non-invasive, physical thrombosis screening took place using impedance plethysmography (Filtrass) RESULTS: During pregnancy a constant increase in PV and E1 (>45 S -1) was accompanied by a delayed but continuous increase in RBC deformability beginning at the end of the 2nd trimester. Thrombelastometry revealed a continuous reduction of clot formation time (CFT; extem: 84 to 38 sec) and an increase in maximal clot firmness (MCF; extem: 64 to 78 sec) after TF-induced coagulation activation while MCF and CFT after contact activation (intem) was barely unchanged. Platelet bleeding-time after EPI/Coll stimulation was temporary prolonged by the onset of Aspirin intake (>300 sec) but normalized soon after 20th gestational week, while ADP/Coll stimulation revealed a trend towards prolonged bleeding times at the same time. There was a strong and statistically significant inverse correlation between E1 and TF induced CFT (r =-0.82; p = 0.002) and a positive correlation between E1 and TF induced MCF (r = 0.89; p <  0.001), while the correlation between E1 and contact activated CFT and MCF was weak or absent, respectively. Until GW 38th routine laboratory- (Platelet-count, Haptoglobin, liver enzymes) and clinical findings remained normal, without evidence of HELLP-Syndrome reoccurrence or development of thrombosis. CONCLUSIONS: During immunotherapy in this high risk patient HELLP-Syndrome did not reoccur. The aggregability of RBC was closely related with the formation speed and firmness of clot after TF activated coagulation but not after contact activated coagulation. At the beginning of 3rd trimester RBC aggregation remained dramatically higher as compared to the normal value range of pregnant women found in a large recent trial which may have been an early indicator of imminent HELLP-Syndrome.

Pre-eclampsia, severe pre-eclampsia and hemolysis, elevated liver enzymes and low platelets syndrome: what is new?

Pre-eclampsia and eclampsia have been known to us for centuries. Significant improvements have been made in our knowledge of the disease, however, delivery remains the only effective form of treatment. There is widespread variation of practice in the management of hypertensive disease in pregnancy, which may lead to substandard care. The use of aspirin in preventing pre-eclampsia, the lack of correlation between urinary protein and adverse outcome, and the ineffectiveness of corticosteroids in the management of hemolysis and elevated liver enzymes and low platelets syndrome are a few of the developments that will alter the way this condition is managed. This article aims to provide a general overview of pre-eclampsia, eclampsia and hemolysis, hemolysis and elevated liver enzymes and low platelets syndrome supported by the latest evidence, which will help the care provider adopt a focused approach and use the latest knowledge to understand and manage this old condition.

[Treatment of severe preeclampsia: until when and for what risks/benefits?]. / Traitement de la prééclampsie sévère: jusqu' où, et pour quels risques/bénéfices?

The four major hypertensive disorders related to pregnancy are preeclampsia, chronic hypertension, preeclampsia superimposed upon chronic hypertension, and gestational hypertension. The development of hypertension and proteinuria in pregnancy is usually due to preeclampsia, particularly in a primigravida. These findings typically become apparent in the latter part of the third trimester and progress until delivery, but some women develop symptoms in the latter half of the second trimester, or intrapartum, or the early postpartum period. Preeclampsia is characterized as mild or severe. Severe hypertension, coagulopathy, thrombocytopenia, liver function abnormalities, and fetal growth restriction are features of severe disease. Laboratory evaluation should assess haemoglobin/hematocrit and platelet count, renal and hepatic function, as well as assessment of fetal well-being and growth. Timing of delivery is based upon gestational age, maternal and fetal condition, and the severity of preeclampsia. Maternal end organ dysfunction and nonreassuring tests of fetal well-being are indications for delivery at any gestational age. Antihypertensive treatment aims at protecting the mother from severe hypertensive encephalopathy, but may jeopardize the fetus. We recommend antenatal corticosteroids (betamethasone) be given to women with preeclampsia at 26 to 34 weeks of gestation. Magnesium sulfate is more effective than phenytoin for prevention of eclamptic seizures.

[Latest developments: management and treatment of preeclampsia]. / Etat des connaissances: prise en charge thérapeutique de la prééclampsie.

Preeclampsia is defined as the association of pregnancy-induced hypertension and proteinuria of 300 mg/24h or more after 20 weeks gestation. It complicates 0.5 to 7% of pregnancies. It is a severe complication of pregnancy, which leads to persisting fetal morbidity and mortality. It is also responsible for maternal morbidity as placental abruption, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and eclampsia. Without treatment, maternal risks are high. Once the disease is confirmed, the treatment consists of ending the pregnancy. Corticosteroids for lung maturity have to be prioritized depending on the term. Antihypertensive drugs are used to limit maternal complications, in particular, in neurological form. Calcium pump inhibitors are increasingly used as a first line choice. Magnesium sulfate, which is probably not used enough in France, needs to be administered with care and strict monitoring. It can be used to prevent a recurrence of eclamptic fits or in the context of early severe preeclampsia with neurological irritability where an eclamptic fit seems imminent. Preventive treatment of preeclampsia consists essentially of low dose aspirin. The efficacy of this treatment is real but moderate. It decreases the risk of recurrence of preeclampsia by 10 to 15%, of prematurity by 8% and of perinatal mortality by 14%. These figures were recently corrected to 10% for the risk of recurrence of preeclampsia: RR=0.95; 90% CI; (0.84-0.97) and prematurity: RR=0.95; 90%CI; (0.83-0.98). It seems that it has no significant effect on intra-uterine growth restriction (IUGR) and perinatal death prevention. For the main outcome of preeclampsia, there was no evidence that women in any of subgroups as preexisting renal disease, preexisting diabetes or hypertension benefited more or less from the use of antiplatelet agents than those in any other subgroup.

Usefulness of a placental profile in high-risk pregnancies.

OBJECTIVE: Test the hypothesis that a placental function profile can reassure most high-risk women with normal test results yet accurately can identify a subset of women who are destined for major complications that will be attributable to placental disease. STUDY DESIGN: This was a prospective study of 212 high-risk pregnancies that used the placental profile (16- to 18-week maternal serum screening, 18- to 23-week uterine artery Doppler imaging, and placental morphologic condition). Odds ratios (95% CI) were derived for intrauterine fetal death (IUFD), preterm delivery at < 34 weeks of gestation, preeclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome (HELLP) syndrome, small for gestational age delivery, and early-onset intrauterine growth restriction (IUGR); all normal test results (n =125) were compared with > or = 1 abnormal test results. RESULTS: The odds of the development of adverse outcomes were significantly less in women with all normal test results (preeclampsia/HELLP [odds ratio, 0.2; 95% CI, 0.1-0.4]), preterm delivery (odds ratio, 0.1; 95% CI, 0.06-0.3), small for gestational age delivery (odds ratio, 0.2; 95% CI, 0.09-0.3), early-onset IUGR (0), and IUFD (odds ratio, 0.05 [0.01-0.2]). Combining those women with two (n = 21) of 3 (n = 15) abnormal test results together predicted 14 of 19 severe IUGR and 15 of 22 IUFD cases. CONCLUSION: This placental function profile at 16-23 weeks of gestation can reassure women with normal test results by identifying a smaller subset of women who are at reduced risk of perinatal morbidity or death from severe IUGR.

[Spinal and epidural anaesthesia for caesarean section in patients with pre-eclampsia]. / Spinal- oder Epiduralanästhesie zur Sectio caesarea bei Präeklampsie.

Neuraxial regional anaesthesia is now widely used in obstetric anaesthesia. Specifically, the rate of spinal anaesthesia increased considerably and is favoured for scheduled caesarean section. Former concerns to use regional anaesthetic techniques in non scheduled cases, e.g. spinal anaesthesia for pre-eclampsia are not supported by recent study data. Spinal and epidural anaesthesia are both safe in patients presenting with pre-eclampsia, if contraindications for neuraxial anaesthesia are taken into account.

Case report: post partum class 1 HELLP syndrome.

The objective of this case report is to highlight the lack of screening tests that is capable of predicting HELLP syndrome before its occurrence. The patient developed severe pre-eclamptic toxaemia at 34+ weeks gestation. The foetus was growth retarded. The patient received anti-hypertensive therapy and was delivered by an emergency caesarean section. The patient developed post partum HELLP syndrome that required supportive treatment and renal haemodialysis; nevertheless, the patient fully recovered.

Smoking and the risk of developing hypertensive diseases in pregnancy: what is the effect on HELLP syndrome?

BACKGROUND: The aim of our study was to investigate the role of smoking in the development of HELLP syndrome, pre-eclampsia and gestational hypertension. METHODS: A self-administered questionnaire was sent to 2,600 women who had contacted the German Pre-eclampsia Self-help Group previously for information on hypertensive disorders in pregnancy and to 1,233 controls. Diagnoses were verified by reviewing medical records and classified according to ISSHP criteria. Student's t-test, Wilcoxon test, Chi-square test, and multiple logistic regressions were used for statistical analysis. RESULTS: After matching age, parity, nationality, and education a total of 905 women with a hypertensive disease in pregnancy and 945 controls were evaluated for the present study. In comparison to the patients, controls smoked significantly more often during their pregnancies (8.5%/18%, p<0.0001). Smoking during pregnancy was associated with a decreased risk of developing hypertensive disorders in pregnancy by 56%. The most prominent effect of smoking was on the risk of developing HELLP syndrome (OR 0.19, 95% CI 0.08-0.43) followed by HELLP syndrome + pre-eclampsia (OR 0.33, 95% CI 0.17-0.63), pre-eclampsia only (OR 0.46, 95% CI 0.26-0.8), and gestational hypertension (OR 0.66, 95% CI 0.41-1.08). CONCLUSIONS: Smoking is associated with an 80% reduction of the risk developing HELLP syndrome. However, pregnant women should be advised to quit smoking. Understanding the different effects of smoking in the etiology of each subtype of hypertensive diseases in pregnancy will improve the knowledge of underlying pathophysiological mechanisms and may help in designing more effective prevention and treatment strategies.

[Pregnancy complicated by HELLP syndrome]. / Ciaza powiklana zespolem HELLP--opis przypadku.

HELLP syndrome belongs to the group of pathological disorders associated with pregnancy-induced hypertension and may accompany preeclampsia. The basic criteria for establishing the diagnosis are as follows: H--for hemolysis, EL--for elevated liver enzymes and LP--for low platelets. In this report the authors present the case of a 32 years old primipara admitted to the Obstetrics Clinic complaining of epigastric pain, nausea and vomiting. Medical history revealed previously diagnosed and treated reflux disease. In the 39th week of gestation epigastric pain manifested again, blood pressure was high (150/100) and on the basis of laboratory parameters HELLP syndrome was diagnosed (GPT 319 U/L, GOT 204 U/L, platelet 80 x 10(9)/L, antithrombin III 63.9%, D-dimer (+++)). With this case report, authors wished to point out the importance of early diagnosis and treatment of this rare, but having high percentage of perinatal mortality syndrome.

[Scientific ethics of therapeutic abortion]. / Etica científica del aborto terapéutico.

Therapeutic abortion is proposed when a pregnancy threatens a woman's life and the fetus is not viable ex utero. As the intention is not to kill the fetus, this action should be named "therapeutic interruption of pregnancy". However, in some cases the fetus directly hampers the mother's health. Thus, the removal of the cause of the disease coincides with killing the fetus. Therapeutic abortion has been proposed for several situations. A) When pregnancy and not the fetus, impairs maternal life (e.g. ovular infection, ectopic pregnancy, decompensation of a preexisting disease or diseases of pregnancy as pre-eclampsia/eclampsia, HELLP and Ballantyne syndromes, choriocarcinoma). B) A risk for maternal survival caused by the embryo or fetal genetic constitution: autoimmune diseases of the mother generated by fetal antigens, some types of eclampsia with or without HELLP syndrome due to an immune or exaggerated inflammatory response of the mother, Ballantyne syndrome associated to eclampsia due to fetal-maternal genetic incompatibility, the classic fetus-maternal genetic incompatibility, embryo or fetus diseases caused by their genomic constitution, mainly hydatidiform mole and the triploid, or fetal cancer. Scientific knowledge and a prudential Medical Ethics are capable to solve most cases.