RESUMO
BACKGROUND: The Society of Australia and New Zealand (SOMANZ) published its first sepsis in pregnancy and the postpartum period guideline in 2017 (Aust N Z J Obstet Gynaecol, 57, 2017, 540). In the intervening 6 years, maternal mortality from sepsis has remained static. AIMS: To update clinical practice with a review of the subsequent literature. In particular, to review the definition and screening tools for the diagnosis of sepsis. MATERIALS AND METHODS: A multi-disciplinary group of clinicians with experience in all aspects of the care of pregnant women analysed the clinical evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system following searches of Cochrane, Medline and EMBASE. Where there were conflicting views, the authors reviewed the topic and came to a consensus. All authors reviewed the final position statement. RESULTS: This position statement has abandoned the use of the quick Sequential Organ Failure Assessment score (qSOFA) score to diagnose sepsis due to its poor performance in clinical practice. Whilst New Zealand has a national maternity observation chart, in Australia maternity early warning system charts and vital sign cut-offs differ between states. Rapid recognition, early antimicrobials and involvement of senior staff remain essential factors to improving outcomes. CONCLUSION: Ongoing research is required to discover and validate tools to recognize and diagnose sepsis in pregnancy. Australia should follow New Zealand and have a single national maternity early warning system observation chart.
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BACKGROUND: The absence of the red cell antigens P, P1 and Pk , known as 'p', represents an extremely rare red cell phenotype. Individuals with this phenotype spontaneously form anti-PP1Pk isoantibodies, associated with severe haemolytic transfusion reactions, recurrent spontaneous abortion and haemolytic disease of the fetus and newborn (HDFN). METHODS: We report a series of four successful pregnancies in three women with anti-PP1Pk isoantibodies, one complicated by HDFN, another by intrauterine growth restriction, all managed supportively. We also review the literature regarding the management of pregnancy involving anti-PP1Pk isoimmunization. RESULTS: The literature surrounding anti-PP1Pk in pregnancy is limited to a very small number of case reports. The majority report management with therapeutic plasma exchange (TPE) with or without intravenous immunoglobulin. The relationship between titre and risk of pregnancy loss remains unclear, though a history of recurrent pregnancy loss appears important. Although a positive cord blood direct antiglobulin test is frequently noted, clinically significant HDFN appears uncommon, though possible. CONCLUSION: Early initiation of TPE in high risk patients should be strongly considered. If possible, pregnancies should be managed in a high-risk obstetric or maternal fetal medicine service. The fetus should be monitored closely with interval fetal ultrasound and middle cerebral artery peak systolic volume Doppler to screen for fetal anaemia. Timely sourcing of compatible blood products is likely to be highly challenging, and both directed and autologous donation should be contemplated where appropriate. The International Red Cell Donor Panel may also provide access to compatible products.
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Incompatibilidade de Grupos Sanguíneos/patologia , Eritroblastose Fetal/patologia , Isoanticorpos/sangue , Adulto , Incompatibilidade de Grupos Sanguíneos/sangue , Incompatibilidade de Grupos Sanguíneos/terapia , Eritroblastose Fetal/sangue , Eritroblastose Fetal/terapia , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Recém-Nascido , Troca Plasmática/métodos , GravidezRESUMO
In this clinical review we highlight aspects of the diagnosis and management of pulmonary embolism (PE) in pregnancy and post-partum and how this may impact on antenatal and postnatal management. Investigation for PE in pregnancy is challenging and includes appropriate patient selection and knowledge of the risks and benefits of pulmonary imaging modalities. The complete Society of Obstetric Medicine of Australia and New Zealand Position Statement on Pulmonary Embolism in Pregnancy and Post-Partum comprehensively reviews all aspects of diagnosis, investigation and management and is accessible at https://www.somanz.org/guidelines.asp. It includes a summary of all recommendations and a guide to developing a management plan for birth in women on anticoagulation.
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Embolia Pulmonar , Austrália , Feminino , Humanos , Nova Zelândia , Período Pós-Parto , Gravidez , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/terapiaRESUMO
Thrombocytopenia in pregnancy is a common occurrence, affecting up to 10% of women by the time of birth. These recommendations aim to provide pragmatic guidance on the investigation, diagnosis and management of thrombocytopenia in pregnancy; including safety of neuraxial anaesthesia and precautions required for birth. Management of neonatal thrombocytopenia is also addressed. The authors are clinicians representing haematology, obstetric medicine, maternal-fetal medicine, and anaesthesia. Each author conducted a detailed literature review then worked collaboratively to produce a series of unanimous recommendations. The recommendation strength is limited by the lack of high-quality clinical trial data, and represents level C evidence.
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Parto , Trombocitopenia , Feminino , Humanos , Recém-Nascido , Gravidez , Trombocitopenia/diagnóstico , Trombocitopenia/terapiaRESUMO
BACKGROUND: Obesity increases risk of venous thromboembolism (VTE) in obstetric patients regardless of delivery mode and for up to six weeks postpartum. AIM: This study aimed to examine postpartum pharmacological VTE prophylaxis practices for obese women at an Australian tertiary referral hospital. MATERIALS AND METHODS: Medical records were retrieved for obese obstetric patients who delivered during May 2016-May 2017. Records were examined for demographic data, VTE risk factors, and LMWH (low-molecular-weight heparin) use. Due to lack of specific Australian or local guidelines, practice was evaluated using recommendations from the Royal College of Obstetricians and Gynaecologists (RCOG-UK). Patients with BMI (body mass index) <30, incomplete/unavailable medical records, and those discharged from other health services were excluded. RESULTS: One hundred and eight postpartum patients (70 caesareans, 38 vaginal deliveries) with a BMI ≥ 30 kg/m2 were reviewed. Of these patients, 53 (49.1%) had a BMI ≥ 40 kg/m2 . Ninety-eight of 108 (90.7%) patients had ≥2 VTE risk factors including a BMI ≥ 30 kg/m2 . One hundred and three of 108 (95.4%) patients were indicated for postpartum VTE prophylaxis with LMWH, and 77 of 103 (74.8%) patients received it. Three of five patients meeting criteria for ≥6 weeks of LMWH thromboprophylaxis had it prescribed. Of the 72 patients whose weight exceeded 90 kg and who also received LMWH, 32 (44.4%) were prescribed a weight-adjusted dose. CONCLUSION: VTE prophylaxis practices using LMWH in obese postpartum patients, including weight-adjusting doses and extended-course prescribing, appear variable. Limited literature, recommendation discrepancies, and varied awareness of recommendations may be contributing factors. Further education and research regarding this high-risk cohort are warranted.
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Obesidade/complicações , Complicações Cardiovasculares na Gravidez/prevenção & controle , Tromboembolia Venosa/prevenção & controle , Adulto , Anticoagulantes/administração & dosagem , Austrália , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Humanos , Período Pós-Parto , Gravidez , Transtornos Puerperais/prevenção & controle , Fatores de Risco , Centros de Atenção Terciária , Adulto JovemRESUMO
The diagnosis and management of pulmonary embolism in pregnancy is difficult, because diagnostic procedures and the use of anticoagulants potentially can expose mother and fetus to adverse effects. This article reviews evidence for current best practice and emerging novel techniques for the diagnosis of pulmonary embolism in pregnancy and includes clinical prediction models, biomarkers, and diagnostic imaging that may offer improvement in the diagnosis and investigation of pulmonary embolism in pregnancy in the future. The usefulness of new anticoagulant agents (fondaparinux, rivaroxaban, and dabigatran) in managing pulmonary embolism in future pregnancies is also explored.
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Complicações na Gravidez , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Anticoagulantes/uso terapêutico , Biomarcadores , Diagnóstico por Imagem , Feminino , Previsões , Humanos , GravidezRESUMO
Hyperactive RAS signaling is caused by mutations in RAS genes or a deficiency of the neurofibromatosis gene (NF1) and is common in myeloid malignancies. In mice, expression of oncogenic K-RAS or inactivation of Nf1 in hematopoietic cells results in myeloproliferative disorders (MPDs) that do not progress to acute myeloid leukemia (AML). Because NF1 is a RAS-GTPase-activating protein it has been proposed that NF1 deficiency is functionally equivalent to an oncogenic RAS. It is not clear, however, whether Nf1 deficiency would be redundant in K-RAS-induced MPD development or whether the 2 mutations would cooperate in leukemogenesis. Here, we show that the simultaneous inactivation of Nf1 and expression of K-RAS(G12D) in mouse hematopoietic cells results in AML that was fatal in primary mice within 4 weeks and transplantable to sublethally irradiated secondary recipients. The data point to a strong cooperation between Nf1 deficiency and oncogenic K-RAS.
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Genes da Neurofibromatose 1/fisiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Neurofibromina 1/deficiência , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Animais , Western Blotting , Cocarcinogênese , Ensaio de Unidades Formadoras de Colônias , Citometria de Fluxo , Hemoglobinas/metabolismo , Integrases/metabolismo , Leucócitos/metabolismo , Camundongos , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/imunologia , Baço/metabolismo , Baço/patologiaRESUMO
The recombinant human keratinocyte growth factor, palifermin, offers a potential means of reducing or preventing mucositis in patient undergoing intensive cancer treatments. This case report details the development of acral erythrodysaesthesia in one patient who underwent palifermin treatment prior to high-intensity re-induction chemotherapy for acute myeloid leukaemia.
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Fator 7 de Crescimento de Fibroblastos/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Parestesia/induzido quimicamente , Parestesia/patologia , Proteínas Recombinantes/efeitos adversos , Humanos , Resultado do TratamentoRESUMO
Venous thromboembolic disease (VTE) risk increases five-fold antenatally and 14-fold during the puerperium. Obesity significantly increases this risk. The D-dimer assay and more novel Calibrated Automated Thrombogram (CAT) assay laboratory tests display potential for use in VTE risk stratification in pregnancy, although to date, research in the performance characteristics of these tests in obese and nonobese pregnant populations is limited. The aim of this study was to compare D-dimer and thrombin generation levels in obese and nonobese pregnant women. Pregnant women were recruited and categorised, as obese (BMI ≥30) or nonobese (BMI 18.5-25). Blood was collected at 26-28 weeks' gestation, 36-40 weeks' gestation and 6-12 weeks postpartum and D-dimer concentrations and endogenous thrombin potential (ETP) were determined. Student's t-test was used to analyse differences in mean D-dimer and ETP. At 36-40 weeks, obese pregnant women had higher D-dimer concentrations (Pâ=â0.001) but lower ETP levels compared with nonobese women (Pâ=â0.044). D-dimer was higher in nonobese than in obese women at 6-12 weeks postpartum (Pâ=â0.026). There was no difference in mean D-dimer (Pâ =â0.825) and mean ETP (Pâ =â0.424) between obese and nonobese women at 26-28 weeks. No difference was observed in mean ETP at 6-12 weeks postpartum (Pâ =â0.472). ETP was lower in both obese and nonobese women postpartum than during pregnancy. D-dimer was lower in obese women but not in nonobese women postpartum. D-dimer concentrations and ETP were not significantly different during multiple time points in pregnancy and postpartum between obese and nonobese pregnant women suggesting limited utility in VTE risk assessment in obese pregnant women.
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Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Obesidade/sangue , Complicações na Gravidez/sangue , Trombina/análise , Adulto , Testes de Coagulação Sanguínea , Feminino , Humanos , Obesidade/complicações , Período Pós-Parto/sangue , Gravidez , Fatores de Risco , Tromboembolia Venosa/sangue , Tromboembolia Venosa/etiologiaRESUMO
Protein geranylgeranyltransferase type I (GGTase-I) is responsible for the posttranslational lipidation of CAAX proteins such as RHOA, RAC1, and cell division cycle 42 (CDC42). Inhibition of GGTase-I has been suggested as a strategy to treat cancer and a host of other diseases. Although several GGTase-I inhibitors (GGTIs) have been synthesized, they have very different properties, and the effects of GGTIs and GGTase-I deficiency are unclear. One concern is that inhibiting GGTase-I might lead to severe toxicity. In this study, we determined the effects of GGTase-I deficiency on cell viability and K-RAS-induced cancer development in mice. Inactivating the gene for the critical beta subunit of GGTase-I eliminated GGTase-I activity, disrupted the actin cytoskeleton, reduced cell migration, and blocked the proliferation of fibroblasts expressing oncogenic K-RAS. Moreover, the absence of GGTase-I activity reduced lung tumor formation, eliminated myeloproliferative phenotypes, and increased survival of mice in which expression of oncogenic K-RAS was switched on in lung cells and myeloid cells. Interestingly, several cell types remained viable in the absence of GGTase-I, and myelopoiesis appeared to function normally. These findings suggest that inhibiting GGTase-I may be a useful strategy to treat K-RAS-induced malignancies.
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Alquil e Aril Transferases/deficiência , Alquil e Aril Transferases/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/prevenção & controle , Sobrevida/fisiologia , Proteínas ras/toxicidade , Alquil e Aril Transferases/antagonistas & inibidores , Animais , Inativação Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , CamundongosRESUMO
Hyperactive signaling through the RAS proteins is involved in the pathogenesis of many forms of cancer. The RAS proteins and many other intracellular signaling proteins are either farnesylated or geranylgeranylated at a carboxyl-terminal cysteine. That isoprenylcysteine is then carboxyl methylated by isoprenylcysteine carboxyl methyltransferase (ICMT). We previously showed that inactivation of Icmt mislocalizes the RAS proteins away from the plasma membrane and blocks RAS transformation of mouse fibroblasts, suggesting that ICMT could be a therapeutic target. However, nothing is known about the impact of inhibiting ICMT on the development of malignancies in vivo. In the current study, we tested the hypothesis that inactivation of Icmt would inhibit the development or progression of a K-RAS-induced myeloproliferative disease in mice. We found that inactivating Icmt reduced splenomegaly, the number of immature myeloid cells in peripheral blood, and tissue infiltration by myeloid cells. Moreover, in the absence of Icmt, the ability of K-RAS-expressing hematopoietic cells to form colonies in methylcellulose without exogenous growth factors was reduced dramatically. Finally, inactivating Icmt reduced lung tumor development and myeloproliferation phenotypes in a mouse model of K-RAS-induced cancer. We conclude that inactivation of Icmt ameliorates phenotypes of K-RAS-induced malignancies in vivo.
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Transtornos Mieloproliferativos/etiologia , Proteínas Metiltransferases/deficiência , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Animais , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/prevenção & controle , Camundongos , Camundongos Knockout , Células Mieloides/patologia , Transtornos Mieloproliferativos/patologia , EsplenomegaliaRESUMO
OBJECTIVE: To examine the adverse drug reactions (ADRs) and the efficacy of intravenous iron polymaltose and ferric carboxymaltose (FCM) among gynecology/obstetric patients with anemia. METHODS: The present retrospective observational study examined data from anemic obstetrics and gynecology patients who received either iron polymaltose or FCM between January 1, 2011, and April 30, 2015, at The Royal Women's Hospital, Victoria, Australia. Patient demographic data, dosage, ADR documentation, and hemoglobin levels were collected from medical records and compared. RESULTS: The study included 221 patients; 111 and 110 received iron polymaltose and FCM, respectively. ADRs were documented for 18 (16.2%) patients in the iron polymaltose group and 2 (1.8%) in the FCM group (P<0.001), with no incidences of anaphylaxis. Both formulations achieved increased hemoglobin levels within 12 weeks (P<0.001 for both). Mean hemoglobin level increases were similar in both groups among non-pregnant patients (P=0.186), but were greater in the iron polymaltose cohort among pregnant patients (P=0.005). FCM dose compliance was suboptimal, with 8 of 57 (14%) patients who required second visits for doses greater than 1000 mg returning for the infusion. CONCLUSION: FCM was associated with a lower incidence of ADRs than iron polymaltose. Patients receiving FCM infusions were less likely to receive their total required iron dose. Further randomized prospective studies are required to compare clinical efficacy of iron polymaltose versus FCM.
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Anemia Ferropriva/tratamento farmacológico , Compostos Férricos/administração & dosagem , Maltose/análogos & derivados , Administração Intravenosa , Adolescente , Adulto , Idoso , Anemia Ferropriva/etiologia , Austrália , Estudos de Coortes , Feminino , Compostos Férricos/efeitos adversos , Humanos , Maltose/administração & dosagem , Maltose/efeitos adversos , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Pulmonary embolism is one of the leading causes of mortality in pregnancy in the Western world. No clinical prediction models have been validated in pregnancy. As a result, any pregnant woman presenting with signs possibly consistent with pulmonary embolism is investigated radiologically. This study investigates whether using clinical prediction models for pulmonary embolism in pregnancy should be pursued in future prospective trials. The aim of this study was to retrospectively evaluate the Wells clinical prediction model and ventilation-perfusion scanning for pulmonary embolism in pregnancy. A retrospective study was performed on consecutive pregnant women who presented with suspected pulmonary emboli and underwent ventilation perfusion scanning at two tertiary institutions from 2007 until 2010. The clinical pretest probability was determined as likely or unlikely by two independent clinicians retrospectively using Wells-modified criteria. Scans were determined as normal, nondiagnostic or high probability for pulmonary emboli independently by two experienced radiologists. Disagreements were resolved by a third assessor independently. In 183 pregnant women, the pretest probability was determined as 'pulmonary emboli likely' in 76 (42%) and 'pulmonary emboli unlikely' in 107 (58%) of women. Scans were of high probability in four (2%), nondiagnostic in six (3%) and normal in 173 (95%) of women. This gives the pretest probability using Wells-modified criteria a sensitivity of 100% [95% confidence interval (CI) 0.4-1.0] and a negative predictive value of 100% (95% CI 0.96-1.0). A structured clinical model such as modified Wells criteria may be useful in pregnancy, but further prospective evaluation is required.
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Complicações na Gravidez/diagnóstico , Embolia Pulmonar/diagnóstico , Adolescente , Adulto , Feminino , Humanos , Modelos Estatísticos , Valor Preditivo dos Testes , Gravidez , Complicações na Gravidez/fisiopatologia , Prognóstico , Embolia Pulmonar/fisiopatologia , Estudos Retrospectivos , Relação Ventilação-Perfusão , Adulto JovemRESUMO
The RAS proteins undergo farnesylation of a carboxyl-terminal cysteine (the "C" of the carboxyl-terminal CaaX motif). After farnesylation, the 3 amino acids downstream from the farnesyl cysteine (the -aaX of the CaaX motif) are released by RAS-converting enzyme 1 (RCE1). We previously showed that inactivation of Rce1 in mouse fibroblasts mislocalizes RAS proteins away from the plasma membrane and inhibits RAS transformation. Therefore, we hypothesized that the inactivation of Rce1 might inhibit RAS transformation in vivo. To test this hypothesis, we used Cre/loxP recombination techniques to simultaneously inactivate Rce1 and activate a latent oncogenic K-RAS allele in hematopoietic cells in mice. Normally, activation of the oncogenic K-RAS allele in hematopoietic cells leads to rapidly progressing and lethal myeloproliferative disease. Contrary to our hypothesis, the inactivation of Rce1 actually increased peripheral leukocytosis, increased the release of immature hematopoietic cells into the circulation and the infiltration of cells into liver and spleen, and caused mice to die more rapidly. Moreover, in the absence of Rce1, splenocytes and bone marrow cells expressing oncogenic K-RAS yielded more and larger colonies when grown in methylcellulose. We conclude that the inactivation of Rce1 worsens the myeloproliferative disease caused by oncogenic K-RAS.