Maternal and neonatal bleeding complications in relation to peripartum management in hemophilia carriers:A systematic review

Currently, there is no consensus on the optimal management to prevent postpartum hemorrhage (PPH) in hemophilia carriers. We aimed to evaluate peripartum management strategies in relation to maternal and neonatal bleeding outcomes by performing an extensive database search up to August 2020. Seventeen case-reports/series and 11 cohort studies were identified of overall 'poor' quality describing 502 deliveries. The PPH incidence in the individual patient data was 63%; 44% for those women receiving prophylaxis to correct coagulation and 77% for those without (OR 0.23, CI 0.09-0.58) and in cohort data 20.3% (26.8% (11/41) vs. 19.4% (55/284) (OR: 1.53, 95% CI: 0.72-3.24), respectively. Peripartum management strategies mostly consisted of clotting factor concentrates, rarely of desmopressin or plasma. Tranexamic acid appears promising in preventing secondary PPH, but was not used consistently. Neonatal bleeding was described in 6 affected male neonates, mostly after instrumental delivery or emergency CS, but insufficient information was provided to reliably investigate neonatal outcome in relation to management. The high PPH risk seems apparent, at most mildly attenuated by prophylactic treatment. Prospective cohort studies are needed to determine the optimal perinatal management in hemophilia.Thrombosis and Hemostasi

Why magnesium sulfate 'coverage' only is not enough to reduce eclampsia: Lessons learned in a middle-income country

Objectives: Determine the eclampsia prevalence and factors associated with eclampsia and recurrent seizures in Suriname and evaluate quality-of-care indicator ‘magnesium sulfate (MgSO4) coverage’. Study design: A two-year prospective nationwide cohort study was conducted in Suriname and included women with eclampsia at home or in a healthcare facility. Main outcome measures: We calculated the prevalence by the number of live births obtained from vital registration. Risk factor denominator data concerned hospital births. Descriptive statistics and multivariate regression analysis were performed. Results: Seventy-two women with eclampsia (37/10.000 live births) were identified, including two maternal deaths (case-fatality 2.8%). Nulliparity, African-descent and adolescence were associated with eclampsia. Adolescents with eclampsia had significantly lower BPs (150/100 mmHg) than adult women (168/105 mmHg). The first seizure occurred antepartum in 54% (n = 39/72), intrapartum in 19% (n = 14/72) and postpartum in 26% (n = 19/72). Recurrent seizures were observed in 60% (n = 43/72). MgSO4 was administered to 99% (n = 69/70) of women; however 26% received no loading dosage and, in 22% of cases MgSO4 duration was <24 h, i.e. guideline adherence existed in only 43%. MgSO4 was ceased during CS in all women (n = 40). Stable BP was achieved before CS in 46%. The median seizure-to-delivery interval was 27 h, and ranged from four to 36 h. Conclusion: Solely ‘MgSO4 coverage’ is not a reliable quality-of-care indicator, as it conceals inadequate MgSO4 dosage and timing, discontinuation during CS, stabilization before delivery, and seizure-to-delivery interval. These other quality-of-care indicators need attention from the international community in order to reduce the prevalence of eclampsia

The randomised uterine septum transsection trial (TRUST) : Design and protocol

Peer reviewedPublisher PD

Identifying duplicate content using statistically improbable phrases

Motivation: Document similarity metrics such as PubMed's ‘Find related articles’ feature, which have been primarily used to identify studies with similar topics, can now also be used to detect duplicated or potentially plagiarized papers within literature reference databases. However, the CPU-intensive nature of document comparison has limited MEDLINE text similarity studies to the comparison of abstracts, which constitute only a small fraction of a publication's total text. Extending searches to include text archived by online search engines would drastically increase comparison ability. For large-scale studies, submitting short phrases encased in direct quotes to search engines for exact matches would be optimal for both individual queries and programmatic interfaces. We have derived a method of analyzing statistically improbable phrases (SIPs) for assistance in identifying duplicate content

ALIFE2 study : low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia : study protocol for a randomized controlled trial

Background A large number of studies have shown an association between inherited thrombophilia and recurrent miscarriage. It has been hypothesized that anticoagulant therapy might reduce the number of miscarriages and stillbirth in these women. In the absence of randomized controlled trials evaluating the efficacy of anticoagulant therapy in women with inherited thrombophilia and recurrent miscarriage, a randomized trial with adequate power that addresses this question is needed. The objective of the ALIFE2 study is therefore to evaluate the efficacy of low-molecular-weight heparin (LMWH) in women with inherited thrombophilia and recurrent miscarriage, with live birth as the primary outcome. Methods/Design Randomized study of LMWH plus standard pregnancy surveillance versus standard pregnancy surveillance alone. Study population: pregnant women of less than 7 weeks’ gestation, and confirmed inherited thrombophilia with a history of 2 or more miscarriages or intra-uterine fetal deaths, or both. Setting: multi-center study in centers from the Dutch Consortium of Fertility studies; centers outside the Netherlands are currently preparing to participate. Intervention: LMWH enoxaparin 40 mg subcutaneously once daily started prior to 7 weeks gestational age plus standard pregnancy surveillance or standard pregnancy surveillance alone. Main study parameters/endpoints: the primary efficacy outcome is live birth. Secondary efficacy outcomes include adverse pregnancy outcomes, such as miscarriage, pre-eclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), fetal growth restriction, placental abruption, premature delivery and congenital malformations. Safety outcomes include bleeding episodes, thrombocytopenia and skin reactions. Discussion After an initial period of slow recruitment, the recruitment rate for the study has increased. Improved awareness of the study and acknowledgement of the need for evidence are thought to be contributing to the improved recruitment rates. We aim to increase the number of recruiting centers in order to increase enrollment into the ALIFE2 study. The study website can be accessed via www.ALIFE2study.org. Trial registration The ALIFE2 study was registered on 19 March 2012 under registration number NTR336

Maternal mortality audit in Suriname between 2010 and 2014, a reproductive age mortality survey

Background: The fifth Millennium Development Goal (MDG-5) aimed to improve maternal health, targeting a maternal mortality ratio (MMR) reduction of 75% between 1990 and 2015. The objective of this study was to identify all maternal deaths in Suriname, determine the extent of underreporting, estimate the reduction, audit the maternal deaths and assess underlying causes and substandard care factors. Methods: A reproductive age mortality survey was conducted in Suriname (South-American upper-middle income country) between 2010 and 2014 to identify all maternal deaths in the country. MMR was compared to vital statistics and a previous confidential enquiry from 1991 to 1993 with a MMR 226. A maternal mortality committee audited the maternal deaths and identified underlying causes and substandard care factors. Results: In the study period 65 maternal deaths were identified in 50,051 live births, indicating a MMR of 130 per 100.000 live births and implicating a 42% reduction of maternal deaths in the past 25 years. Vital registration indicated a MMR of 96, which marks underreporting of 26%. Maternal deaths mostly occurred in the urban hospitals (84%) and the causes were classified as direct (63%), indirect (32%) or unspecified (5%). Major underlying causes were obstetric and non-obstetric sepsis (27%) and haemorrhage (20%). Substandard care factors (95%) were mostly health professional related (80%) due to delay in diagnosis (59%), delay or wrong treatment (78%) or inadequate monitoring (59%). Substandard care factors most likely led to death in 47% of the cases. Conclusion: Despite the reduction in maternal mortality, Suriname did not reach MDG-5 in 2015. Steps to reach the Sustainable Development Goal in 2030 (MMR ≤ 70 per 100.000 live births) and eliminate preventable deaths include improving data surveillance, installing a maternal death review committee, and implementing national guidelines for prevention and management of major complications of pregnancy, childbirth and puerperium

Factor Xa Generation by Computational Modeling: An Additional Discriminator to Thrombin Generation Evaluation

Factor (f)Xa is a critical enzyme in blood coagulation that is responsible for the initiation and propagation of thrombin generation. Previously we have shown that analysis of computationally generated thrombin profiles is a tool to investigate hemostasis in various populations. In this study, we evaluate the potential of computationally derived time courses of fXa generation as another approach for investigating thrombotic risk. Utilizing the case (n = 473) and control (n = 426) population from the Leiden Thrombophilia Study and each individual's plasma protein factor composition for fII, fV, fVII, fVIII, fIX, fX, antithrombin and tissue factor pathway inhibitor, tissue factor-initiated total active fXa generation was assessed using a mathematical model. FXa generation was evaluated by the area under the curve (AUC), the maximum rate (MaxR) and level (MaxL) and the time to reach these, TMaxR and TMaxL, respectively. FXa generation was analyzed in the entire populations and in defined subgroups (by sex, age, body mass index, oral contraceptive use). The maximum rates and levels of fXa generation occur over a 10- to 12- fold range in both cases and controls. This variation is larger than that observed with thrombin (3–6 fold) in the same population. The greatest risk association was obtained using either MaxR or MaxL of fXa generation; with an ∼2.2 fold increased risk for individuals exceeding the 90th percentile. This risk was similar to that of thrombin generation(MaxR OR 2.6). Grouping defined by oral contraceptive (OC) use in the control population showed the biggest differences in fXa generation; a >60% increase in the MaxR upon OC use. FXa generation can distinguish between a subset of individuals characterized by overlapping thrombin generation profiles. Analysis of fXa generation is a phenotypic characteristic which may prove to be a more sensitive discriminator than thrombin generation among all individuals

Cost-effectiveness of fibronectin testing in a triage in women with threatened preterm labor: alleviation of pregnancy outcome by suspending tocolysis in early labor (APOSTEL-I trial)

BACKGROUND: At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective. METHODS/DESIGN: We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, beta 0.2, alpha 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin. DISCUSSION: This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor. TRIAL REGISTRATION: Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl

Assessment of perinatal outcome after sustained tocolysis in early labour (APOSTEL-II trial)

Contains fulltext : 80242.pdf (publisher's version ) (Open Access)BACKGROUND: Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours. METHODS/DESIGN: The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, beta 0.2 at alpha 0.05). DISCUSSION: This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks. TRIAL REGISTRATION: Clinical trial registration: http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008

Counseling and surveillance of obstetric risks for female childhood, adolescent, and young adult cancer survivors: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group

Female childhood, adolescent, and young adult cancer survivors have an increased risk of adverse pregnancy outcomes related to their cancer- or treatment-associated sequelae. Optimal care for childhood, adolescent, and young adult cancer survivors can be facilitated by clinical practice guidelines that identify specific adverse pregnancy outcomes and the clinical characteristics of at-risk subgroups. However, national guidelines are scarce and vary in content. Here, the International Late Effects of Childhood Cancer Guideline Harmonization Group offers recommendations for the counseling and surveillance of obstetrical risks of childhood, adolescent, and young adult survivors. A systematic literature search in MEDLINE database (through PubMed) to identify all available evidence published between January 1990 and December 2018. Published articles on pregnancy and perinatal or congenital risks in female cancer survivors were screened for eligibility. Study designs with a sample size larger than 40 pregnancies in childhood, adolescent, and young adult cancer survivors (diagnosed before the age of 25 years, not pregnant at that time) were eligible. This guideline from the International Late Effects of Childhood Cancer Guideline Harmonization Group systematically appraised the quality of available evidence for adverse obstetrical outcomes in childhood, adolescent, and young adult cancer survivors using Grading of Recommendations Assessment, Development, and Evaluation methodology and formulated recommendations to enhance evidence-based obstetrical care and preconception counseling of female childhood, adolescent, and young adult cancer survivors. Healthcare providers should discuss the risk of adverse obstetrical outcomes based on cancer treatment exposures with all female childhood, adolescent, and young adult cancer survivors of reproductive age, before conception. Healthcare providers should be aware that there is no evidence to support an increased risk of giving birth to a child with congenital anomalies (high-quality evidence). Survivors treated with radiotherapy to volumes exposing the uterus and their healthcare providers should be aware of the risk of adverse obstetrical outcomes such as miscarriage (moderate-quality evidence), premature birth (high-quality evidence), and low birthweight (high-quality evidence); therefore, high-risk obstetrical surveillance is recommended. Cardiomyopathy surveillance is reasonable before pregnancy or in the first trimester for all female survivors treated with anthracyclines and chest radiation. Female cancer survivors have increased risks of premature delivery and low birthweight associated with radiotherapy targeting the lower body and thereby exposing the uterus, which warrant high-risk pregnancy surveillance