OPtimal TIming of antenatal COrticosteroid administration in pregnancies complicated by early-onset fetal growth REstriction (OPTICORE): study protocol of a multicentre, retrospective cohort study.

INTRODUCTION: Early-onset fetal growth restriction (FGR) requires timely, often preterm, delivery to prevent fetal hypoxia causing stillbirth or neurologic impairment. Antenatal corticosteroids (CCS) administration reduces neonatal morbidity and mortality following preterm birth, most effectively when administered within 1 week preceding delivery. Optimal timing of CCS administration is challenging in early-onset FGR, as the exact onset and course of fetal hypoxia are unpredictable. International guidelines do not provide a directive on this topic. In the Netherlands, two timing strategies are commonly practiced: administration of CCS when the umbilical artery shows (A) a pulsatility index above the 95thh centile and (B) absent or reversed end-diastolic velocity (a more progressed disease state). This study aims to (1) use practice variation to compare CCS timing strategies in early-onset FGR on fetal and neonatal outcomes and (2) develop a dynamic tool to predict the time interval in days until delivery, as a novel timing strategy for antenatal CCS in early-onset FGR. METHODS AND ANALYSIS: A multicentre, retrospective cohort study will be performed including pregnancies complicated by early-onset FGR in six tertiary hospitals in the Netherlands in the period between 2012 and 2021 (estimated sample size n=1800). Main exclusion criteria are multiple pregnancies and fetal congenital or genetic abnormalities. Routinely collected data will be extracted from medical charts. Primary outcome for the comparison of the two CCS timing strategies is a composite of perinatal, neonatal and in-hospital mortality. Secondary outcomes include the COSGROVE core outcome set for FGR. A multivariable, mixed-effects model will be used to compare timing strategies on study outcomes. Primary outcome for the dynamic prediction tool is 'days until birth'. ETHICS AND DISSEMINATION: The need for ethical approval was waived by the Ethics Committee (University Medical Center Utrecht). Results will be published in open-access, peer-reviewed journals and disseminated by presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05606497.

The prevalence of underlying bleeding disorders in patients with heavy menstrual bleeding with and without gynecologic abnormalities.

OBJECTIVE: The purpose of this study was to assess the prevalence of underlying bleeding disorders in women with heavy menstrual bleeding (HMB) with and without gynecologic abnormalities. STUDY DESIGN: We performed a single-center prospective cohort study of 112 consecutive patients who were referred for heavy menstrual bleeding. Control subjects were 28 healthy volunteers who reported no HMB. Patients and control subjects had hemostatic testing in the first week after menstruation. Patients underwent gynecologic evaluation. RESULTS: The median age was 42.5 years (range, 17-55 years) in patients and 40.0 years (range, 25-55 years) in control subjects. Forty-six percent of patients had anemia; the median pictorial bleeding assessment chart score was 271. Seven percent of the control subjects with a subjectively normal menstruation had anemia. Twenty-six percent of patients had gynecologic abnormalities, which was considered to explain HMB. Overall, we found an underlying bleeding disorder in 29% of the patients, which was comparable for unexplained and explained HMB (31% vs 27%; P = .75). We diagnosed 6 cases of Von Willebrand's disease, 4 cases of factor XI deficiency, and 1 case of factor VII deficiency. The only abnormalities that we found in control subjects were platelet aggregation defects (11% in control subjects vs 23% in patients). Patients had a significantly longer activated partial thromboplastin time compared with control subjects (26.5 vs 25.0 seconds; P = .001) that was caused by lower median levels of factor XI (100 vs 124 IU/dL; P < .001). CONCLUSION: Bleeding disorders play an equally important role in the cause of both unexplained and explained heavy menstrual bleeding. A novel finding is the occurrence of low, but not deficient, levels of factor XI.

The risk of postpartum hemorrhage in women using high dose of low-molecular-weight heparins during pregnancy.

BACKGROUND: Low-molecular-weight heparins (LMWH) are the most commonly used anticoagulant during pregnancy for prevention or treatment of VTE. However, the size of the associated risk of postpartum haemorrhage (PPH) is unknown. OBJECTIVE: To assess the bleeding risk of high dose LMWH, also in relation to time between last dose LMWH and delivery. MATERIAL AND METHODS: From 1999 to 2009, we followed 88 pregnant women who were started on therapeutic anticoagulation. Controls were pregnant women without LMWH, matched 1:4 for parity, mode of delivery, age, gestational age and delivery date. PPH was defined as >500 ml blood loss for vaginal delivery (severe PPH in vaginal delivery as >1000 ml) and >1000 ml for cesarean section (CS). Women were divided into subgroups by the interval between last dose of anticoagulation and delivery (<12, 12-24 hrs, >24 hrs). RESULTS: Risk of PPH after vaginal delivery was 30% and 18% for LMWH-users and non-users, respectively (OR 1.9, 95%CI 1.1-3.5). Risk of severe PPH after vaginal delivery was not different (5.6 vs 5.0%; OR 1.1; 0.4-3.6). Risk of PPH after CS was 12% in LMWH-users and 4% in non-users (OR 2.9; 0.5-19.4). Both events of LMWH-users occurred after emergency CS. The risk of PPH associated with delivery within 24 hours after last dose of LMWH was 1.2 fold higher (95%CI 0.4-3.6) compared to a larger interval. CONCLUSION: High dose LMWH carries an increased risk of more than 500 mL blood loss after vaginal delivery. However, this results not in more clinical relevant severe PPHs. The interval between last dose of LMWH and delivery does not influence the risk of PPH.

Haemostatic variables during normal menstrual cycle. A systematic review.

For a number of haemostatic factors menstrual cycle variation has been studied. Such variation could have clinical implications for the timing of haemostatic testing in women. It was our objective to systematically review the literature about evidence for timing of haemostatic testing during menstrual cycle.We searched MEDLINE, EMBASE and the Cochrane library to identify studies that measured haemostatic variables [platelet function, von Willebrand factor (VWF), factor VIII (FVIII), factor IX (FIX), factor XI (FXI), factor XIII (FXIII), D-dimer, plasminogen activator inhibitor-I (PAI-I), tissue plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), α2-antiplasmin and fibrinogen] during normal menstrual cycle without hormonal contraceptives. Two investigators independently selected studies, and abstracted data in duplicate. We identified 1,046 studies of which we included 30 studies (25 longitudinal and 5 cross-sectional studies). All studies reported on haemostatic variables during menstrual cycle. Overall, most of the studies found no cyclic variation in VWF, FVIII, FXI, FXIII, fibrinolytic factors (PAI, t-PA, uPA, D-dimer and α2-antiplasmin) and fibrinogen. However, in studies where these variables showed any variation, they reached the lowest levels during menstrual and early follicular phase, especially for VWF, FVIII and platelet function tests. In conclusion, the optimal timing for haemostatic testing during menstrual cycle seems to be menstrual and early follicular phase.

Routine evaluation and treatment of unexplained menorrhagia: do we consider haemostatic disorders?

OBJECTIVE: Unexplained menorrhagia can be caused by underlying bleeding disorders. The aim of this study was to investigate the current work-up of menorrhagia in routine gynaecological practice, with a special interest in haemostatic evaluation. Secondly, we investigated the outcome of individualized treatment in our centre. STUDY DESIGN: Retrospective medical chart review of 112 consecutive patients referred with menorrhagia to a general gynaecology clinic of a university teaching hospital in the Netherlands between January 2006 and January 2007. In April 2008 we performed a structured telephone interview evaluating the effectiveness of their therapy. RESULTS: We included 112 patients, whose median age was 42 years. Twenty-nine percent were anaemic (hemoglobin <12.0g/dL). Seventy-one (63%) had unexplained menorrhagia. Only two patients had haemostatic evaluation and neither had von Willebrand's disease. Forty percent (29/71) needed two or more different therapies, 17% (12/71) needed three different therapies and two patients needed a total of seven different therapies. Eight patients underwent hysterectomy, six of them after endometrial ablation. Most patients (80%) were successfully treated medically or surgically and were satisfied with their therapy during follow-up. Eleven patients declined therapy and accepted their heavy periods. CONCLUSION: Haemostatic evaluation in women with unexplained menorrhagia is uncommon in gynaecological practice in our centre. Although most of the patients were satisfied with their treatment, a significant number required hysterectomy and another important proportion had to accept their menorrhagia. We hypothesize that the identification of haemostatic disorders might improve care for these women.