Low-molecular-weight heparin for prevention of placenta-mediated pregnancy complications: protocol for a systematic review and individual patient data meta-analysis (AFFIRM)

BACKGROUND: Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality in developed nations. Women who have experienced these complications are at an elevated risk of recurrence in subsequent pregnancies. However, despite decades of research no effective strategies to prevent recurrence have been identified, until recently. We completed a pooled summary-based meta-analysis that strongly suggests that low-molecular-weight heparin reduces the risk of recurrent placenta-mediated complications. The proposed individual patient data meta-analysis builds on this successful collaboration. The project is called AFFIRM, An individual patient data meta-analysis oF low-molecular-weight heparin For prevention of placenta-medIated pRegnancy coMplications. &nbsp; METHODS/DESIGN: We conducted a systematic review to identify randomized controlled trials with a low-molecular-weight heparin intervention for the prevention of recurrent placenta-mediated pregnancy complications. Investigators and statisticians representing eight trials met to discuss the outcomes and analysis plan for an individual patient data meta-analysis. An additional trial has since been added for a total of nine eligible trials. The primary analyses from the original trials will be replicated for quality assurance prior to recoding the data from each trial and combining it into a common dataset for analysis. Using the anonymized combined data we will conduct logistic regression and subgroup analyses aimed at identifying which women with previous pregnancy complications benefit most from treatment with low-molecular-weight heparin during pregnancy. &nbsp; DISCUSSION: The goal of the proposed individual patient data meta-analysis is a thorough estimation of treatment effects in patients with prior individual placenta-mediated pregnancy complications and exploration of which complications are specifically prevented by low-molecular-weight heparin. &nbsp; SYSTEMATIC REVIEW REGISTRATION: PROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD42013006249.</div

Low-molecular-weight heparin for prevention of placenta-mediated pregnancy complications : protocol for a systematic review and individual patient data meta-analysis (AFFIRM)

Abstract Background Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality in developed nations. Women who have experienced these complications are at an elevated risk of recurrence in subsequent pregnancies. However, despite decades of research no effective strategies to prevent recurrence have been identified, until recently. We completed a pooled summary-based meta-analysis that strongly suggests that low-molecular-weight heparin reduces the risk of recurrent placenta-mediated complications. The proposed individual patient data meta-analysis builds on this successful collaboration. The project is called AFFIRM, An individual patient data meta-analysis oF low-molecular-weight heparin For prevention of placenta-medIated pRegnancy coMplications. Methods/Design We conducted a systematic review to identify randomized controlled trials with a low-molecular-weight heparin intervention for the prevention of recurrent placenta-mediated pregnancy complications. Investigators and statisticians representing eight trials met to discuss the outcomes and analysis plan for an individual patient data meta-analysis. An additional trial has since been added for a total of nine eligible trials. The primary analyses from the original trials will be replicated for quality assurance prior to recoding the data from each trial and combining it into a common dataset for analysis. Using the anonymized combined data we will conduct logistic regression and subgroup analyses aimed at identifying which women with previous pregnancy complications benefit most from treatment with low-molecular-weight heparin during pregnancy. Discussion The goal of the proposed individual patient data meta-analysis is a thorough estimation of treatment effects in patients with prior individual placenta-mediated pregnancy complications and exploration of which complications are specifically prevented by low-molecular-weight heparin. Systematic review registration PROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD4201300624

Relationship between thrombophilic disorders and type of severe early-onset hypertensive disorder of pregnancy

OBJECTIVE: To determine whether specific subtypes of early-onset hypertensive disorders of pregnancy (haemolysis, elevated liver enzymes, low platelets [HELLP] syndrome; severe preeclampsia; eclampsia; and fetal growth restriction) differ in increased prevalences of thrombophilic disorders. DESIGN: Cohort study. SETTING: Two university hospitals in Amsterdam, the Netherlands. POPULATION: 216 patients participating in a randomized clinical trial with severe and early-onset hypertensive disorders of pregnancy. METHODS: More than 3 months after delivery, all patients were invited for a thrombophilia screening protocol, including hereditary thrombophilic disorders (Factor II or V-Leiden mutation, APC-resistance, protein S deficiency), antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant activity), and hyperhomocysteinemia (before and after methionin challenge). Disease expression was classified by HELLP syndrome, severe preeclampsia, or neonatal birth weight ratio below the median (0.65). Univariate and multinomial regression analyses examined the association of disease expression with thrombophilic disorders, and other associated factors (chronic hypertension, smoking, body mass index, positive family history of cardiovascular morbidity, and demographic parameters). MAIN OUTCOME MEASURES: incidence of thrombophilic disorders in different subtypes of disease. RESULTS: Overall prevalence of thrombophilic disorders in 206 (95%) screened women was 36%. Chronic hypertension was present in 32%, and 34% had a positive family history of cardiovascular morbidity. Multinomial regression analysis showed that hereditary thrombophilia was more frequent among women with infants with a birth weight ratio <0.65 than in women with HELLP syndrome or severe preeclampsia (p = 0.01, OR 5.1 (1.5 to 7.3) and OR 3.4 (1.1 to 10.6), respectively). High body mass index was less frequent in women with HELLP syndrome than in those with severe preeclampsia or fetal growth restriction (p = 0.06, OR 0.5 (0.3 to 0.9) and OR 0.4 (0.2 to 1.0), respectively). CONCLUSION: In this population, the high prevalence of thrombophilic factors and chronic hypertension was confirmed. There were small differences between groups. Hereditary thrombophilic disorders were associated with fetal growth restriction but not with type of maternal disease, suggesting an effect on placental function. Maternal body mass index was lower in women with HELLP syndrom

Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial

Background: Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain. Methods: In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete. Findings: Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32–1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65–2·09]). Interpretation: In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism. Funding: French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer