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

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

The mammalian E3 ubiquitin ligases RNF8 and RNF168 facilitate recruitment of the DNA damage response protein 53BP1 to sites of DNA double-strand breaks (DSBs). The mechanism involves recruitment of RNF8, followed by recruitment of RNF168, which ubiquitinates histones H2A/H2AX on K15. 53BP1 then binds to nucleosomes at sites of DNA DSBs by recognizing, in addition to methyl marks, histone H2A/H2AX ubiquitinated on K15. We report here that expressing H2AX fusion proteins with N-terminal bulky moieties can rescue 53BP1 recruitment to sites of DNA DSBs in cells lacking RNF8 or RNF168 or in cells treated with proteasome inhibitors, in which histone ubiquitination at sites of DNA DSBs is compromised. The rescue required S139 at the C-terminus of the H2AX fusion protein and was occasionally accompanied by partial rescue of ubiquitination at sites of DNA DSBs. We conclude that recruitment of 53BP1 to sites of DNA DSBs is possible in the absence of RNF8 or RNF168, but still dependent on chromatin ubiquitination.</p

Use of inhaled corticosteroids during pregnancy and risk of pregnancy induced hypertension: nested case-control study

Objective To determine whether the use of inhaled corticosteroids during pregnancy increases the risk of pregnancy induced hypertension and pre-eclampsia among asthmatic women. Design Nested case-control study. Setting Three administrative health databases from Quebec: RAMQ, MED-ECHO, and Fichier des événements démographiques. Participants 3505 women with asthma, totalling 4593 pregnancies, between 1990 and 2000. Main outcome measures Pregnancy induced hypertension and pre-eclampsia. Results 302 cases of pregnancy induced hypertension and 165 cases of pre-eclampsia were identified. Use of inhaled corticosteroids from conception until date of outcome was not associated with an increased risk of pregnancy induced hypertension (adjusted odds ratio 1.02, 95% confidence interval 0.77 to 1.34) or pre-eclampsia (1.06, 0.74 to 1.53). No significant dose-response relation was observed between inhaled corticosteroids and pregnancy induced hypertension or pre-eclampsia. Oral corticosteroids were significantly associated with the risk of pregnancy induced hypertension (adjusted odds ratio 1.57, 1.02 to 2.41), and a trend was seen for pre-eclampsia (1.72, 0.98 to 3.02). Conclusion No significant increase of the risk of pregnancy induced hypertension or pre-eclampsia was detected among users of inhaled corticosteroids during pregnancy, while markers of uncontrolled and severe asthma were found to significantly increase the risks of pregnancy induced hypertension and pre-eclampsia