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BackgroundPlacenta-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/DesignWe 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.DiscussionThe 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 registrationPROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD42013006249

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc.

Objective Does low-molecular-weight heparin (LMWH) added to low-dose aspirin influence fetal growth and flow velocity in uterine and umbilical arteries in women with an inheritable thrombophilia and previous early-onset uteroplacental insufficiency?Design Secondary outcomes of the FRUIT-RCT.Setting Multicentre, international.Population The FRUIT-RCT included 139 women with inheritable thrombophilia before 12 weeks of gestation. Inclusion criteria were previous delivery before 34 weeks of gestation with a hypertensive disorder of pregnancy and/or small-for-gestationalage infant and an inheritable thrombophilia.Methods After randomisation to either daily LMWH with aspirin, or aspirin only, ultrasound measurements were performed at 22-24, 28-30 and 34-36 weeks of gestation. Development during gestation of growth, birthweight and flow velocity of the umbilical artery was examined using the linear mixed model. Uterine artery flow velocity at a single time-point (22-24 weeks) was examined using a chi-square test.Main outcome measures Fetal growth over time including birthweight, using Scandinavian, Dutch and customised growth curves; and flow velocity within the uterine and umbilical arteries.Results No difference of fetal growth over time could be demonstrated between the study arms, regardless of which reference criteria were used. The flow velocity within the uterine artery and umbilical artery did not differ between study arms. ConclusionThe addition of LMWH to aspirin did not influence fetal growth or umbilical artery flow velocity over time; nor did it influence uterine artery flow velocity.Keywords Aspirin, fetal growth restriction, hypertensive disorders, inheritable thrombophilia, low-molecular-weight heparin, umbilical and uterine artery Doppler.