Exome sequencing identifies the first genetic determinants of sirenomelia in humans.

Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio-based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2. We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.

Postpartum acute renal failure: a multicenter study of risk factors in patients admitted to ICU.

BACKGROUND: Even in developed countries, severe specific pregnancy complications may occur in the immediate postpartum period and require admission to the ICU. The characteristics and risk factors of acute renal failure (ARF) induced by these complications and their treatments are not well known. METHODS: We performed a retrospective multicenter study in three intensive care departments linked to level III maternity wards in the north of France. All patients admitted to ICU for postpartum complications over a 5-year period (2008 to 2012) were included. Clinical and biological data, delivery characteristics, type of complications, and treatments were compared by univariate and multivariate analyses according to the occurrence and severity of ARF. RESULTS: One hundred eighty-two patients admitted to ICU for postpartum complications were included in the study. Sixty-eight patients (37%) developed an ARF: 49 with a low or medium severity and 19 with a severe ARF requiring renal replacement therapy. Hemolysis, elevated liver enzyme, and low platelet count (HELLP) syndrome on its own (p = 0.047) or combined with postpartum haemorrhage (p = 0.003), previous treatment by hyperoncotic albumin infusion (p = 0.001) and blockade of fibrinolysis by tranexamic acid (p = 0.03), was associated with secondary ARF. By multivariate analysis, the only independent factors were the association of HELLP syndrome with postpartum haemorrhage and the use of hyperoncotic albumin infusion. CONCLUSIONS: HELLP syndrome associated with postpartum haemorrhage induces a high risk of ARF in the complicated postpartum setting. A particular attention should be given to treatments that could worsen the kidney function in that situation.

High-dose tranexamic acid reduces blood loss in postpartum haemorrhage.

INTRODUCTION: Our purpose in conducting this study was to determine whether administration of high-dose tranexamic acid (TA) at the time of diagnosis of postpartum haemorrhage (PPH) could reduce blood loss. METHODS: This was a randomised, controlled, multicentred, open-label trial. Women with PPH >800 mL following vaginal delivery were randomly assigned to receive TA (loading dose 4 g over 1 hour, then infusion of 1 g/hour over 6 hours) or not. In both groups, packed red blood cells (PRBCs) and colloids could be used according to French guidelines. The use of additional procoagulant treatments was permitted only in cases involving intractable bleeding. The primary objective was to assess the efficacy of TA in the reduction of blood loss in women with PPH, and the secondary objectives were the effect of TA on PPH duration, anaemia, transfusion and the need for invasive procedures. RESULTS: A total of 144 women fully completed the protocol (72 in each group). Blood loss between enrolment and 6 hours later was significantly lower in the TA group than in the control group (median, 173 mL; first to third quartiles, 59 to 377) than in controls (221 mL; first to third quartiles 105 to 564) (P = 0.041). In the TA group, bleeding duration was shorter and progression to severe PPH and PRBC transfusion was less frequent than in controls (P < 0.03). Invasive procedures were performed in four women in the TA group and in seven controls (P = NS). PPH stopped after only uterotonics and PRBC transfusion in 93% of women in the TA group versus 79% of controls (P = 0.016). Mild, transient adverse manifestations occurred more often in the TA group than in the control group (P = 0.03). CONCLUSIONS: This study is the first to demonstrate that high-dose TA can reduce blood loss and maternal morbidity in women with PPH. Although the study was not adequately powered to address safety issues, the observed side effects were mild and transient. A larger international study is needed to investigate whether TA can decrease the need for invasive procedures and reduce maternal morbidity in women with PPH. TRIAL REGISTRATION: Controlled Trials ISRCTN09968140.

Role of fetal ultrasound and magnetic resonance imaging in the prenatal diagnosis of migration disorders.

OBJECTIVES: To evaluate the contribution and limitations of fetal ultrasonography (US) and magnetic resonance imaging (MRI) for the diagnosis and management of migration disorders. METHODS: Over a 5-year period, 14 fetuses with pathological migration disorders, without an infectious context, were taken care of in our centre. All underwent US; nine underwent MRI as well. Sonographic and MRI data were compared with neuropathological data. RESULTS: The diagnosis of gyral disorders was obtained by US in 1/14 cases; other cerebral abnormalities were found suggesting neuronal disorder in the remainder. Cerebral MRI suggested gyral abnormality in eight of the nine cases. CONCLUSIONS: US performance is increasing. MRI appears to be a promising method for the diagnosis of fetal migration disorders, giving better results than US. It may be recommended in cases of abnormal cerebral US findings or familial clinical history. However, interpretation of MRI can be tricky and the resulting diagnosis occurs late within the pregnancy.