Matteo Bruschettini, Olga Romantsik, Simona Zappettini, Rita Banzi, Luca Antonio Ramenghi, Maria Grazia Calevo

Preterm birth remains the major risk factor for the development of intraventricular haemorrhage, an injury that occurs in 25% of very low birth weight infants. Intraventricular haemorrhage is thought to be venous in origin and intrinsic thromboses in the germinal matrix are likely to play a triggering role. Heparin activates antithrombin and promotes the inactivation of thrombin and other target proteinases. The administration of anticoagulants such as heparin may offset the increased risk of developing intraventricular haemorrhage and may also reduce the risk of developing parenchymal venous infarct, a condition known to complicate intraventricular haemorrhage. To assess whether the prophylactic administration of heparin reduces the incidence of germinal matrix-intraventricular haemorrhage in very preterm neonates when compared to placebo, no treatment, or other anticoagulants. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2015), MEDLINE (1996 to 22 November 2015), EMBASE (1980 to 22 November 2015) and CINAHL (1982 to 22 November 2015), applying no language restrictions. We searched the abstracts of the major congresses in the field (Perinatal Society of Australia and New Zealand and Pediatric Academic Societies) from 2000 to 2015. Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing the administration of early, i.e. within the first 24 hours of life, heparin in very preterm infants (gestational age < 32 weeks). For each of the included trials, two authors independently extracted data (e.g. number of participants, birth weight, gestational age, dose of heparin, mode of administration, and duration of therapy, etc.) and assessed the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow up). The primary outcomes considered in this review are intraventricular haemorrhage, severe intraventricular haemorrhage and neonatal mortality. Two randomised controlled trials enrolling a total of 155 infants met the inclusion criteria of this review. Both trials compared low-dose heparin to the same solution without heparin in very preterm newborns requiring umbilical catheterisation. No trials were identified that specifically studied the use of heparin in infants at risk of germinal matrix-intraventricular haemorrhage.We found no differences in the rates of intraventricular haemorrhage (typical RR 0.93, 95% CI 0.61 to 1.41; typical RD -0.03, 95% CI -0.17 to 0.12; 2 studies, 155 infants; I² = 57% for RR and I² = 65% for RD), severe intraventricular haemorrhage (typical RR 1.01, 95% CI 0.46 to 2.23; typical RD 0.00, 95% CI -0.11 to 0.11; 2 studies, 155 infants; I² = 0% for RR and I² = 0% for RD) and neonatal mortality (typical RR 0.69, 95% CI 0.28 to 1.67; typical RD -0.04, 95% CI -0.14 to 0.06; 2 studies, 155 infants; I² = 28% for RR and I² = 50% for RD). We judged the quality of the evidence supporting these findings as very low (rates of intraventricular haemorrhage) and low (severe intraventricular haemorrhage and neonatal mortality) mainly because of limitations in the study designs and the imprecision of estimates. We found very few data on other relevant outcomes, such as bronchopulmonary dysplasia, pulmonary haemorrhage and patent ductus arteriosus; and no study assessing long-term outcomes (e.g. neurodevelopmental disability). There is very limited data on the effect of prophylactic administration of heparin on the incidence and severity of IVH in very preterm neonates. Both the identified trials used heparin in the context of maintaining umbilical line patency and not specifically as an agent to prevent germinal matrix-intraventricular haemorrhage. Given the imprecision of our estimates, the results of this systematic review are consistent with either a benefit or a detrimental effect of heparin and do not provide a definitive answer to the review question. Limited evidence is available on other clinically relevant outcomes.