The use of the anticoagulant antithrombin to reduce the risk of intraventricular hemorrhage (i.e. bleeding in the brain) in very preterm infants

Review question: Does antithrombin reduce the risk of intraventricular hemorrhage (i.e. bleeding in the brain) and mortality in very preterm infants?

Background: Antithrombin is a drug that modulates blood coagulation together with other factors. Very low birth weight newborn infants (i.e. those neonates with a gestational age less than 32 weeks) have low level of antithrombin in the blood. On the basis of an observational study in very preterm infants, it has been suggested that the administration of drugs that prevent clotting (anticoagulants) such as antithrombin may reduce the risk of intraventricular hemorrhage and progression of intraventricular hemorrhage, a frequent complication of preterm neonates. This systematic review synthesizes the available evidence on the effectiveness of antithrombin in preventing intraventricular hemorrhage in very preterm neonates.

Study characteristics: We included two trials for a total of 182 newborn infants comparing antithrombin with placebo (sugar or albumin solution).

Results: The use of antithrombin does not reduce the risks of bleeding in the brain, mortality or any other relevant outcomes in very preterm neonates when compared to placebo. However, the data collected are too limited to draw definitive conclusions on the use of antithrombin in the prevention of intraventricular hemorrhage (i.e. bleeding in the brain).

Conclusions: The results of this systematic review are consistent with either a benefit or a detrimental effect of antithrombin and do not provide a definitive answer to the review question.

Authors' conclusions: 

The administration of antithrombin seems not to reduce the incidence and severity of intraventricular hemorrhage in very preterm infants. Limited evidence is available on other clinically relevant outcomes. Given the imprecision of the estimate, the results of this systematic review are consistent with either a benefit or a detrimental effect of antithrombin and do not provide a definitive answer to the review question.

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Background: 

Preterm birth remains the major risk factor for the development of intraventricular hemorrhage, an injury that occurs in 25% of very low birth weight infants. Intraventricular hemorrhage is thought to be venous in origin and intrinsic thromboses in the germinal matrix are likely to play a triggering role. Antithrombin, a glycoprotein synthesized in the liver, is the major plasma inhibitor of thrombin thus modulating blood coagulation. Very low birth weight newborn infants have low levels of antithrombin and the risk of developing intraventricular hemorrhage is increased by the presence of hypercoagulability in the first hours of life. The administration of anticoagulants such as antithrombin may offset the increased risk of developing intraventricular hemorrhage. Anticoagulants may also reduce the risk of developing parenchymal venous infarct, a condition known to complicate intraventricular hemorrhage.

Objectives: 

To assess whether the prophylactic administration of antithrombin (started within the first 24 hours after birth) reduces the incidence of germinal matrix-intraventricular hemorrhage in very preterm neonates when compared to placebo, no treatment, or heparin.

Search strategy: 

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). No language restrictions were applied. 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.

Selection criteria: 

Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing the administration of early, i.e. within the first 24 hours of life, antithrombin in very preterm infants (gestational age < 32 weeks, any birth weight).

Data collection and analysis: 

For each of the included trials, two authors independently extracted data (e.g. number of participants, birth weight, gestational age, antithrombin formulation (plasma-derived or recombinant), mode of administration, and duration of therapy, etc.) and assessed the risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). The primary outcomes considered in this review are intraventricular hemorrhage and severe intraventricular hemorrhage.

Main results: 

Two randomized controlled trials, for a total of 182 infants, met the inclusion criteria of this review. Both trials compared antithrombin with placebo. We found no significant differences in the rates of intraventricular hemorrhage (typical RR 1.30, CI 95% 0.87 to 1.93, typical RD 0.09, 95% CI −0.05 to 0.23; 2 studies, 175 infants; I² = 18% for RR and I² = 42% for RD) and severe intraventricular hemorrhage (typical RR 1.04, CI 95% 0.55 to 1.94; typical RD 0.01, 95% CI −0.11 to 0.12; 2 studies, 175 infants; I² = 0% for RR and I² = 0% for RD). Among secondary outcomes, we found no significant differences in terms of neonatal mortality (typical RR 2.00, CI 95% 0.62 to 6.45; typical RD 0.04, 95% CI −0.03 to 0.12; 2 studies, 182 infants; I² = 46% for RR and I² = 61% for RD) and in the other specified outcomes, such as bronchopulmonary dysplasia. The quality of the evidence supporting these findings is limited due to the imprecision of the estimates.

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