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Antithrombin for the prevention of intraventricular hemorrhage in very preterm infants

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Authors

Matteo Bruschettini1, Olga Romantsik1, Simona Zappettini2, Rita Banzi3, Luca Antonio Ramenghi4, Maria Grazia Calevo5

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Paediatrics, Lund University, Skane University Hospital, Lund, Sweden [top]
2Health Regional Agency of the Liguria Region, Genoa, Italy [top]
3Laboratory of Regulatory Policies, IRCCS - Mario Negri Institute for Pharmacological Research, Milan, Italy [top]
4Neonatal Intensive Care Unit, Istituto Giannina Gaslini, Genoa, Italy [top]
5Epidemiology, Biostatistics and Committees Unit, Istituto Giannina Gaslini, Genoa, Italy [top]

Citation example: Bruschettini M, Romantsik O, Zappettini S, Banzi R, Ramenghi LA, Calevo MG. Antithrombin for the prevention of intraventricular hemorrhage in very preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 3. Art. No.: CD011636. DOI: 10.1002/14651858.CD011636.pub2.

Contact person

Matteo Bruschettini

Department of Paediatrics
Lund University, Skane University Hospital
Lund
Sweden

E-mail: matteo.bruschettini@med.lu.se
E-mail 2: matbrus@gmail.com

Dates

Assessed as Up-to-date: 22 November 2015
Date of Search: 22 November 2015
Next Stage Expected: 22 November 2017
Protocol First Published: Issue 4, 2015
Review First Published: Issue 3, 2016
Last Citation Issue: Issue 3, 2016

Abstract

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 methods

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.

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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Plain language summary

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.

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Background

Description of the condition

Preterm birth remains the major risk factor for the development of germinal matrix-intraventricular hemorrhage (GM-IVH), an injury that occurs in 25% of very low birth weight infants, with 6% of very low birth weight infants having severe grades of IVH (Horbar 2012). Often, these hemorrhages occur in the first day of life (Dolfin 1983). The etiology of GM-IVH is multifactorial, not completely elucidated, and involves the intrinsic vulnerability of the germinal matrix (Perlman 1983). This hemorrhagic disorder is thought to be venous in origin (Volpe 2008), and venous vessels are known to be more vulnerable to thrombotic phenomena compared to arteries. Moreover, in the absence of significant environmental fluctuations in cerebral blood flow, intrinsic thromboses in the tiniest vessels of the germinal matrix are likely to play a crucial and triggering role (Ghazi-Birry 1997; Ramenghi 2005). The first retrospective analysis between thrombophilia and increased risk of developing GM-IVH was published in 2001 (Petäjä 2001). Subsequently, our group demonstrated that genetic prothrombotic factors significantly increase the risk of developing GM-IVH to a similar extent as low Apgar score or the use of inotropic agents (Ramenghi 2011). Development of the hemostatic system in neonates is an age-dependent process, with lower levels of both pro-coagulants and anti-coagulants especially in preterm infants (Tripodi 2008). Severe IVH may be associated with cystic periventricular leukomalacia, though they might be separate entities (Kuster 2009). According to one biological theory, free iron released during GM-IVH enhances oxidative stress, thus provoking pre-oligodendrocytes damage (Khwaja 2008). In animal models, similar white matter damage, induced by injecting thrombin, may be prevented by a thrombin inhibitor (Xue 2005).

Description of the intervention

Antithrombin, a glycoprotein synthesized in the liver, irreversibly inactivates several endogenous active clotting factors, acting on thrombin and activated factors IX, X, XI and XII (Rodgers 2009; Roemisch 2002). Antithrombin is the major plasma inhibitor of thrombin (Rosenberg 1975). Together with other factors, antithrombin modulates blood coagulation. Consequently, inherited antithrombin deficiency is associated with an increased risk of venous thrombosis in adults (Bick 2003); and of significant morbidity and mortality in the neonate (Seguin 1994). The prevalence of congenital antithrombin deficiency is 1 in every 500 to 20,000 (Tait 1994; Wells 1994). Plasma-derived and recombinant antithrombin concentrates are available; the latter is administered in continuous infusion because of its short half-life (rEVO Biologics 2009). Both formulations are administered by the intravenous route. Dosage is determined on an individual basis, according to plasma antithrombin levels. Antithrombin activity is greatly accelerated in the presence of heparin (Rosenberg 1975).

How the intervention might work

Reference values for antithrombin concentrations are not well defined in the neonate. Infants born at term reach adult antithrombin levels at six months of age (Orkin 2003). Concentrations of antithrombin are lower in very low birth weight newborn infants with respiratory distress (Schmidt 1992). In addition, the risk of developing of GM-IVH has been shown to be increased by the presence of hypercoagulability in the first hours of life (McDonald 1984). Therefore, the administration of anticoagulants such as antithrombin may offset the increased risk of developing GM-IVH due to congenital thrombophilia aggravated by the hypercoagulable state of the first hours of life. Moreover, anticoagulants may prove useful in reducing the risk of developing parenchymal venous infarct, a thrombotic/occlusive condition (Volpe 2008) known to complicate IVH (grade IV). An observational study in very preterm infants reported that administration of antithrombin on the day of birth may reduce the incidence and progression of GM-IVH (Brangenberg 1997). In addition to a direct protective effect on the brain, antithrombin might improve non-neurological outcomes in preterm infants, as the depletion of antithrombin activity may be associated with the severity of respiratory distress syndrome (Schmidt 1992). Beneficial effects of antithrombin might vary in specific populations, e.g. neonates with antithrombin deficiency, complex coagulation disorders, sepsis with disseminated intravascular coagulation, and transient neonatal protein C deficiency. Low cord blood levels of protein C (< 0.1 unit/ml) may reflect delayed maturation or increased turnover in certain infants and appear to convey an independent risk of thrombosis (Manco-Johnson 1991). It has been suggested that antithrombin levels should be high (> 140% of normal antithrombin activity) in order to achieve an anti-inflammatory effect (Schinzel 1998). Taken together, the developmental immaturity of the hemostasis system as well as the frequent need for medical interventions in critically ill preterm infants increase the risk for thromboembolism. These newborns might benefit from antithrombin treatment by avoiding thrombus formation.

Why it is important to do this review

A large retrospective cohort study, involving 43 centers in the United States and more than 4000 participants, described the use of antithrombin in infants and children in tertiary care pediatric hospitals (Wong 2013). Neonates comprised nearly half of the treated participants. During the ten-year study period (2002 to 2011), the administration of antithrombin during extracorporeal membrane oxygenation — the most common procedure associated with antithrombin administration — increased from 5% to 51% (nearly 1000 extracorporeal membrane oxygenation procedures were performed in 2011 within this cohort study) (Wong 2013). Despite this, few studies have investigated the efficacy and safety of antithrombin administration.

Two Cochrane systematic reviews have been published on the use of antithrombin, one in critically ill adults (Afshari 2008), and one in preterm infants with respiratory distress syndrome (Bassler 2006). The present review investigated the use of antithrombin in a different population, i.e. preterm infants regardless of critical illness or respiratory function. This review focuses on the effect of antithrombin on the prevention of GM-IVH, one of the most relevant concerns in preterm infants.

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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.

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Methods

Criteria for considering studies for this review

Types of studies

We included prospective randomized controlled clinical trials, quasi-randomised trials and cluster trials. We excluded cross-over trials.

Types of participants

Preterm infant newborns admitted to neonatal intensive care units, gestational age less than 32 weeks, any birth weight.

Types of interventions

  1. Antithrombin compared to placebo or no treatment (specific subgroup analyses for each comparison are described in Subgroup analysis and investigation of heterogeneity)
  2. Antithrombin compared to unfractionated heparin
  3. Antithrombin compared to low-molecular-weight heparin

We included any dose, mode of administration, and duration of antithrombin therapy in this review. We excluded trials where antithrombin was administered during extracorporeal membrane oxygenation.

As the aim of the review was to assess the ability of antithrombin to prevent GM-IVH, we included trials in which antithrombin administration was started within the first 24 hours of life.

Types of outcome measures

Primary outcomes
Secondary outcomes
  • Mortality: neonatal mortality (< 28 days of age); infant mortality (one year of age)
  • Bronchopulmonary dysplasia/chronic lung disease
  • Pneumothorax (on chest X-ray)
  • Duration of mechanical ventilation (intermittent positive pressure ventilation; days)
  • Duration of respiratory support (intermittent positive pressure ventilation or continuous positive airway pressure; days)
  • Duration of oxygen therapy (days)
  • Duration of hospital stay (days)
  • Retinopathy of prematurity: any and severe (stage 3 or greater; ICROP 1984)
  • Necrotizing enterocolitis: any grade; requiring surgery (Bell 1978)
  • Need for blood transfusions
  • Need for medical or surgical treatment for persistent ductus arteriosus
  • Pulmonary hemorrhage
  • Clinically apparent bleeding during treatment during the first week of life
  • Central catheter (umbilical line or peripherally inserted central catheter) occlusion
  • Stroke during treatment (yes/no)
  • Cerebellar hemorrhage at brain ultrasound in the first month of life
  • Cystic periventricular leukomalacia at brain ultrasound in the first month of life
  • Brain magnetic resonance imaging (MRI) abnormalities at term-equivalent age
  • Cerebral hemodynamics impairment, based on cerebral near-infrared spectroscopy in the first three days of life
  • Major neurodevelopmental disability assessed at age of 12 months or more (defined as cerebral palsy, developmental delay (Bayley or Griffith assessment more than two standard deviations (SD) below the mean) or intellectual impairment (intelligence quotient (IQ) more than two SD below mean), blindness (vision < 6/60 in both eyes) or sensorineural deafness requiring amplification)

Search methods for identification of studies

See: Cochrane Neonatal Review Group External Web Site Policy (CNRG) search strategy.

Electronic searches

We used the criteria and standard methods of Cochrane and the Neonatal Review Group. We undertook a comprehensive search including:

  • The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, Issue 11, 2015;
  • MEDLINE (January 1996 to 22 November 2015);
  • EMBASE (January 1980 to 22 November 2015);
  • CINAHL (1982 to 22 November 2015);
  • Perinatal Society of Australia and New Zealand (PSANZ) (2005 to November 2015);
  • The abstracts of the Pediatric Academic Societies (PAS) (2000 to November 2015).

The full search strategies for each database are included in Appendix 1. We applied no language restrictions. We searched the reference lists of any cited articles.

Searching other resources

We searched for ongoing or completed unpublished trials in the clinical trial registries ClinicalTrials.gov (https://clinicaltrials.gov/) and the International Standard Randomised Controlled Trial Number (ISRCTN) Registry (http://www.isrctn.com/ External Web Site Policy).

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group. Two review authors (OR, MB) independently performed the screening of abstracts retrieved through the database search, the extraction of data and the assessments of risk of bias. At each stage, disagreements were resolved by consensus or by discussion with a third review author (MGC). Data were extracted from the published report and, where necessary, by contacting the investigators of each trial.

Selection of studies

Two review authors (OR, MB) independently screened the titles and abstracts to identify potentially eligible trials that met inclusion criteria. We then retrieved the full publications of all potentially relevant articles and independently assessed the eligibility of the trials by filling out eligibility forms designed in accordance with the specified inclusion criteria.

Data extraction and management

Two authors (OR, MB) independently undertook data abstraction using a standardized data extraction form integrated with a modified version of the Cochrane Effective Practice and Organisation of Care (EPOC) Group data collection checklist (EPOC 2015).

We extracted the following characteristics from each included trial.

  • Administrative details: author(s); published or unpublished; year of publication; year of trial conduct; details of other relevant papers cited.
  • Details on the trial: study design; duration and completeness of follow-up (i.e. > 80%); country and setting; informed consent and ethics approval.
  • Details on participants: birth weight, gestational age, and number of participants.
  • Details on intervention: dose, formulation (i.e. plasma-derived or recombinant), mode of administration, and duration of antithrombin therapy.
  • Details on outcomes (see Types of outcome measures).

For ongoing trials we reported first author, research question(s), methods and outcome measures together with an estimate of the reporting date, where available.

We used Cochrane's software for data entry and management (Review Manager 2014).

Assessment of risk of bias in included studies

Two authors (SZ, MB) independently assessed the methodological quality of all the included trials by using Cochrane's tool for assessing risk of bias (Higgins 2011).

We assessed the following risk of bias domains:

  1. sequence generation (randomization sequence adequately generated);
  2. allocation sequence concealment (allocation adequately concealed);
  3. blinding of participants and personnel (knowledge of the allocated intervention adequately prevented during the trial);
  4. blinding of outcome assessment (detection bias);
  5. incomplete outcome data (incomplete outcome data adequately addressed);
  6. selective outcome reporting (reports of the study free of suggestion of selective outcome reporting);
  7. other potential sources of bias (trial apparently free of other problems that could put it at a high risk of bias).

We summarized risk of bias for the primary outcomes within and across trials; a 'Risk of bias' graph was used to illustrate risk across trials. We resolved any disagreement by consensus and, if necessary, by adjudication by a third author (MGC).

Sequence generation and allocation sequence concealment (Selection bias)
  • Sequence generation
    • Low risk - adequate (any truly random process e.g. random number table; computer random number generator)
    • High risk - inadequate (any non-random process e.g. odd or even date of birth; hospital or clinic record number)
    • Unclear risk - no or unclear information provided
  • Allocation sequence concealment
    • Low risk - adequate (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes)
    • High risk - inadequate (open random allocation; unsealed or non opaque envelopes, alternation; date of birth)
    • Unclear risk - no or unclear information provided
Blinding (Performance and detection bias)

For each included trial, we categorized the methods used to blind study personnel and outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.

Incomplete outcome data (Attrition bias)

For each included trial and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. In order to reduce bias from trials with high loss to follow-up, we performed a sensitivity analysis only including data which reported follow-up data for at least 80% of the randomized sample.

Selective outcome reporting (Reporting bias)

For each included trial, we described how we investigated the risk of selective outcome reporting bias and what we found. We tried to access all the protocols of the included trials through clinical trials registries (e.g. ClinicalTrials.gov), and direct contact with the authors.

We assessed the methods as follows.

  • Low risk - adequate (where it is clear that all of the trial’s pre-specified outcomes and all expected outcomes of interest to the review have been reported).
  • High risk - inadequate (where not all the trial’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; trial fails to include results of a key outcome that would have been expected to have been reported).
  • Unclear risk - no or unclear information provided (the study protocol was not available).
Other potential sources of bias (Other bias)

For each included trial, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process).

We assessed whether each trial was free of other problems that could put it at risk of bias as follows.

  • Low risk - no concerns of other bias raised.
  • High risk - concerns raised about multiple looks at the data with the results made known to the investigators, difference in number of participants enrolled in abstract and final publications of the paper.
  • Unclear - concerns raised about potential sources of bias that could not be verified by contacting the authors

Quality of evidence

Although this was not planned in the review protocol (see Differences between protocol and review), we summarized the evidence of this review in a 'Summary of findings' table. We used the control arm data to calculate the 'assumed risk' values and selected incidence and severity of IVH and neonatal mortality as critical outcomes.

We assessed the overall quality of the evidence for each outcome using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Guyatt 2011a; Higgins 2011; Schünemann 2013). We considered the following quality domains: study design and limitations, consistency of results, directness (generalisability), precision (sufficient data), and reporting of the results across all studies that measure that particular outcome (Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e). The quality starts at high when high-quality RCTs provide results for the outcome, and reduces by a level for each of the factors not met.

  • High-quality evidence: there are consistent findings among at least 75% of RCTs with no limitations of the study design, consistent, direct and precise data, and no known or suspected publication biases. Further research is unlikely to change either the estimate or our confidence in the results.
  • Moderate-quality evidence: one of the domains is not met. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
  • Low-quality evidence: two of the domains are not met. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
  • Very low-quality evidence: three of the domains are not met. We are very uncertain about the results.
  • No evidence: no RCTs were identified that addressed this outcome.

We entered data (i.e. pooled estimates of the effects and corresponding 95% confidence intervals (CIs)) and explicit judgments for each of the above aspects assessed into the Guideline Development Tool, the software used to create 'Summary of findings' tables (GRADEpro 2008). We explained all judgments involving the assessment of the study characteristics described above in footnotes or comments in the 'Summary of findings' table.

Measures of treatment effect

We followed the standard methods of the Cochrane Neonatal Review Group for data synthesis. We extracted categorical data for each intervention group and calculated relative risks (RRs) and absolute risk differences (RDs). If RDs were statistically significant, we would further calculate numbers needed to treat for an additional beneficial outcome (NNTBs) and numbers needed to treat for an additional harmful outcome (NNTHs). We would obtain means and standard deviations (SDs) for continuous data and perform analysis using mean differences (MDs). For each measure of effect, we would provide the corresponding 95% CIs.

Unit of analysis issues

We described, for each included trial, the observations on participants at selected time points. We planned to analyze follow-up data available at the point of discharge from the hospital as well as at the age of one month, three months, six months and one year as we would be assessing some of the outcomes at these different time points. We assessed whether the unit of analysis was appropriate for the unit of randomization. If we had included cluster RCTs, we would have used the intra-class correlation coefficient (ICC) to convert trials to their effective sample size before incorporating them into the meta-analysis.

Dealing with missing data

We recorded the drop-out rate for each trial. A drop-out rate equal to or greater than the event rate of the control group was considered to be significant and additional information was sought from the trial author(s) to facilitate an intention-to-treat analysis. When this was not possible, we performed a complete case analysis. We planned to perform a sensitivity analysis to evaluate the overall results with and without the inclusion of trials with significant drop-out rates. We contacted the study author(s) to obtain additional information

Assessment of heterogeneity

We assessed statistical heterogeneity by examining the I² statistic (Higgins 2011), a quantity that describes the proportion of variation in point estimates that is due to variability across trials rather than sampling error.

We interpreted the I² statistic as described below (Higgins 2003).

  • less than 25%: no heterogeneity;
  • 25% to 49%: low heterogeneity;
  • 50% to 74%: moderate heterogeneity; and
  • 75% or more: high heterogeneity.

In addition, we planned to do a Chi² test of homogeneity to determine the strength of evidence that heterogeneity was genuine.

If enough trials had been included, we would have explored clinical variation across trials by comparing the distribution of important participant factors among trials (for example, age) and trial factors (randomization, allocation concealment, blinding of outcome assessment, losses to follow-up, treatment type and co-interventions).

Assessment of reporting biases

If more than 10 trials had been included, we would have explored publication bias using funnel plots (Egger 1997; Higgins 2011).

Data synthesis

For each outcome reviewed, meta-analysis was feasible if more than one eligible trial was identified and there was sufficient homogeneity among the trials with respect to participants and reported outcomes. We summarized all eligible trials in Review Manager 2014. We used the standard methods of the Cochrane Neonatal Review Group to synthesize data using RRs, RDs, NNTBs, NNTHs, weighted mean differences (WMDs), and 95% CIs. We preferred a fixed-effect model to perform meta-analyses.

Subgroup analysis and investigation of heterogeneity

  1. Gestational age (< 28 weeks; greater than/or equal to 28 weeks)
  2. Birth weight (< 1000 grams; greater than/or equal to 1000 grams)
  3. Infants requiring assisted ventilation versus infants not requiring assisted ventilation
  4. Plasma-derived versus recombinant antithrombin concentrate
  5. Antithrombin compared with placebo versus antithrombin compared to no treatment

Sensitivity analysis

If enough trials had been included, we would have conducted sensitivity analyses to explore the effect of the methodological quality of the trials, checking to ascertain if trials with a high risk of bias overestimate the effect of treatment.

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Results

Description of studies

See Characteristics of included studies and Characteristics of studies awaiting classification.

Results of the search

The literature search run in April 2015 identified 241 references (Figure 1). After screening, we included only two randomized controlled trials (Fulia 2003; Schmidt 1998); and we classified one trial as awaiting classification (Muntean 1989).

We did not find other relevant studies by searching clinical trial registries.

Included studies

Two trials recruiting 182 infants met the inclusion criteria (Fulia 2003; Schmidt 1998). Details of the trials are described in Characteristics of included studies. Both studies were single center, randomized controlled trials enrolling preterm infants within 12 hours of life and comparing antithrombin to placebo. We did not find trials that compared antithrombin with other anticoagulants, e.g. heparin.

Schmidt 1998 included infants requiring ventilation for respiratory distress syndrome, birth weight 750 to 1900 g, postnatal age between 2 and 12 hours, presence of indwelling arterial catheter, ratio of arterial to alveolar oxygen pressure less than 0.3 after the first dose of exogenous surfactant. Infants were excluded if they had congenital infection, congenital malformation(s), hydrops, pulmonary hypoplasia, clinically apparent bleeding disorder, or thrombocytopenia (platelet count < 50 x 109/l), or were judged to be moribund. A total of 122 preterm infants were enrolled (61 in the experimental group and 61 in the control group). Gestational age and birth weights were similar in the two groups, i.e. 28.3 weeks ± 2.03 and 1198 ± 300 g in the antithrombin group and 28.8 weeks ± 2.25 and 1,201 ± 314.4 g in the control group. The first dose of antithrombin was 100 U/kg, given intravenously (on average 7 h after birth), followed by 50 U/kg every 6 hours for 48 hours. In the control group 1% Human Albumin solution was used. The primary efficacy endpoints were alveolar oxygen pressure and ventilator efficiency index. After 122 participants had been recruited randomization was halted because seven deaths had occurred in infants receiving antithrombin (with two cases of pulmonary hemorrhage) and two with placebo. The final rates of death before discharge were 11.5% with antithrombin and 4.9% with placebo (OR 2.65; 95% CI, 0.64 to 11.02; P = 0.18). Cranial ultrasonography was performed at baseline and again on day 7 of life.

Fulia 2003 included infants with a gestational age less than 30 weeks, postnatal age less than 12 hours, and antithrombin activity less than 40%. Infants were excluded if they had sepsis, congenital malformations, cerebral hemorrhage, bleeding disorders, or thrombocytopenia (platelet count < 50 x 109/l). A total of 60 preterm infants were enrolled (30 in the experimental group and 30 in the control group). Average gestational age was similar to that of Schmidt 1998, but birth weights were lower: in the antithrombin group (n = 30) birth weight was 1060 ± 218 g, and gestational age was 28.5 ± 1.5 weeks; in the placebo group (n = 30) 1054 ± 223 g and 28.5 ± 1.3 weeks. Dosage was the same as in Schmidt 1998, i.e. a loading dose of 100 U/kg of antithrombin intravenously, followed by 50 U/kg for 48 hours. However interval between doses was longer (8 hours). A 5% glucose solution was used as placebo. Arterial catheters were perfused with 1 ml/h of 5% glucose containing 1 IU/ml of unfractionated heparin; no other anticoagulants were administered. The primary endpoint was the rate of GM-IVH. Each infant received cranial ultrasonography before randomization and then on the second, fourth and seventh day of life.

Excluded studies

We excluded one study that was available only as abstract presentation, as we tried to contact the authors but we did not receive any response (Muntean 1989).

Risk of bias in included studies

Figure 2 summarizes the risk of bias of the trials included in this review.

Allocation (selection bias)

We judged Schmidt 1998 at low risk of selection bias, as it adopted adequate methods for generating and concealing the randomization sequence. We judged Fulia 2003 at high risk of bias as assignment envelopes were used without appropriate safeguards.

Blinding (performance bias and detection bias)

We judged Schmidt 1998 at low risk of performance and detection bias, as it provided sufficient data on blinding of study personnel and outcome assessors. Fulia 2003 did not provide sufficient information on blinding and was therefore judged at unclear risk of bias.

Incomplete outcome data (attrition bias)

Both trials had complete follow-up and were judged at low risk of attrition bias.

Selective reporting (reporting bias)

Fulia 2003 was not registered in a trial registry and we could not ascertain if there were deviations from the original protocol in the final publication. In Schmidt 1998 all protocol-specified primary and secondary outcomes were reported as per additional information from the authors.

Other potential sources of bias

Schmidt 1998 was halted at the request of the "External Safety and Efficacy Monitoring Committee" after 122 infants had been recruited (six participants less than the planned sample size) for safety reasons. The final rates of death before discharge were 11.5% with antithrombin and 4.9% with placebo (OR 2.65; 95% CI, 0.64 to 11.02; P = 0.18).

Effects of interventions

Antithrombin versus placebo or no treatment (comparison 1)

Two trials (Fulia 2003; Schmidt 1998), with a total of 182 infants, met the eligibility criteria. Schmidt 1998 compared antithrombin to a 5% glucose solution while Fulia 2003 compared antithrombin to a 1% Human Albumin solution (see Summary of findings table 1).

Primary outcomes
GH-IVH: Any severity (grade 1 to 4) (Outcome 1.1)

See: Analysis 1.1 Figure 3

Both trials (n = 175 infants) reported this outcome measured at seven days of life. Schmidt 1998 reported brain ultrasound data only on 115 out of 122 randomised infants. Prophylactic administration of antithrombin did not alter the risk of developing any GM-IVH (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).

Severe intraventricular hemorrhage: (grade 3 and 4) (Outcome 1.2)

See: Analysis 1.2, Figure 4

Both trials (n = 175 infants) reported this outcome measured at seven days of life. Schmidt 1998 reported brain ultrasound data only on 115 out of 122 randomised infants. Prophylactic administration of antithrombin did not alter the risk of developing any severe IVH (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).

Secondary outcomes
Neonatal mortality: < 28 days of age (Outcome 1.3)

See: Analysis 1.3

Neonatal mortality was reported in both trials. In Schmidt 1998, nine infants died within 28 days of life (seven in antithrombin group and two in control group); one more infant in the control group died after the neonatal period (32 days of life). In Fulia 2003 only three deaths occurred, one in the antithrombin group and two in the control group. There was no statistical difference in either of the studies (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).

Bronchopulmonary dysplasia (Outcome 1.4)

See: Analysis 1.4

Bronchopulmonary dysplasia was only reported in the Fulia 2003 study (typical RR 1.25, 95% CI 0.37 to 4.21; typical RD 0.03, 95% CI −0.15 to 0.21; 1 study, 60 infants.) The test for heterogeneity was not applicable. The study authors did not specify which definition of bronchopulmonary dysplasia was used.

Pneumothorax (on chest X-ray) (Outcome 1.5)

See: Analysis 1.5

The Fulia 2003 study of 60 infants was the only study to report data for pneumothorax (on chest X-ray) and found no difference (typical RR 0.67, 95% CI 0.12 to 3.71; typical RD −0.03, 95% CI −0.17 to 0.11; 1 study, 60 infants.) The test for heterogeneity was not applicable.

Duration of mechanical ventilation

Schmidt 1998 reported that median days of mechanical ventilation were 7.1 in the antithrombin group versus 4.8 in the placebo group (P < 0.001). The test for heterogeneity was not applicable.

Duration of oxygen therapy

Schmidt 1998 reported that median days of supplemental oxygen were 7.9 in the antithrombin group versus 5.5 in the placebo group (P < 0.0001). The test for heterogeneity was not applicable.

Persistent ductus arteriosus, defined as need for medical or surgical treatment (Outcome 1.6)

See: Analysis 1.6

Fulia 2003 reported no significant effect of antithrombin on the risk of PDA (typical RR 1.07, 95% CI 0.65 to 1.74; typical RD 0.03, 95% CI −0.22 to 0.29; 1 study, 60 infants.) The test for heterogeneity was not applicable.

Pulmonary hemorrhage (Outcome 1.7)

See: Analysis 1.7

One trial (Fulia 2003) reported on this outcome (typical RR 0.75, 95% CI 0.18 to 3.07; typical RD −0.03, 95% CI −0.20 to 0.13; 1 study, 60 infants). The test for heterogeneity was not applicable.

Clinically apparent bleeding during treatment during the first week of life (Outcome 1.7)

See: Analysis 1.8

The Schmidt 1998 study of 122 infants was the only study to report this outcome and found no difference (typical RR 1.23, 95% CI 0.89 to 1.71; typical RD 0.11, 95% CI −0.06 to 0.29; 1 study, 122 infants). The test for heterogeneity was not applicable.

We did not find any data on the following outcomes:

Infant mortality (one year of age); duration of respiratory support; duration of hospital stay; retinopathy of prematurity; necrotizing enterocolitis; need for blood transfusions; central catheter occlusion; stroke during treatment; cerebellar hemorrhage; cystic periventricular leukomalacia; brain MRI abnormalities; cerebral hemodynamics impairment, based on cerebral near-infrared spectroscopy; major neurodevelopmental disability assessed at 12 months of age or more.

Antithrombin versus unfractionated heparin (comparison 2)

We did not find trials comparing antithrombin to other anticoagulants.

Antithrombin versus low-molecular-weight heparin (comparison 3)

We did not find trials comparing antithrombin to other anticoagulants.

Subgroup Analysis

We were unable to conduct any of the planned subgroup analyses as only two trials were included.

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Discussion

Summary of main results

We evaluated the efficacy of antithrombin administration in the prevention of germinal matrix-intraventricular hemorrhage (GM-IVH) in very preterm infants. Only two trials (Fulia 2003; Schmidt 1998), with a total of 182 preterm infants, met the inclusion criteria of this review. Both trials enrolled infants with an average gestational age of about 29 weeks. Antithrombin activity was low in both trials, i.e. less than 40% in Fulia 2003 (as inclusion criterion) and 0.3 unit/ml in Schmidt 1998 (ventilated infants with ratio of arterial to alveolar oxygen pressure less than 0.3 after surfactant). Antithrombin was not better than placebo in terms of incidence or severity of GM-IVH, the primary outcomes of this review. When considering secondary outcomes, such as neonatal mortality, bronchopulmonary dysplasia, or bleeding we found no benefit of antithrombin over placebo.

Overall completeness and applicability of evidence

The available evidence is insufficient to understand if antithrombin is an effective and safe intervention for preventing GM-IVH in very preterm neonates. Only two randomised trials (182 newborns) assessed this study question. There were insufficient data available to assess the primary outcome of this review and other important outcomes such as infant mortality and long-term neurodevelopmental outcome. One study was stopped early due to an apparent imbalance in deaths between the treatment groups (Schmidt 1998). We found no trials comparing antithrombin with other anticoagulants or other preventive intervention, thus we cannot draw any conclusion on its comparative effectiveness.

Quality of the evidence

According to the GRADE approach, we rated the overall quality of the evidence for clinically relevant outcomes as "low" and "very low" (see Summary of findings table 1). We downgraded the overall quality of the evidence for the critical outcomes because of 1) limitations in the study design (i.e. selection bias due to the lack of allocation concealment for Fulia 2003), and 2) the imprecision of results (a small number of participants) that could be a source of random error risk. Random error is closely related to imprecision as the results of smaller studies are subject to greater sampling variation and hence are less precise (Higgins 2011). The estimate of neonatal mortality (< 28 days of age) was also affected by moderate heterogeneity, thus we further downgraded the overall quality of the evidence supporting this outcome (Guyatt 2011d).

Potential biases in the review process

It is unlikely that the literature search applied to this review has missed relevant trials, thus we are confident that this systematic review summarizes all the presently available evidence from randomized trials on the prophylactic use of antithrombin in very preterm infants. We obtained additional information on the population included in the trial by Schmidt et al from the main author (Schmidt 1998). It has been clarified that the trial included a small group of neonates with gestational age of 32 and 33 weeks (13 out of 122 neonates). We could not gain access to the individual trial data that would have allowed the extraction of the outcome data concerning neonates with gestational age less than 32 weeks, the inclusion criterion of this review. We decided to include the entire study as this slight discrepancy was not considered to impact on the overall validity and applicability of the results of this review.

Agreements and disagreements with other studies or reviews

We are not aware of other reviews that address the same clinical question, i.e. use of antithrombin to prevent GM-IVH in very preterm neonates. A Cochrane systematic review has been published on the use of antithrombin in preterm infants with respiratory distress syndrome (Bassler 2006). Though criteria for selecting studies differ, the same two trials were included as in the present review (Fulia 2003; Schmidt 1998). Bassler et al concluded against the routine use of antithrombin for the treatment of neonatal respiratory distress syndrome as it may increase mortality in preterm infants, though without reaching statistical significance (Bassler 2006). A review on the prevention of GM-IVH is currently assessing the effects of another anticoagulant, i.e. heparin (Bruschettini 2015).

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Authors' conclusions

Implications for practice

We found very few data on the prophylactic administration of antithrombin to reduce the incidence and severity of IVH in very preterm neonates. Given the imprecision of our estimates, 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. Limited evidence is available on other clinically relevant outcomes.

Implications for research

The value of further trials assessing antithrombin in the general population of very preterm infants appears to be limited as other promising preventive approaches exist. Antithrombin might be considered for investigation in specific conditions such as antithrombin deficiency, complex coagulation disorders, sepsis with disseminated intravascular coagulation, and transient neonatal protein C deficiency. In this context, future trials might compare the use of antithrombin with either placebo or other anticoagulants, e.g. heparin.

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Acknowledgements

We thank Roger Soll for his very valuable advice, Yolanda Brosseau and Colleen Ovelman for their kind and efficient support, Barbara Schmidt for providing additional data. We also thank Dr. Georg M. Schmölzer for his feedback as external referee.

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Contributions of authors

Study concept: MB, OR
Selection of studies: MB, OR
Acquisition of data: SZ, MGC
'Risk of bias' assessment: SZ, MGC, RB
Analysis of data: SZ, MGC, MB, OR.
Drafting of the manuscript: MB, OR
Interpretation and critical revision of the manuscript for important intellectual content: MB, OR, SZ, RB, LAR, MGC.

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Declarations of interest

MB, OR, SZ, RB, LAR and MC have no known conflicts of interest to declare.

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Differences between protocol and review

When we prepared the protocol of this review, we did not plan to summarize the review results into a 'Summary of findings' table, which was included at the review stage to be consistent with Cochrane's and the Cochrane Neonatal Review Group's requirements (see Summary of findings table 1).

One trial (Schmidt 1998) included a small group of neonates with gestational age of 32 and 33 weeks (13 out of 122 neonates). We decided to include the entire study as this slight discrepancy with the inclusion criterion of this review was not considered to impact on the overall validity and applicability of the results of this review.

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Published notes

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Characteristics of studies

Characteristics of included studies

Fulia 2003

Methods

Single-center randomized trial.

Neonatal Intensive Care Unit, Barone Romeo Hospital, Patti, Messina, Italy, between July 1999 and June 2001

Participants

60 preterm newborns admitted to Neonatal Intensive Care Unit, fulfilling the following criteria: gestational age less than 30 weeks; postnatal age less than 12 h, and antithrombin activity less than 40%.

Exclusion criteria: sepsis; congenital malformations; cerebral hemorrhage; bleeding disorders; or thrombocytopenia (platelet count < 50 x 109/l).

Antithrombin group (n = 30): birth weight 1060 ± 218 g, gestational age 28.5 ± 1.5 weeks.

Placebo group (n = 30): birth weight 1054 ± 223 g, gestational age 28.5 ± 1.3 weeks.

Interventions

Antithrombin: loading dose of 2ml/kg (equivalent to 100 U/kg of antithrombin) intravenously, followed by 1 ml/kg (equivalent to 50 U/kg) every 8 h for 48 h.

Placebo: 5% glucose solution.

Outcomes

Primary outcome was the risk of intraventricular hemorrhage. Secondary outcomes included mortality, pneumothorax, pulmonary hemorrhage, patent ductus arteriosus, bronchopulmonary dysplasia, and need for surfactant and inotropes.

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

"Sequence of treatments was chosen by a computerized series of randomized closed envelopes".

Allocation concealment (selection bias) High risk

Assignment envelopes were used without appropriate safeguards.

Blinding of participants and personnel (performance bias) Unclear risk

No information.

Blinding of outcome assessment (detection bias) Unclear risk

No information.

Incomplete outcome data (attrition bias) Low risk

No infant lost at follow-up.

Selective reporting (reporting bias) Unclear risk

We could not ascertain if there were deviations from the original protocol in the final publication (trial not registered, protocol not available).

Other bias Low risk  

Schmidt 1998

Methods

Single-center randomized trial.

Neonatal Intensive Care Unit, McMaster University Medical Centre, Hamilton, Ontario, Canada from November 1992 to February 1996.

Participants

122 premature infants fulfilling all of the following inclusion criteria: birth weight, 750 to 1900 g; postnatal age between 2 and 12 h; endotracheal intubation and positive pressure ventilation for respiratory distress syndrome; indwelling arterial catheter; ratio of arterial to alveolar oxygen pressure less than 0.3 after the first dose of exogenous surfactant.

Exclusion criteria: congenital infection; congenital malformation(s); hydrops; pulmonary hypoplasia; clinically apparent bleeding disorder; or thrombocytopenia (platelet count < 50 x 109/l). Infants considered to be moribund were also excluded.

Antithrombin group (n = 61): gestational age (weeks) 28.3 ± 2.03, birth weight: 1198 ± 300 g;

Placebo group (n = 61): gestational age (weeks) 28.8 ± 2.25, birth weight: 1201 ± 314.4 g.

Interventions

Antithrombin: loading dose of 2 ml/kg (equivalent to 100 U/kg of antithrombin) intravenously, followed by 1 ml/kg (equivalent to 50 U/kg) every 6 h for 48 h.

Placebo: 1% Human Albumin solution.

Outcomes

The primary efficacy endpoints were alveolar oxygen pressure and ventilator efficiency index.

The safety of antithrombin therapy was evaluated primarily by comparing the incidence of severe (grade 3) intraventricular hemorrhage and of periventricular echodensities in the two treatment groups. Brain ultrasound data were reported only on 115 out of 122 randomised infants.

Notes

The therapy was initiated on average 7.2 h after birth in each group.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

The sequence of treatments was determined by random assignment with an allocation ratio of 1:1, using a computer program developed by Hoechst AG (Frankfurt, Germany).

Allocation concealment (selection bias) Low risk

Packages containing lyophilized study medication labeled with the unique participant number were provided to the study center by the manufacturer.

Blinding of participants and personnel (performance bias) Low risk

No unblinding occurred during the entire trial period. The allocation code was released to the study statistician by the company after the database was declared closed.

Blinding of outcome assessment (detection bias) Low risk

The allocation code was released to the study statistician by the company after the database was declared closed.

Incomplete outcome data (attrition bias) Low risk

No infant lost at follow-up.

Selective reporting (reporting bias) Low risk

All protocol-specified primary and secondary outcomes were reported as per additional information from the authors.

Other bias Unclear risk

After 122 infants had been recruited, randomization was halted, at the request of the External Safety and Efficacy Monitoring Committee, 6 participants short of the planned sample size.

Characteristics of excluded studies

Muntean 1989

Reason for exclusion

Open-label, randomized trial in premature infants administered with antithrombin (< 1500 grams: 100 U; > 1500 grams: 200 U) plus standard therapy (45 infants) versus standard therapy alone (53 infants); main outcomes: frequency and duration of ventilation.

Published only as abstract. We contacted the trial authors by email (April 2015) in order to obtain further information on the study population and thus confirm the possible inclusion in the review. We did not receive any answer.

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Summary of findings tables

1 Antithrombin versus placebo for the prevention of intraventricular hemorrhage in very preterm infants

Antithrombin versus placebo for the prevention of intraventricular hemorrhage in very preterm infants

Patient or population: very preterm infants at risk of intraventricular hemorrhage
Intervention: Antithrombin

Comparison: Placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Antithrombin

Intraventricular hemorrhage (any severity, grade 1 to 4)

Study population

RR 1.30
(0.87 to 1.93)

175
(2 studies)

⊕⊕⊝⊝
low 1,2

 

315 per 1000

409 per 1000
(274 to 608)

Severe Intraventricular hemorrhage (grade 3 to 4)

Study population

RR 1.04
(0.55 to 1.94)

175
(2 studies)

⊕⊕⊝⊝
low 1,2

 

180 per 1000

187 per 1000
(99 to 349)

Neonatal mortality (all-cause, < 28 days of age)

Study population

RR 2
(0.62 to 6.45)

182
(2 studies)

⊕⊝⊝⊝
very low 1,2,3

 

44 per 1000

88 per 1000
(27 to 284)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Footnotes

The assumed risk is the risk of the control arm

1 limitations in study design: high risk of selection bias due to the lack of allocation concealment in one study; unclear risk of bias of reporting bias
2 imprecision: small number of participants, few events
3 inconsistency: moderate heterogeneity

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References to studies

Included studies

Fulia 2003

Fulia F, Cordaro S, Meo P, Gitto P, Gitto E, Trimarchi G, et al. Can the administration of antithrombin III decrease the risk of cerebral hemorrhage in premature infants? Biology of the Neonate 2003;83(1):1-5.

Schmidt 1998

Schmidt B, Gillie P, Mitchell L, Andrew M, Caco C, Roberts R. A placebo-controlled randomized trial of antithrombin therapy in neonatal respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 1998;158(2):470-6.

Excluded studies

Muntean 1989

Muntean W, Rosegger H. Antithrombin III concentrate in preterm infants with IRDS: an open, controlled, randomized clinical trial (abstract). Thrombosis and Haemostasis 1989;62:288.

Studies awaiting classification

None noted.

Ongoing studies

None noted.

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Data and analyses

1 Antithrombin versus placebo

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Intraventricular hemorrhage, grade 1 to 4 2 175 Risk Ratio (M-H, Fixed, 95% CI) 1.30 [0.87, 1.93]
1.2 Intraventricular hemorrhage, grade 3 to 4 2 175 Risk Difference (M-H, Fixed, 95% CI) 0.01 [-0.11, 0.12]
1.3 Neonatal mortality (< 28 days of age) 2 182 Risk Difference (M-H, Fixed, 95% CI) 0.04 [-0.03, 0.12]
1.4 Bronchopulmonary dysplasia 1 Risk Difference (M-H, Fixed, 95% CI) No totals
1.5 Pneumothorax 1 Risk Difference (M-H, Fixed, 95% CI) Subtotals only
1.6 Patent ductus arteriosus 1 Risk Difference (M-H, Fixed, 95% CI) Subtotals only
1.7 Pulmonary hemorrhage 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.8 Clinically apparent bleeding during treatment during the first week of life 1 122 Risk Difference (M-H, Fixed, 95% CI) 0.11 [-0.06, 0.29]
 

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Figures

Figure 1

Refer to Figure 1 caption below.

Study flow diagram (Figure 1).

Figure 2

Refer to Figure 2 caption below.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study (Figure 2).

Figure 3 (Analysis 1.1)

Refer to Figure 3 caption below.

Forest plot of comparison: 1 Antithrombin versus placebo, outcome: 1.1 Intraventricular hemorrhage, grade 1 to 4 (Figure 3).

Figure 4 (Analysis 1.2)

Refer to Figure 4 caption below.

Forest plot of comparison: 1 Antithrombin versus placebo, outcome: 1.2 Intraventricular hemorrhage, grade 3 to 4 (Figure 4).

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Sources of support

Internal sources

  • Institute for Clinical Sciences, Lund University, Lund, Sweden

    MB and OR are employed by this organization

  • Istituto Giannina Gaslini, Genoa, Italy

    LAR and MGC are employed by this organization

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

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Appendices

1 Search strategies

  • Cochrane Library: (Antithrombin OR antithrombin* OR antithrombin III OR ATIII) AND (infant or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW)
  • MEDLINE: (Antithrombins[Mesh] OR antithrombin* OR antithrombin III OR ATIII) AND ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR Clinical Trial[ptyp] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh]))
  • EMBASE: ((Antithrombin or antithrombin III or ATIII) and (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) and (human not animal) and (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
  • CINHAL: (Antithrombins[Mesh] OR antithrombin* OR antithrombin III OR ATIII) AND (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)
  • Pediatric Academic Societies' 2000 - 2015 Archive Abstracts2Vie site (http://www.abstracts2view.com/pasall/ External Web Site Policy): antithrombin AND infant
  • ClinicalTrials.gov (https://clinicaltrials.gov/) and ISRCTN Registry (http://www.isrctn.com/ External Web Site Policy): (Antithrombin OR antithrombin III OR ATIII) AND infant

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2016 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.