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Antithrombin for respiratory distress syndrome in preterm infants

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Authors

Dirk Bassler1, David Millar2, Barbara Schmidt3

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


1Department of Neonatology, University Children's Hospital, Tuebingen, Germany [top]
2Regional Neonatal Unit, Royal Maternity Hospital, Belfast, Ireland [top]
3Department of Clinical Epidemiology and Biostatistics, McMaster University and University of Pennsylvania, Philadelphia, Pennsylvania, USA [top]

Citation example: Bassler D, Millar D, Schmidt B. Antithrombin for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD005383. DOI: 10.1002/14651858.CD005383.pub2.

Contact person

Dirk Bassler

Department of Neonatology
University Children's Hospital
Tuebingen
Germany

E-mail: dirk.bassler@med.uni-tuebingen.de

Dates

Assessed as Up-to-date: 21 December 2009
Date of Search: 21 December 2009
Next Stage Expected: 21 December 2011
Protocol First Published: Issue 3, 2005
Review First Published: Issue 4, 2006
Last Citation Issue: Issue 4, 2006

What's new

Date / Event Description
22 December 2009
Updated

This review updates the existing review "Antithrombin for respiratory distress syndrome in preterm infants" published in the Cochrane Database of Systematic Reviews (Bassler 2006).

Updated search found no new trials.

No changes to conclusions.

History

Date / Event Description
11 September 2008
Amended

Converted to new review format.

Abstract

Background

Acquired Antithrombin (AT) deficiency is a common and prognostically important finding in sick preterm infants with respiratory distress syndrome (RDS). It has been hypothesised that AT concentrate may improve clinical outcomes in preterm infants with RDS.

Objectives

To determine the effect of administration of AT concentrate compared with placebo or no treatment on mortality in preterm infants with RDS.

Search methods

An electronic literature search in CENTRAL, MEDLINE, and EMBASE was performed in August 2006. References from identified studies were cross checked for possible additional studies. Experts in the field and pharmaceutical companies were contacted for unpublished data. Abstracts of the American Society of Pediatric Research and European Society of Pediatric Research meetings (1983 to 2005) were searched and authors of relevant studies were contacted to obtain additional information. The electronic search was updated in December 2009.

Selection criteria

Randomized controlled trials comparing any dose and duration of AT therapy with placebo or no treatment in preterm infants with RDS.

Data collection and analysis

Two review authors independently extracted data from included studies. Data for similar outcomes were combined where appropriate, using a fixed-effects model in RevMan 4.

Results

Two trials consisting of 182 preterm infants fulfilled the inclusion criteria. Mean gestational age of patients included was 28 weeks. In one trial, patients had to be intubated and ventilated for RDS to be eligible for the study. In the other trial, RDS was not mentioned as an inclusion criteria; however, the vast majority of infants in the study received surfactant. No individual trial showed a significant difference in mortality. One of the trials was stopped early because of an increase in deaths in the AT group. The pooled analysis for mortality within the first week of life showed a typical relative risk of 2.67 (95% CI 0.72 to 9.83) in favour of the control group. Only the trial that was stopped early followed the infants long enough to report neonatal mortality. This trial reported 7 deaths (11.5%) in the AT group and two deaths (3.3%) in the placebo group within 28 days of life. Secondary outcomes included days of mechanical ventilation and supplemental oxygen which were only reported in 1 trial. Both outcomes were in favour of the control group and statistically significant (p < 0.05).

Authors' conclusions

Preterm infants with RDS are unlikely to benefit from AT treatment and may be harmed.

Plain language summary

Antithrombin for respiratory distress syndrome in preterm infants

Antithrombin (AT) is a substance that is produced by the liver and that plays an important role in the control of blood clotting and the subsequent breakdown of the clot. Critically ill infants, such as those born prematurely with immature lungs leading to respiratory distress (Respiratory Distress Syndrome; RDS) have low concentrations of AT in the blood. Studies have been conducted to examine whether preterm infants with RDS benefit from the administration of AT. In our systematic review, we found that preterm infants with RDS do not benefit from therapy with AT and may be harmed.

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Background

Antithrombin (AT), a potent inhibitor of the reactions of the coagulation cascade, is a glycoprotein synthesized by the liver. Although the name, antithrombin, implies that it works only on thrombin, it inhibits other coagulation enzymes as well (activated factors IX, X, XI and XII) (Roemisch 2002). The ability of AT to limit coagulation through multiple pathways makes it one of the primary natural anticoagulant proteins. The well-recognised association between inherited AT deficiency and the risk of venous thrombosis in adults points to the importance of AT as a modulator of blood coagulation (Bick 2003).

Healthy neonates have physiologically low levels of AT as compared with adults (Hathaway 1978; Andrew 1987; Andrew 1988). Activities of AT are decreased in preterm (Peters 1985) and critically ill infants, such as those with respiratory distress syndrome (RDS) (van den Berg 1989). RDS is an acute lung disease in preterm infants that is characterized by diffuse atelectasis, high permeability edema, hyaline membrane formation and right to left shunting of pulmonary blood flow. The primary cause of neonatal RDS is surfactant deficiency in the immature lung (Avery 1959) and surfactant replacement has significantly reduced mortality and morbidity from neonatal RDS (Soll 1992). However, sometimes residual lung injury remains despite surfactant therapy.

It was hypothesised that increased thrombin formation due to acquired AT deficiency contributes to the progression and abnormal resolution of neonatal RDS. In animals studies, unopposed intravascular thrombin activity leads to an increasing endothelial permeability resulting in pulmonary oedema (Malik 1987). Intravascular thrombin formation also contributes to pulmonary hypertension by vasoconstriction in rabbits (Malik 1987). In the extravascular lung compartment, thrombin may inhibit surfactant function and therefore contribute to the progression of neonatal RDS (Seeger 1993). The effects of acquired AT deficiency on the regulation of neonatal thrombin formation have been studied extensively during the course of RDS in preterm infants. Schmidt demonstrated a strong direct relationship between the activation of the clotting system, the depletion of AT activity, and the severity of RDS (Schmidt 1992). These observations were later confirmed and extended by Brus (Brus 1997).

It was therefore reasonable to hypothesize that unopposed thrombin activity may contribute to the progression of neonatal diseases that are accompanied by hypercoagulopathy and that antithrombotic therapy with AT might improve clinical outcomes of preterm infants with RDS.

Description of the condition

RDS is an acute lung disease in preterm infants that is characterized by diffuse atelectasis, high permeability edema, hyaline membrane formation and right to left shunting of pulmonary blood flow. The primary cause of neonatal RDS is surfactant deficiency in the immature lung (Avery 1959) and surfactant replacement has significantly reduced mortality and morbidity from neonatal RDS (Soll 1992). However, sometimes residual lung injury remains despite surfactant therapy.

Description of the intervention

Antithrombin (AT), a potent inhibitor of the reactions of the coagulation cascade, is a glycoprotein synthesized by the liver. Although the name, antithrombin, implies that it works only on thrombin, it inhibits other coagulation enzymes as well (activated factors IX, X, XI and XII) (Roemisch 2002). The ability of AT to limit coagulation through multiple pathways makes it one of the primary natural anticoagulant proteins. The well-recognised association between inherited AT deficiency and the risk of venous thrombosis in adults points to the importance of AT as a modulator of blood coagulation (Bick 2003).

Healthy neonates have physiologically low levels of AT as compared with adults (Hathaway 1978; Andrew 1987; Andrew 1988). Activities of AT are decreased in preterm (Peters 1985) and critically ill infants, such as those with respiratory distress syndrome (RDS) (van den Berg 1989).

How the intervention might work

It was hypothesised that increased thrombin formation due to acquired AT deficiency contributes to the progression and abnormal resolution of neonatal RDS. In animals studies, unopposed intravascular thrombin activity leads to an increasing endothelial permeability resulting in pulmonary oedema (Malik 1987). Intravascular thrombin formation also contributes to pulmonary hypertension by vasoconstriction in rabbits (Malik 1987). In the extravascular lung compartment, thrombin may inhibit surfactant function and therefore contribute to the progression of neonatal RDS (Seeger 1993). The effects of acquired AT deficiency on the regulation of neonatal thrombin formation have been studied extensively during the course of RDS in preterm infants. Schmidt demonstrated a strong direct relationship between the activation of the clotting system, the depletion of AT activity, and the severity of RDS (Schmidt 1992). These observations were later confirmed and extended by Brus (Brus 1997).

It was, therefore, reasonable to hypothesize that unopposed thrombin activity may contribute to the progression of neonatal diseases that are accompanied by hypercoagulopathy and that antithrombotic therapy with AT might improve clinical outcomes of preterm infants with RDS.

Objectives

To compare mortality in the first 28 days of life in preterm infants with RDS treated with AT or placebo or no treatment.

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Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials and quasi-randomized trials, published and unpublished, were considered for this review.

Types of participants

Preterm infants (< 37 weeks gestation) with RDS (based on at least two of the four signs and symptoms: need of supplemental oxygen, tachypnea, intercostal retractions, grunting and/or receiving surfactant).

Types of interventions

Intravenous AT was compared to placebo or no treatment. Any dose and any duration of AT therapy was included in this review.

Types of outcome measures

Primary outcomes
  1. mortality (measured in the first week of life, in the first 28 days of life, up to the time of discharge from hospital
Secondary outcomes
  1. rates of intraventricular hemorrhages (IVH) on ultrasounds grades 1 to 3 by Papile classification) assessed after one week of life;
  2. rates of severe IVH on ultrasounds [grade 3 by Papile classification and grade 4 (periventricular echodensity, PVED)] assessed after one week of life;
  3. rates of PVED (grade 4 IVH by Papile classification) on ultrasound assessed after one week of life;
  4. duration of mechanical ventilation (days);
  5. duration of supplemental oxygen (days);
  6. ratio of arterial to alveolar oxygen pressure (a/A)PO2 throughout the first week of life;
  7. ratio of ventilator efficiency index (VEI) throughout the first week of life;
  8. total number of patients needing surfactant;
  9. patients with pneumothoraces;
  10. patients needing inotropes;
  11. patients with persistent ductus arteriosus;
  12. patients with pulmonary hemorrhages;
  13. clinically apparent bleeding during treatment during the first week of life;
  14. patients with bronchopulmonary dysplasia;
  15. coagulation screens during treatment;
  16. platelet counts during treatment;
  17. blood levels of AT during treatment.

Search methods for identification of studies

Electronic searches

The following terms were used to search the electronic databases (antithrombin OR antithrombin III OR AT OR ATIII OR AT III OR AT-III). The standard search strategy of the Cochrane Neonatal Review Group was used. The initial search strategy included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), a MEDLINE search (1966 to Jan 2005) that was limited to clinical trials and limited by age to newborn (birth - one month), and further searches in EMBASE (1980 to Jan 2005). No language restriction was applied.

The searches in all three databases [CENTRAL (The Cochrane Library, Issue 3, 2006), MEDLINE, EMBASE] were updated in August 2006 by using the same strategy.

In December 2009, we updated the search as follows: MEDLINE (search via PubMed), CINAHL, EMBASE and CENTRAL (The Cochrane Library) were searched from 2006 to 2009. Search terms: antithrombin OR antithrombin III OR ATIII OR AT III OR AT-III. Limits: human, infant and clinical trial. No language restrictions were applied.

Searching other resources

References from identified studies were crosschecked for possible additional studies. Experts in the field and pharmaceutical companies were contacted for unpublished data. We also searched abstracts of the American Society of Pediatric Research (SPR) and European Society of Pediatric Research (ESPR) meetings (1983 to 2005). The authors of relevant abstracts were contacted if necessary to obtain additional information.

Data collection and analysis

The standard methods of the Cochrane Neonatal Review Group Guidelines were employed.

Selection of studies

The abstract of each reference generated by the literature search was examined by two review authors (DB, DM) for inclusion criteria and where relevant a full article was obtained. Interobserver agreement was measured by Cohens unweighted kappa statistic.

Data extraction and management

Two reviewer authors (DB, DM) independently extracted data from included studies on data collection forms. Additional information was requested from the authors of each trial to clarify methodology and results as necessary. Data entry was done by two reviewer authors (DB, DM) independently and the analysis was done using Revman 4.

Assessment of risk of bias in included studies

The relevant studies were reviewed for methodological quality by two review authors (DB, DM). Areas of disagreement were discussed with a third review author (BS) and consensus had to be reached before analysis of the results. Criteria for assessing methodological quality were: adequate randomization, allocation concealment, blinding of parents and caregivers and assessors of outcome, completeness of follow-up (> 95%) in randomized subjects for the primary outcome. All criteria were defined as "yes", "no" or "unsure". These data were entered into the table "Characteristic of Included Studies".

In addition, the following issues were evaluated and entered into the Risk of Bias table:

  1. Sequence generation: Was the allocation sequence adequately generated?
    • For each included study, we described the method used to generate the allocation sequence as: adequate (any truly random process e.g. random number table; computer random number generator); inadequate (any nonrandom process e.g. odd or even date of birth; hospital or clinic record number); or unclear.
  2. Allocation concealment: Was allocation adequately concealed?
    • For each included study, we described the method used to conceal the allocation sequence as: adequate (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes); inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); or unclear.
  3. Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
    • For each included study, we described the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We assessed the methods as: adequate, inadequate or unclear for participants; adequate, inadequate or unclear for study personnel; and adequate, inadequate or unclear for outcome assessors and specific outcomes assessed.
  4. Incomplete outcome data: Were incomplete outcome data adequately addressed?
    • For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We stated 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. We assessed methods as: adequate (< 20% missing data); inadequate (> 20% missing data) or unclear.
  5. Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?
    • For each included study, we assessed the possibility of selective outcome reporting bias as: adequate (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported); inadequate (where not all the study'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; study fails to include results of a key outcome that would have been expected to have been reported); or unclear.
  6. Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?
    • For each included study, we described any important concerns regarding 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 study was free of other problems that could put it at risk of bias as: yes; no; or unclear.

Measures of treatment effect

Statistical analyses were performed using Review Manager software. Categorical data were analyzed using relative risk (RR), risk difference (RD) and the number needed to treat (NNT). Continuous data were analyzed using weighted mean difference (WMD). The 95% Confidence interval (CI) was reported on all estimates as a measure of uncertainty.

Assessment of heterogeneity

Heterogeneity in the results of the trials was assessed using the I2 test. The results of these tests were used as a trigger to explore sources of heterogeneity.

Data synthesis

If appropriate, meta-analyses of pooled data from all contributing trials were performed using a fixed effect model. Heterogeneity in the results of the trials was assessed using the I2 test. The results of these tests were used as a trigger to explore sources of heterogeneity.

Subgroup analysis and investigation of heterogeneity

Heterogeneity in the results of the trials was assessed using the I2 test. The results of these tests were used as a trigger to explore sources of heterogeneity.

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Results

Description of studies

The electronic search strategy yielded a total of 1360 citations: 23 (PubMed), 1145 (Embase), 192 (Central). After reading the titles/abstracts, six articles were identified as potentially relevant and full text versions were obtained. Two reviewers independent of each other identified these studies with good inter-observer agreement (Cohens unweighted kappa = 0.8, SE = 0.05). Handsearching abstracts of the American Society of Pediatric Research (SPR) and European Society of Pediatric Research (ESPR) meetings (1983 to 2005) yielded three potentially relevant citations, one of them already identified by the electronic search. The other two were finally regarded as not relevant by both reviewer authors (DB, DM) after independent review. Crosschecking the references of the six articles did not yield any additional studies. All six studies were performed in different countries (Italy, Germany, Austria, Turkey, Canada, and the US) and were published in English language. Contact of experts in the field and pharmaceutical companies did not reveal any additional studies.

Four of the six studies (Yurdakok 1997; Muntean 1989; Brangenberg 1997; Ambrus 1990) were excluded because of the following reasons: no randomization, no antithrombin as intervention (Yurdakok 1997); RDS not as an inclusion criteria, antithrombin used as prophylaxis, not as treatment (Muntean 1989); observational study, no randomization (Brangenberg 1997); no antithrombin as intervention (Ambrus 1990). See table "characteristics of excluded studies" for further details.

Two trials consisting of 182 preterm infants, were included in the systematic review.
Schmidt 1998 studied 122 preterm infants with birth weights between 750 and 1900 g who required mechanical ventilation for RDS. Only infants with moderate to severe disease were included. AT was given as a loading dose of 2 ml/kg (equivalent to 100 U/kg of AT) intravenously, followed by 1 ml/kg (equivalent to 50 U/kg) every 6 h for 48 h.

Fulia 2003 examined whether the administration of AT decreases the risk of cerebral hemorrhage in premature infants. They studied 60 infants who were born at less than 30 weeks' gestation and who had an AT activity less than 40% in the first 12 h of life. Only infants without sonographic evidence of ICH were enrolled. AT was given as a loading dose of 2 ml/kg (equivalent to 100 U/kg of AT) intravenously, followed by 1 ml/kg (equivalent to 50 U/kg) every 8 h for 48 h. RDS was not mentioned as an inclusion criteria, however 27/30 infants randomized to the placebo group and 28/30 infants randomized to the AT group received surfactant. The study report does not explicitly describe whether surfactant was given for treatment or prophylaxis; the study states that "all newborns received the same exogenous surfactant". It is likely that the majority of infants in this study cohort suffered from at least mild RDS, an assumption that is further supported by the relatively low rates of antenatal steroids in this study (53.3% in the AT group, 56.6% in the placebo group). The study by Fulia 2003 was included following independent agreement of the two reviewer authors (DB & DM) despite RDS being included as an inclusion criterion; this decision is a post hoc decision that was also supported by the third review author (BS).

See table "Characteristics of Included Studies" for further details.

Risk of bias in included studies

Schmidt 1998: This was a single centre randomized study with an adequate method of generating the randomization sequence. Allocation was concealed and parents, caregivers and outcome assessors were blinded to the study intervention/control. No unblinding occurred during the study period. All patients randomized were followed until discharge and included in the analysis. However randomization was halted six patients short of the planned sample size at the request of the External Safety and Efficacy Monitoring Committee due to safety concerns. Initially the trial was powered (80%) to detect an increase in postrandomization (a/A)PO2 of about 0.17 with AT.

Fulia 2003: This was a single centre randomized study with an adequate method of generating the randomization sequence. Allocation concealment is questionable as the authors just mention "closed envelopes" containing the randomization sequences. Nothing is mentioned in the manuscript in regards to blinding of the different groups. A 5% glucose solution was used as placebo and the authors did not comment whether staff in the nursery was able to distinguish between the crystalloid and colloid study solutions in the two treatment groups. All patients randomized were followed until 1 week of life and included in the analysis.

Effects of interventions

Primary outcome

Mortality (Outcomes 1.1 - 1.3):

We assessed mortality at three different time points. Only Schmidt reported mortality to 28 days (RR 3.5, 95%CI 0.76, 16.18) (Outcome table 1.1) and mortality before discharge from hospital (RR 2.33, 95%CI 0.63, 8.61) (Outcome 1.3). Data on mortality at seven days were provided in both studies (outcome table 1.2). Schmidt found an increase in mortality at seven days in the AT group which was of borderline statistical significance (RR 7.00, 95%CI 0.89, 55.2; RD 0.10, 95%CI 0.01, 0.18). The meta-analysis of both trials suggests a trend towards increased mortality at seven days in the AT groups, but this did not reach statistical significance (typical RR 2.67, 95%CI 0.72, 9.83; typical RD 0.05, 95%CI -0.01, 0.12).

Secondary outcomes

Intraventricular hemorrhages (IVH) / Periventricular echodensity (PVED) (Outcomes 1.4 - 1.6):

Neither of the two studies was able to detect a significant difference in the overall incidence of IVH between the AT and the placebo group. Schmidt 1998 showed a trend towards a higher combined rate of any intraventricular hemorrhage and periventricular echodensities on day seven, which was still present after adjustment for birth weight and gender stratum as well as the presence or absence of intraventricular and periventricular lesions at baseline: the adjusted odds ratio was 2.30 (95% CI, 0.86 to 6.16; p = 0.06). In the study by Fulia 2003 there was no significant difference in the overall incidence of IVH 26.7% vs 30% (RR 0.89, 95% CI 0.40, 1.99) but they reported a higher incidence of IVH Grade 3 in the placebo group in contrast with the AT group (21.4% vs 13.7%, no CI provided). Fulia 2003 did not report any cases with PVED (grade 4 IVH), while in the study by Schmidt 1998, seven infants in the AT group and six infants in the control group developed PVED (grade 4 IVH) (outcome table 01.06). When outcomes from both studies were pooled, no statistical difference was found (IVH grade 1 to 3 after one week: typical RR 1.27, 95%CI 0.79, 2.05) (Outcome 1.4); (IVH grade 3 after one week: typical RR 0.90, 95% CI 0.39, 2.10) (Outcome 1.5).

Mechanical ventilation / Oxygen therapy / Gas exchange:

Only the study by Schmidt 1998 reported data on mechanical ventilation, oxygen therapy and measures of gas exchange. Infants allocated to the AT group needed mechanical ventilation and oxygen therapy for a significantly longer period of time than infants who were allocated to the placebo group. Median days of mechanical ventilation were 7.1 in the AT group versus 4.8 in the placebo group (p < 0.001). Median days of supplemental oxygen were 7.9 in the AT group versus 5.5 in the placebo group (p < 0.0001). The ratio of arterial to alveolar oxygen pressure (a/A)PO2 and the Ventilator Efficiency Index (VEI) were similar in both groups throughout the first week of life.

Patients needing surfactant (Outcome 1.7):

Only the study by Fulia 2003 reported the number of patients that received surfactant in each group. The study report does not explicitly describe when the surfactant was given nor whether it was given for treatment or prophylaxis. The manuscript states that "all newborns received the same exogenous surfactant". 28/30 infants randomized to the AT group and 27/30 infants randomized to the placebo group received surfactant (RR 1.04, 95%CI 0.89, 1.21).

Patients with pneumothorax (Outcome 1.8):

Only the study by Fulia 2003 reported the number of patients with pneumothorax. 2/30 infants randomized to the AT group and 3/30 infants randomized to the placebo group developed a pneumothorax in the study (RR 0.67, 95%CI 0.12, 3.71). At what time point the outcome was assessed is not explicitly described in the study report. Schmidt 1998 reported in their published manuscript, that the rates of pulmonary air leaks were very similar in the two groups.

Patients needing inotropes (Outcome 1.9):

Only the study by Fulia 2003 reported the number of patients needing inotropes. 4/30 infants randomized to the AT group and 6/30 infants randomized to the placebo group received inotropes during the study (RR 0.67, 95%CI 0.21, 2.13). At what time point the outcome was assessed is not explicitly described in the study report.

Patients with persistent ductus arteriosus (Outcome 1.10):

Only the study by Fulia 2003 reported the number of patients with PDA. 16/30 infants randomized to the AT group and 15/30 infants randomized to the placebo group had a PDA during the study (RR 1.07, 95%CI 0.65, 1.74). At what time point the outcome was assessed is not explicitly described in the study report. Schmidt 1998 reported in their published manuscript, that the rates of PDA were very similar in the two groups.

Pulmonary hemorrhage (Outcome table 1.11)/ Clinical apparent bleeding (Outcome 1.12):

Only the study by Schmidt 1998 reported data on patients with clinical apparent bleeding. 37/61 infants in the AT group and 30/61 infants in the placebo group suffered from clinical apparent bleeding from puncture sites, the umbilicus, nasogastric tubes, or endotracheal tubes throughout the first week of life (RR 1.23, 95%CI 0.89, 1.71).

The study by Fulia 2003 was the only study that explicitly reported data on patients with pulmonary hemorrhage. 3/30 infants randomized to the AT group and 4/30 infants randomized to the placebo group developed a pulmonary hemorrhage (RR 0.75, 95%CI 0.18, 3.07). At what time point the outcome was assessed is not explicitly described in this study report.

Patients with bronchopulmonary dysplasia (BPD) (Outcome 1.13):

Only the study by Fulia 2003 reported the number of patients with bronchopulmonary dysplasia. 5/30 infants randomized to the AT group and 4/30 infants randomized to the placebo group developed BPD (RR 1.25, 95%CI 0.37, 4.21). What definition of BPD was used and at what time point the outcome was assessed is not explicitly described in the study report.

Coagulation screens during treatment:

Only the study by Fulia 2003 provided information on Quick's PT and PTT. The manuscript just mentions that no statistical differences were observed, actual data are not shown.

Platelet counts during treatment:

Only the study by Fulia 2003 provided information on platelet counts. The manuscript just mentions that no statistical differences were observed, actual data are not shown.

Blood levels of AT during treatment:

Both studies measured AT concentration in infants at baseline and during treatment. Neither study found a significant difference in AT concentration between the treatment and the control group at baseline. In the study by Schmidt 1998, AT activity in treated infants was raised to means of 1.69 and 2.25 U/ml at 24 and 48 hours, respectively. Corresponding means in control infants were 0.37 and 0.44 U/ml (p < 0.0001). In the study by Fulia 2003, blood levels of AT in treated infants was raised to means of 12.73, 14.96, and 17.45 mg/dl on day one, two, and three, respectively. Corresponding means in control infants were 10.53, 11.61, and 13.13 mg/dl (p < 0.001).

Subgroup analyses

In the protocol for this review, we considered subgroup analyses according to birth weight, severity of RDS, and era (pre or post surfactant). However, no data were found that permitted such analyses.

Discussion

Although AT concentrates have been available for more than 20 years, the evidence to justify their use in neonatal RDS remains weak. Our systematic review of this therapy in newborn infants did not document clinically important benefits of neonatal AT therapy. Moreover, there is some suggestion that AT therapy may be harmful in preterm infants with moderate to severe RDS.

Only two studies with a total of 182 preterm infants fulfilled the inclusion criteria for our systematic review. Our primary outcome, mortality, did not reach statistical significance. There is a trend towards increased mortality in the AT group that is consistent among the assessment of this outcome at three different time points. However, these findings are mostly driven by the study from Schmidt 1998. This study was stopped early because of an observed imbalance in deaths between the treatment groups. Early stopping of a trial may have lead to a biased result, overestimating the real difference in mortality between the 2 groups. However randomization in this study was halted only six patients short of the planned sample size of 128 patients.

The duration of mechanical ventilation and oxygen therapy was significantly prolonged in the group that was treated with AT-concentrate. All other secondary outcomes describing the clinical course of the patients showed no difference between the groups. Like most of the results in this systematic review, the significant findings in favour of the control group are based on data from only one of the trials because of inconsistency in the reported outcomes. However, the study by Schmidt 1998, including 122 patients, is a study with rigorous methodology: adequate method of generating randomisation sequence, allocation concealment, blinding of parents, caregivers and outcome assessors, complete follow-up. Therefore the significant findings in favour of the control group for the duration of mechanical ventilation and oxygen therapy are likely to be true and different interpretations for the treatment failure of AT concentrate in the preterm population with RDS need to be considered. Acquired AT deficiency and increased thrombin formation may just be coincidental markers of the disease process, and therefore thrombin inhibition may not alter the course of neonatal RDS. Alternatively, as Schmidt 1998 speculate "thrombin may indeed play a pathogenetic role in neonatal acute lung injury, but AT concentrate was not sufficiently effective in suppressing unopposed thrombin activity".

One of the strengths of this meta-analysis is its comprehensive and sensitive literature search. In addition to an electronic search, we hand searched conference abstracts of the two most important paediatric conferences for a time period of more than 20 years and contacted pharmaceutical industry and experts. We did not apply a language restriction to our literature search. Therefore we consider it very unlikely that our literature search may have missed relevant trials and are confident, that this systematic review summarizes all the presently available evidence from RCTs on AT for RDS in preterm infants.

Authors' conclusions

Implications for practice

The results of this systematic review suggest that AT therapy may increase mortality in preterm infants with RDS. Based on one well-designed trial, the review also shows that the administration of AT concentrate during the first two days of life prolongs the time on mechanical ventilation and the time needing supplemental oxygen. The potential harm together with the certain lack of benefit strongly argue against the routine use of AT concentrate for the treatment of neonatal RDS in preterm infants

Implications for research

Possible adverse effects of antithrombotic agents have to be carefully considered in this high-risk population. Future studies for AT in RDS are not indicated. The role of AT administration in sick neonates for indications other than RDS should only be considered in the context of well-designed controlled clinical trials.

Acknowledgements

We would like to thank H. Rieger who provided additional information about his study, and G. Guyot for his helpful review of the manuscript.

The Cochrane Neonatal Review Group has been funded in part 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. HHSN267200603418C.

Contributions of authors

Dirk Bassler (DB): literature search, eligibility check, data extraction, data entry, preparation of manuscript
David Millar (DM): eligibility check, data extraction, data entry, review of manuscript
Barbara Schmidt (BS): adjudicator, review of manuscript

The recent update (December 2009) was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Diane Haughton and Roger Soll) and reviewed and approved by DB.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Fulia 2003

Methods

Single centre randomized study;
Adequate randomization: yes; Method of generating randomization sequence: computerized series of randomized closed envelopes; Allocation concealment: unsure (closed envelopes were used);
Blinding: unsure (not described)
Completeness of follow-up: yes (all patients randomized were followed until ultrasonography after 1 week of life)

Participants

60 infants who were born at less than 30 weeks' gestation and who had an AT activity less than 40% in the first 12 hours of life. Only infants without sonographic evidence of ICH were enrolled. RDS was not specifically mentioned as an inclusion criteria, however 27/30 infants in the placebo group and 28/30 infants in the AT group received surfactant.

Interventions

AT was given as a loading dose of 2ml/kg (equivalent to 100 U/kg of AT) intravenously, followed by 1 ml/kg (equivalent to 50 U/kg) every 8h for 48h to 30 infants. A 5% glucose solution was used as placebo in 30 infants.

Outcomes

The primary outcome was the risk of intraventricular hemorrhages. Overall, 8 clinical outcomes were reported: surfactant use, pneumothorax, pulmonary hemorrhage, patent ductus arteriosus, use of inotropes, bronchopulmonary dysplasia, intraventricular hemorrhages (grade 0-4 according to Papile), death.

Notes

Period of enrollment: July 1999 to June 2001
Published: 2003
Source of funding: not mentioned

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Single centre randomized study;
Adequate randomization: yes; Method of generating randomization sequence: computerized series of randomized closed envelopes.

Allocation concealment? Yes

Allocation concealment: unsure (closed envelopes were used).

Blinding? Unclear

Blinding: unsure (not described).

Incomplete outcome data addressed? Yes

Completeness of follow-up: yes (all patients randomized were followed until ultrasonography after 1 week of life).

Free of selective reporting? Unclear
Free of other bias? Unclear

Schmidt 1998

Methods

Single centre randomized study;
Adequate randomization: yes;
Method of generating randomization sequence: computer program developed by Hoechst AG (Frankfurt, Germany)
Allocation concealment: Yes (packages containing study medication labelled with the unique patient number were provided to the study centre by the manufacturer);
Blinding of parents, caregivers and outcome assessors: yes (no unblinding occurred during the study period; the allocation code was released to the study statistician after the database was declared closed)
Completeness of follow-up: yes (all patients randomized were followed until discharge);
Other: randomization was halted six patients short of the planned sample size at the request of the External Safety and Efficacy Monitoring Committee due to safety concerns.

Participants

122 preterm infants with birth weights between 750 and 1900g who required mechanical ventilation for RDS. Only infants with moderate to severe disease were included, i.e. those with a ratio of arterial to alveolar oxygen pressure (a/A PO2) less than 0.3 after the first dose of exogenous surfactant when the infants were between 2 and 12 hours old.

Interventions

AT was given as a loading dose of 2ml/kg (equivalent to 100 U/kg of AT) intravenously, followed by 1 ml/kg (equivalent to 50 U/kg) every 6h for 48h to 61 infants. A 1% human albumin solution was used as placebo in 61 infants

Outcomes

The primary outcome was the ratio of arterial to alveolar oxygen pressure a/A P02. Overall, 9 clinical outcomes were reported: measures of gas exchange (a/A PO2 and the ventilator efficiency index), the median duration of mechanical ventilation and need for supplemental oxygen, rates of pulmonary air leaks and patent ductus arteriosus, rates of ICH, clinically apparent bleeding from puncture sides, the umbilicus, nasogastric tubes, or endotracheal tubes, and mortality.

Notes

Period of study: November 1992 to February 1996
Published: 1998
Source of funding: Supported by Physicians' Services Incorporated Foundation, Toronto, and Behringwerke AG, Germany

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Single centre randomized study;
Adequate randomization: yes;
Method of generating randomization sequence: computer program developed by Hoechst AG (Frankfurt, Germany).

Allocation concealment? Yes

Allocation concealment: Yes (packages containing study medication labelled with the unique patient number were provided to the study centre by the manufacturer).

Blinding? Yes

Blinding of parents, caregivers and outcome assessors: yes (no unblinding occurred during the study period; the allocation code was released to the study statistician after the database was declared closed)

Incomplete outcome data addressed? Yes

Completeness of follow-up: yes (all patients randomized were followed until discharge).

Free of selective reporting? Yes

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

Free of other bias? Unclear

Randomization was halted six patients short of the planned sample size at the request of the External Safety and Efficacy Monitoring Committee due to safety concerns.

Ambrus 1990

Reason for exclusion

500 premature infants were treated on a randomized double-blind basis with human plasminogen or placebo. In a second randomized double-blind study infants with RDS were treated with human plasmin or placebo
Reason for exclusion: Antithrombin was not used as an intervention

Brangenberg 1997

Reason for exclusion

103 preterm infants (gestational age 25-32) received antithrombin as a single dose on the day of birth and subsequently only in the case of a new decrease below an antithrombin activity of 50%. Coagulation studies, intracranial hemorrhages and other clinical outcomes were reported.
Reason for exclusion: Observational study without control group and randomization

Muntean 1989

Reason for exclusion

103 premature infants (gestational age 26-34, mean 31), were treated in an open randomized trial with a single dose of antithrombin immediately after birth in addition to standard therapy or with standard therapy alone. Frequency of artificial ventilation required as therapy for RDS and the duration of ventilation were the main outcomes.
Reason for exclusion: RDS is not specified as an inclusion criteria in the trial. Antithrombin was used as a prophylaxis rather than a treatment for RDS.

Yurdakok 1997

Reason for exclusion

Serum Thrombin/Antithrombin complex and prothrombin fragment 1.2 were studied in 35 preterm infants with or without RDS in the first few hours of life.
Reason for exclusion: No randomized controlled trial; no Antithrombin as intervention.

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References to studies

Included studies

Fulia 2003

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

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;158:470-6.

Excluded studies

Ambrus 1990

Ambrus JL, Ambrus CM. Changes in the fibrinolysin system in infantile and adult respiratory distress syndrome (ARDS), caused by trauma and/or septic shock in patients and in experimental animals. Journal of Medicine 1990;21:67-84.

Brangenberg 1997

Brangenberg R, Bodensohn M, Buerger U. Antithrombin-III substitution in preterm infants - effects on intracranial hemorrhage and coagulation parameters. Biology of the Neonate 1997;72:76-83.

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.

Yurdakok 1997

Yurdakok M, Yigit S. Plasma thrombomodulin, plasminogen activator and plasminogen activator inhibitor levels in preterm infants with or without respiratory distress syndrome. Acta Paediatrica 1997;86:1022-3.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Andrew 1987

Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefesen DM, Powers P. Development of the human coagulation system in the full-term infant. Blood 1987;70:165-72.

Andrew 1988

Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Castle V, Powers P. Development of the human coagulation system in the healthy premature infant. Blood 1988;72:1651-7.

Avery 1959

Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. A.M.A. Journal of Diseases of Children 1959;97:517-23.

Bick 2003

Bick RL. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and Protein S defects. Hematology/oncology Clinics of North America 2003;17:9-36.

Brus 1997

Brus F, Van Oeveren W, Okken A, Oetomo SB. Disease severity is correlated with plasma clotting and fibrinolytic and kinin-kallikrein activity in neonatal respiratory distress syndrome. Pediatric Research 1997;41:120-7.

Hathaway 1978

Hathaway WE, Neumann LL, Borden CA, Jacobson LJ. Immunologic studies of antithrombin III heparin cofactor in the newborn. Thrombosis and Haemostasis 1978;39:624-30.

Malik 1987

Malik AB, Horgan MJ. Mechanisms of thrombin-induced lung vascular injury and oedema. American Review of Respiratory Disease 1987;136:467-70.

Peters 1985

Peters M, ten Cate JW, Jansen E, Breederveld C. Coagulation and fibrinolytic factors in the first week of life in healthy infants. Journal of Pediatrics 1985;106:292-5.

Roemisch 2002

Roemisch J, Gray E, Hoffmann JN, Wiedermann CJ. Antithrombin: a new look at the actions od a serine protease inhibitor. Blood Coagulation & Fibrinolysis 2002;13:657-70.

Schmidt 1992

Schmidt B, Vegh P, Weitz J, Johnston M, Caco C, Roberts R. Thrombin/Antithrombin III complex formation in the neonatal respiratory distress syndrome. American Review of Respiratory Disease 1992;145:767-70.

Seeger 1993

Seeger W, Elssner A, Guenther A, Kraemer H, Kalinowski HO. Lung surfactant phospholipids associate with polymerizing fibrin: loss of surface activity. American Journal of Respiratory Cell and Molecular Biology 1993;9:213-20.

Soll 1992

Soll RF, McQueen MC. Respiratory distress syndrome. In: Sinclair JC, Bracken MB, editor(s). Effective care of the newborn infant. Oxford: Oxford University Press, 1992:325-358.

van den Berg 1989

van den Berg W, Breederveld C, ten Cate JW, Peters M, Borm JJ. Low antithrombin III: accurate predictor of idiopathic respiratory distress syndrome in premature neonates. European Journal of Pediatrics 1989;148:455-8.

Other published versions of this review

Bassler 2006

Bassler D, Millar D, Schmidt B. Antithrombin for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD005383. DOI: 10.1002/14651858.CD005383.pub2.

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Data and analyses

1 Antithrombin versus Control

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Neonatal Mortality 1 122 Risk Ratio (M-H, Fixed, 95% CI) 3.50 [0.76, 16.18]
1.2 Mortality within 7 days 2 182 Risk Ratio (M-H, Fixed, 95% CI) 2.67 [0.72, 9.83]
1.3 Mortality before discharge 1 122 Risk Ratio (M-H, Fixed, 95% CI) 2.33 [0.63, 8.61]
1.4 IVH Grade 1-3 after 1 week 2 182 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.79, 2.05]
1.5 IVH Grade 3 after 1 week 2 182 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.39, 2.10]
1.6 PVED (grade 4 IVH) after 1 week 1 122 Risk Ratio (M-H, Fixed, 95% CI) 1.17 [0.42, 3.27]
1.7 Patients needing surfactant 1 60 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.89, 1.21]
1.8 Patients with pneumothorax 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.12, 3.71]
1.9 Patients needing inotropes 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.21, 2.13]
1.10 Patients with PDA 1 60 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.65, 1.74]
1.11 Patients with pulmonary hemorrhage 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.18, 3.07]
1.12 Clinical apparent bleeding during the first week of life 1 122 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [0.89, 1.71]
1.13 Bronchopulmonary dysplasia 1 60 Risk Ratio (M-H, Fixed, 95% CI) 1.25 [0.37, 4.21]

This review is published as a Cochrane review in The Cochrane Library, Issue 2, 2010 (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 recent version of the review.