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.
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. 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 Experts in the field and pharmaceutical companies were contacted for unpublished data.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 - 2005). The authors of relevant abstracts were contacted if necessary to obtain additional information.
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.
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.
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 01.01) and mortality before discharge from hospital (RR 2.33, 95%CI 0.63, 8.61) (outcome table 01.03). Data on mortality at seven days were provided in both studies (outcome table 01.02). 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)
(Outcome tables 01.04 - 01.06)
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 - 3 after one week: typical RR 1.27, 95%CI 0.79, 2.05) (outcome
table 01.04); (IVH grade 3 after one week: typical RR 0.90, 95% CI
0.39, 2.10) (outcome table 01.05).
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 table 01.07)
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 table 01.08)
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 table 01.09)
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 table 01.10)
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 01.11)/ Clinical apparent bleeding (Outcome table 01.12)
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 table
01.13)
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.
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.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Fulia 2003 | 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) |
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. | 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. | 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. | Period of enrollment: July 1999 to June 2001 Published: 2003 Source of funding: not mentioned |
B |
| Schmidt 1998 | 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. |
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. | 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 | 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. | Period of study: November 1992 to February 1996 Published: 1998 Source of funding: Supported by Physicians' Services Incorporated Foundation, Toronto, and Behringwerke AG, Germany |
A |
| Study | Reason for exclusion |
| Ambrus 1990 | 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 | 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 | 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 | 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. |
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 {published data only}
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.
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 {published data only}
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 {published data only}
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 {published data only}
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.
* indicates the primary reference for the study
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 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 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 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 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 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 AB, Horgan MJ. Mechanisms of thrombin-induced lung vascular injury and oedema. American Review of Respiratory Disease 1987;136:467-70.
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 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 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 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 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 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.
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Antithrombin versus Control | ||||
| 01 Neonatal Mortality | 1 | 122 | RR (fixed), 95% CI | 3.50 [0.76, 16.18] |
| 02 Mortality within 7 days | 2 | 182 | RR (fixed), 95% CI | 2.67 [0.72, 9.83] |
| 03 Mortality before discharge | 1 | 122 | RR (fixed), 95% CI | 2.33 [0.63, 8.61] |
| 04 IVH Grade 1-3 after 1 week | 2 | 182 | RR (fixed), 95% CI | 1.27 [0.79, 2.05] |
| 05 IVH Grade 3 after 1 week | 2 | 182 | RR (fixed), 95% CI | 0.90 [0.39, 2.10] |
| 06 PVED (grade 4 IVH) after 1 week | 1 | 122 | RR (fixed), 95% CI | 1.17 [0.42, 3.27] |
| 07 Patients needing surfactant | 1 | 60 | RR (fixed), 95% CI | 1.04 [0.89, 1.21] |
| 08 Patients with pneumothorax | 1 | 60 | RR (fixed), 95% CI | 0.67 [0.12, 3.71] |
| 09 Patients needing inotropes | 1 | 60 | RR (fixed), 95% CI | 0.67 [0.21, 2.13] |
| 10 Patients with PDA | 1 | 60 | RR (fixed), 95% CI | 1.07 [0.65, 1.74] |
| 11 Patients with pulmonary hemorrhage | 1 | 60 | RR (fixed), 95% CI | 0.75 [0.18, 3.07] |
| 12 Clinical apparent bleeding during the first week of life | 1 | 122 | RR (fixed), 95% CI | 1.23 [0.89, 1.71] |
| 13 Bronchopulmonary dysplasia | 1 | 60 | RR (fixed), 95% CI | 1.25 [0.37, 4.21] |
01.03 Mortality before discharge
01.04 IVH Grade 1-3 after 1 week
01.05 IVH Grade 3 after 1 week
01.06 PVED (grade 4 IVH) after 1 week
01.07 Patients needing surfactant
01.08 Patients with pneumothorax
01.09 Patients needing inotropes
01.11 Patients with pulmonary hemorrhage
01.12 Clinical apparent bleeding during the first week of life
01.13 Bronchopulmonary dysplasia
Prof Barbara Schmidt
Department of Paediatrics. Department of Clinical Epidemiology and
Biostatistics
McMaster university
Room 3N11
McMaster University Medical Centre
Hamilton
Ontario CANADA
L8N 3Z5
Telephone 1: +1 905 521 2100 extension: 73243
Facsimile: +1 905 521 5007
| This review is published as a
Cochrane review in The Cochrane Library, Issue 4, 2006 (see http://www.thecochranelibrary.com
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. |
