Haematological interventions for treating disseminated

intravascular coagulation during pregnancy and postpartum

(Protocol)

Martí-Carvajal AJ, Comunián-Carrasco G, Peña-Martí GE

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane
Library 2010, Issue 7
http://www.thecochranelibrary.com

Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol) i
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Haematological interventions for treating disseminated

intravascular coagulation during pregnancy and postpartum

Arturo J Martí-Carvajal1 , Gabriella Comunián-Carrasco2 , Guiomar E Peña-Martí2

1 Iberoamerican Cochrane Network, Valencia, Venezuela. 2 Departamento de Obstetricia y Ginecología, Universidad de Carabobo,
Valencia, Venezuela

Contact address: Arturo J Martí-Carvajal, Iberoamerican Cochrane Network, Valencia, Edo. Carabobo, 2001, Venezuela.
arturo.marti.carvajal@gmail.com.

Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: New, published in Issue 7, 2010.

Citation: Martí-Carvajal AJ, Comunián-Carrasco G, Peña-Martí GE. Haematological interventions for treating disseminated intravas-
cular coagulation during pregnancy and postpartum. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD008577.
DOI: 10.1002/14651858.CD008577.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess the clinical effectiveness and safety of heparins (LMWH and UFH), danaparoid sodium, synthetic protease inhibitor,
antithrombin, human recombinant activated protein C, recombinant human soluble thrombomodulin, recombinant tissue factor
pathway inhibitor, recombinant activated factor VIIa and any other types of haematological interventions for treating DIC during
pregnancy and postpartum.

Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol) 1
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
BACKGROUND
Description of the condition
Definition of disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) is an acquired syn-
drome characterized by systemic intravascular activation of coag-
ulation. This leads to deposition of fibrin in the circulation and
occurs in the course of severe diseases (Dalainas 2008). The mor-
bidity of DIC is related to organ dysfunction and bleeding, which
accounts for the high risk of death associated with the condition
(Levi 2007). Organ dysfunction is caused by intravascular fib-
rin deposition (ischaemic phase); these microvascular thromboses
lead to end organ damage (Williams 2008). The bleeding phase
is due to massive and ongoing activation of coagulation, which
leads to the depletion of platelets and coagulation factors. This
explains why DIC is also known as consumption coagulopathy
(Levi 2001). In summary, DIC is an acquired coagulopathy, and
can never be considered as an isolated clinical entity; it is a haema-
tological emergency.
Burden of disseminated intravascular coagulation
It has been suggested that DIC represents up to 26.8% of the
acquired bleeding disorders (Asthana 2009). DIC is considered
as a critical care clotting catastrophe (DeLoughery 2005). “The
frequency by which peripartum haemostatic emergencies result in
DIC is dependent on the characteristics of the centre. In Western
hospitals, it is estimated that 1% to 5% of patients with DIC have
a peripartum haemostatic emergency as the underlying cause. In
developing countries this frequency is thought to be much higher”
(Levi 2009a).
Obsteric disorders of disseminated intravascular
coagulation
The common obstetric causes of DIC are: amniotic fluid em-
bolism; intrauterine fetal demise; HELLP syndrome (haemolysis,
elevated liver enzymes and low platelets); pre-eclampsia/eclamp-
sia; placental abruption and placenta praevia; septic abortion and
intrauterine infection; acute fatty liver of pregnancy (Levi 2009b;
Thachil 2009). Additionally, some pregnant women have a risk of
massive transfusion which is associated with DIC (Lurie 2000).
These several clinical entities show the “varied modes of clinical
expression of DIC and illustrate the diverse clinical and anatomic
manifestations of this syndrome” (Bick 2000). Recently, patho-
physiology of DIC in obstetric disorders has been widely reviewed
(Thachil 2009). One aspect with remarkable importance is that
the placenta plays a major role for activating coagulation system
(Thachil 2009).
Mechanisms of disseminated intravascular
coagulation generation
The pathogenesis of DIC “is based on tissue factor-mediated initi-
ation of systemic coagulation activation that is insufficiently con-
tained by physiologic anticoagulant pathways and amplified by
impaired endogenous fibrinolysis” (Levi 2007). The clinical entity
is “initiated by intravascular release of procoagulant substances,
such as tissue thromboplastin, or by damage to vascular endothe-
lium and platelets” (Prentice 1985). A number of researchers have
investigated the pathogenetic mechanisms of DIC (Levi 2001;
Saba 2006; Thachil 2009; Wada 2004). However, the core of DIC
is “enhanced generation of thrombin in vivo” (Levi 2009b). It has
been suggested that, in DIC related with HELLP syndrome, the
condition is generated by microangiopathic haemolytic anaemia
accompanying vascular endothelial damage, and platelet adhesion
and activation, facilitating fibrin formation (Levi 2009a).
Diagnosis of disseminated intravascular coagulation
generation
Guidelines for diagnosis of DIC have recently been published (Levi
2009b). Table 1 shows the International Society of Thrombosis
and Haemostasis (ISHT) scoring system for overt DIC.

Table 1. Diagnostic scoring system for disseminated intravascular coagulation (Levi 2009)

Scoring system for overt DIC

A) Risk assessment:
Does the patient have and un-
derlying disorder known to be
associated with overt DIC?
If yes: proceed.
If no: do not use this algorithm.
B) Order global coagulation C) Score the test results
tests Platelet count:
(Prothrombin time (PT) > 100 x 109 /l = 0;
, platelet count, fibrinogen, fib- < 100 x 109 /l = 1;
rin related marker.) < 50 x 109 /l = 2).
Elevated fibrin marker (D-
dimer, fibrin degradation prod-
ucts)
D) Calculate score
≥ 5 compatible with overt DIC:
repeat score daily.
< 5 suggestive for non-overt
DIC: repeat next 1-2 d.

Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol) 2
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Diagnostic scoring system for disseminated intravascular coagulation (Levi 2009)
Description of the intervention
Levi 2009b’s guidance indicates that DIC must be managed by
treating the underlying disease; it is the cornerstone of the ther-
apy (Dalainas 2008; Levi 2007; Prentice 1985). Additionally, sup-
portive anticoagulant interventions aim to resolve coagulation ab-
normalities. These drugs include low molecular weight heparin
(LMWH), unfractionated heparin (UFH), danaparoid sodium,
synthetic protease inhibitor, antithrombin, human recombinant
activated protein C, recombinant activated factor VIIa, recom-
binant human soluble thrombomodulin, and recombinant tissue
factor pathway inhibitor (Levi 2009b; Nohira 2008; Wada 2009).
How the intervention might work
Anticoagulant drugs try to play the role of natural anticoagulants
(protein C system and the antithrombin system) which are dis-
rupted during DIC. Additionally, there is a close relationship be-
tween coagulation and inflammation pathways during DIC: “in-
flammation leads to activation of coagulation and coagulation con-
siderably affects inflammatory activity” (Levi 2008).
Why it is important to do this review
It is important to conduct this systematic review for many rea-
sons. First, obstetric disorders are a major cause of DIC. Second,
there is uncertainty about the true role of the anticoagulant ap-
proaches for treating DIC in pregnant women. Third, the new
generation of anticoagulants (recombinant anticoagulant) are ex-
pensive; therefore, their clinical effectiveness and safety must be
assessed. Fourth, the older anticoagulant (heparin), although less
expensive than new generation anticoagulants, needs to be evalu-
ated in terms of clinical effectiveness and safety .
OBJECTIVES
To assess the clinical effectiveness and safety of heparins (LMWH
and UFH), danaparoid sodium, synthetic protease inhibitor, an-
Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
(No increase = 0, moderate in-
crease = 2; strong increase = 3.
Prolonged PT
(< 3 s = 0; > 3 but < 6 s = 1; > 6
s = 2).
Fibrinogen level (> 1 g/l = 0; <
1 g/l = 1).
tithrombin, human recombinant activated protein C, recombi-
nant human soluble thrombomodulin, recombinant tissue fac-
tor pathway inhibitor, recombinant activated factor VIIa and any
other types of haematological interventions for treating DIC dur-
ing pregnancy and postpartum.
METHODS
Criteria for considering studies for this review
Types of studies
Randomized clinical trials (RCTs) irrespective of publication status
(trials may be unpublished or published as an article, an abstract,
or a letter), language (no language limitations will be applied) and
country. We will apply no restrictions with respect to periods of
follow up, or to diagnostic criteria of disseminated intravascular
coagulation (DIC).
We will exclude quasi-randomised studies and prospective obser-
vational studies for evaluating clinical effectiveness. However, we
will consider these studies for reports on adverse events.
Types of participants
Pregnant women with DIC. We will apply no restriction by age
or cause of DIC.
Types of interventions
Since DIC must requires resolution of the underlying condition
plus different approaches, we will consider the following ’primary
or conventional care’ interventions: surgical and non-surgical or
both; antibiotic therapy; replacement of blood products; fluid
therapy; uterine evacuation; and hysterectomy. We will consider
anticoagulants as a complementary treatment of the conventional
care interventions. Thus, for the purpose of this review, eligible
RCTs will compare the same conventional interventions with and
3
without anticoagulants for treating DIC during pregnancy and
postpartum.
• Intervention: LMWH, UFH, danaparoid sodium,
synthetic protease inhibitor, antithrombin, human recombinant
activated protein C, recombinant activated factor VIIa,
recombinant human soluble thrombomodulin, recombinant
tissue factor pathway inhibitor plus conventional care (antibiotic
therapy, replacement of blood products, fluid therapy, uterine
evacuation, hysterectomy or both).
• Control: conventional care (antibiotic therapy, replacement
of blood products, fluid therapy, uterine evacuation,
hysterectomy or both) alone or plus placebo.
Types of outcome measures
Primary outcomes
• Maternal death: defined as “death of a woman while
pregnant or within 42 days of termination of pregnancy,
irrespective of the duration and the site of pregnancy, from any
cause related to or aggravated by the pregnancy or its
management but not from accidental or incidental causes” (Porta
2008).
• Perinatal mortality: defined as death during “time limited
to the period between 28 weeks’ gestation and one week
postnatally” (Porta 2008).
Secondary outcomes
• Safety
Adverse events: “any untoward medical occurrence that may present
during treatment with a pharmaceutical product but which does
not necessarily have a causal relationship with this treatment” (
Nebeker 2004);
Adverse drug reaction: “a response to a drug which is noxious and
uninitiated and which occurs at doses normally used in man for
prophylaxis, diagnosis, or therapy of disease, or for the modifica-
tion of physiologic functions” (Nebeker 2004).
Search methods for identification of studies
Electronic searches
We will contact the Trials Search Co-ordinator to search the
Cochrane Pregnancy and Childbirth Group’s Trials Register.
The Cochrane Pregnancy and Childbirth Group’s Trials Register
is maintained by the Trials Search Co-ordinator and contains trials
identified from:
Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1. quarterly searches of the Cochrane Central Register of
Controlled Trials (CENTRAL);
2. weekly searches of MEDLINE;
3. handsearches of 30 journals and the proceedings of major
conferences;
4. weekly current awareness alerts for a further 44 journals
plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL and MEDLINE,
the list of handsearched journals and conference proceedings, and
the list of journals reviewed via the current awareness service can
be found in the ‘Specialized Register’ section within the edito-
rial information about the Cochrane Pregnancy and Childbirth
Group.
Trials identified through the searching activities described above
are each assigned to a review topic (or topics). The Trials Search
Co-ordinator searches the register for each review using the topic
list rather than keywords.
In addition we will search LILACS (1982 to current) (see:Appendix
1), trials registries via the World Health Organization International
Clinical Trials Platform Search Portal (ICTRP), (see:Appendix 2)
and the following websites (see:Appendix 3):
1. Food and Drug Administration;
2. European Medicines Agency;
3. MedWatch. The FDA Safety Information and Adverse
Event Reporting Program
4. Medicines and Healthcare products Regulatory Agency (
MHRA);
5. Scirus;
6. (CenterWatch);
7. Sistema de Información Esencial en Terapéutica y Salud (
SIETES);
8. NHS Evidence in Health and Social Care;
9. DailyMed (DailyMed);
10. Excelencia Clinica.
We will not apply any language restrictions.
Data collection and analysis
Selection of studies
Two review authors (Arturo Martí-Carvajal (AMC) and Gabriella
Comunián (GC)) will independently assess for inclusion all the
potential studies we identify as a result of the search strategy. We
will resolve any disagreement through discussion or, if required,
we will consult to Guiomar Peña-Marti (GPM).
Data extraction and management
We will use a form to extract data (Zavala 2006). For eligible stud-
ies, two review authors (AMC and GC) will extract the data using
the agreed form. We will resolve discrepancies through discussion
4
or, if required, we will consult to GPM. We will enter data into
Review Manager software (RevMan 2008) and check for accuracy.
When information regarding any of the above is unclear, we will
attempt to contact authors of the original reports to provide further
details.
Assessment of risk of bias in included studies
Three review authors will independently assess risk of bias for each
study using the criteria outlined in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2009). We will resolve
any disagreement by discussion.
(1) Sequence generation (checking for possible selection
bias)
We will describe for each included study the method used to gen-
erate the allocation sequence in sufficient detail to allow an assess-
ment of whether it should produce comparable groups.
We will assess the method as:
• adequate (any truly random process, e.g. random number
table; computer random number generator);
• inadequate (any non-random process, e.g. odd or even date
of birth; hospital or clinic record number);
• unclear.
(2) Allocation concealment (checking for possible selection
bias)
We will describe for each included study the method used to
conceal the allocation sequence in sufficient detail and determine
whether intervention allocation could have been foreseen in ad-
vance of, or during recruitment, or changed after assignment.
We will assess the methods as:
• adequate (e.g. telephone or central randomisation;
consecutively numbered sealed opaque envelopes);
• inadequate (open random allocation; unsealed or non-
opaque envelopes, alternation; date of birth);
• unclear.
(3) Blinding (checking for possible performance bias)
We will describe for each included study the methods used, if
any, to blind study participants and personnel from knowledge of
which intervention a participant received. We will judge studies
at low risk of bias if they were blinded, or if we judge that the
lack of blinding could not have affected the results. We will assess
blinding separately for different outcomes or classes of outcomes.
We will assess the methods as:
• adequate, inadequate or unclear for participants;
• adequate, inadequate or unclear for personnel;
• adequate, inadequate or unclear for outcome assessors.
Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(4) Incomplete outcome data (checking for possible attrition
bias through withdrawals, dropouts, protocol deviations)
• Yes, adequate, the numbers and reasons for dropouts and
withdrawals in all intervention groups were described or if it was
specified that there were no dropouts or withdrawals.
• Unclear, the report gave the impression that there had been
no dropouts or withdrawals, but this was not specifically stated.
• No, inadequate, the number or reasons for dropouts and
withdrawals were not described.
We will further examine the percentages of dropouts overall in
each trial and per randomisation arm and we will evaluate whether
intention-to-treat analysis has been performed or could be per-
formed from the published information.
Were all randomised participants analyzed in the group to
which they were allocated? (intention-to-treat (ITT) analysis)
• Yes (low risk of bias): specifically reported by authors that
ITT was undertaken and this was confirmed on study
assessment, or not stated but evident from study assessment that
all randomized participants are reported/analyzed in the group
they were allocated to for the most important time point of
outcome measurement irrespective of non-compliance and co-
interventions.
• No (high risk of bias): lack of ITT confirmed on study
assessment (patients who were randomized were not included in
the analysis because they did not receive the study intervention,
they withdrew from the study or were not included because of
protocol violation) regardless of whether ITT reported or not.
• ‘As-treated’ analysis done with substantial departure of the
intervention received from that assigned at randomization;
potentially inappropriate application of simple imputation.
• Unclear (uncertain risk of bias): described as ITT analysis,
but unable to confirm on study assessment, or not reported and
unable to confirm by study assessment.
(5) Selective reporting bias
We will describe for each included study how we investigated the
possibility of selective outcome reporting bias and what we found.
We will assess the methods 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);
• unclear.
5
(6) Free of other bias (baseline imbalance, early stopping,
academic, drug company involvement)
We will describe for each included study any important concerns
we have about other possible sources of bias (Gurusamy 2009;
Ioannidis 2008a; Ioannidis 2008b).
• Yes (low risk of bias), the trial appears to be free of other
components that could put it at risk of bias.
• Unclear (uncertain risk of bias), the trial may or may not be
free of other components that could put it at risk of bias.
• No (high risk of bias), there are other factors in the trial that
could put it at risk of bias, e.g., no sample size calculation made,
early stopping, industry involvement, or an extreme baseline
imbalance.
(7) Overall risk of bias
We will make explicit judgements about whether studies are at
high risk of bias, according to the criteria given in the Handbook
(Higgins 2009). With reference to (1) to (6) above, we will assess
the likely magnitude and direction of the bias and whether we
consider it is likely to impact on the findings. We will explore the
impact of the level of bias through undertaking sensitivity analyses
- see Sensitivity analysis.
1. We will consider trials that achieve a ’yes’ for generation of
allocation sequence, adequate allocation concealment, adequate
blinding, adequate handling of incomplete outcome data, no
selective outcome reporting, and without other bias risks as low-
bias risk trials.
2. Trials at moderate risk of bias will be in between and trials
at high risk of bias are either ’no’ or ’unclear’ on the majority of
domains.
Arturo Martí-Carvajal will enter the risk of bias data into RevMan
(RevMan 2008), and Gabriela Comunián and Guiomar Peña-
Martí will check it.
Measures of treatment effect
Dichotomous data
For dichotomous data, we will present results as summary risk
ratio with 95% confidence intervals.
1. Maternal death and perinatal death;
2. safety.
Unit of analysis issues
The unit of analysis will be the included RCTs considering the
studied patients. We will collect and analyze a single measurement
for each outcome from each participant.
Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Dealing with missing data
For included studies, we will note levels of attrition. We will explore
the impact of including studies with high levels of missing data
in the overall assessment of treatment effect by using Sensitivity
analysis.
For all outcomes we will carry out analyses, as far as possible, on an
intention-to-treat basis; i.e. we will attempt to include all partici-
pants randomized to each group in the analyses. The denominator
for each outcome in each trial will be the number randomized
minus any participants whose outcomes are known to be missing.
Assessment of heterogeneity
We will use the I² statistic to measure statistical heterogeneity
among the trials in each analysis. If we identify substantial hetero-
geneity we will explore it by pre-specified subgroup analysis. The
I² statistic describes the percentage of total variation across trials
that is due to heterogeneity rather than sampling error (Higgins
2003). We will consider there to be substantial statistical hetero-
geneity if I² greater than 50% (Higgins 2009).
Assessment of reporting biases
Where we suspect reporting bias (see ‘Selective reporting bias’
above), we will attempt to contact study authors asking them to
provide missing outcome data. Where this is not possible, and the
missing data are thought to introduce serious bias, we will explore
the impact of including such studies in the overall assessment of
results by a sensitivity analysis.
We will also attempt to assess whether the review is subject to
publication bias by using a funnel plot to graphically illustrate
variability between trials. If asymmetry is detected, we will explore
causes other than publication bias. We will conduct a funnel plot
if we include 10 or more RCTs.
Data synthesis
We will carry out statistical analysis using the Review Manager
software (RevMan 2008). We will use fixed-effect inverse variance
meta-analysis for combining data where trials are examining the
same intervention, and the trials’ populations and methods are
judged sufficiently similar. Where we suspect clinical or method-
ological heterogeneity between studies sufficient to suggest that
treatment effects may differ between trials we will use random-
effects meta-analysis.
If we identify substantial heterogeneity in a fixed-effect meta-anal-
ysis we will note this and repeat the analysis using a random-effects
method.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses:
6
 1. type of obstetric DIC (e.g. sepsis);
2. teenage and non-teenage pregnant women and older
mothers (over 35 years);
3. country of publication;
4. pre- and peripartum and post-partum DIC;
5. type of intervention.
We will restrict subgroup analysis to the review’s primary out-
comes.
For fixed-effect meta-analyses we will conduct planned subgroup
analyses classifying whole trials by interaction tests as described by
Deeks 2001. For random-effects meta-analyses we will assess dif-
ferences between subgroups by inspection of the subgroups’ con-
fidence intervals; non-overlapping confidence intervals indicate a
statistically significant difference in treatment effect between the
subgroups.
Sensitivity analysis
REFERENCES
Additional references
Asthana 2009
Asthana B, Sharma P, Ranjan R, Jain P, Aravindan A, Chandra
Mishra P, et al.Patterns of acquired bleeding disorders in a tertiary
care hospital. Clinical and Applied Thrombosis/Hemostasis 2009;15:
448–53. [MEDLINE: 19520680]
Bick 2000
Bick RL. Syndromes of disseminated intravascular coagulation in
obstetrics, pregnancy, and gynecology. Objective criteria for
diagnosis and management. Hematology/Oncology Clinics of North
America 2000;15:999–1044. [MEDLINE: 11005032]
Dalainas 2008
Dalainas I. Pathogenesis, diagnosis, and management of
disseminated intravascular coagulation: a literature review.
European Review for Medical and Pharmacological Sciences 2008;12:
19–31. [MEDLINE: 18401969]
Deeks 2001
Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for
examining heterogeneity and combining results from several studies
in meta-analysis. In: Egger M, Davey Smith G, Altman DG editor
(s). Systematic reviews in health care: meta-analysis in context.
London: BMJ Books, 2001.
DeLoughery 2005
DeLoughery TG. Critical care clotting catastrophies. Critical Care
Clinics 2005;21:531–62. [MEDLINE: 15992672]
Gurusamy 2009
Gurusamy KS, Gluud C, Nikolova D, Davidson BR. Assessment of
risk of bias in randomized clinical trials in surgery. British Journal of
Surgery 2009;96:324–9. [MEDLINE: 19283747]
Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
If sufficient trials are identified, we plan to conduct a sensitivity
analysis comparing the results using all trials as follows.
1. Those RCTs with high methodological quality (studies
classified as having a ’low risk of bias’ versus those identified as
having a ’high risk of bias’) (Higgins 2009).
We will also evaluate the risk of attrition bias, as estimated by
the percentage of participants lost. We will exclude trials with a
total attrition of more than 20% or where differences between
the groups exceed 10%, or both, from meta-analysis, but we will
include them in the review.
ACKNOWLEDGEMENTS
As part of the pre-publication editorial process, this protocol has
been commented on by three peers (an editor and two referees
who are external to the editorial team), a member of the Pregnancy
and Childbirth Group’s international panel of consumers and the
Group’s Statistical Adviser.
Higgins 2003
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring
inconsistency in meta-analyses. BMJ 2003;327(7414):557–60.
[MEDLINE: 12958120]
Higgins 2009
Higgins JPT, Green S, editors. Cochrane Handbook for Systematic
Reviews of Interventions Version 5.0.2 [updated September 2009].
The Cochrane Collaboration, 2009. Available from www.cochrane-
handbook.org.
Ioannidis 2008a
Ioannidis JP. Why most discovered true associations are inflated.
Epidemiology 2008;19:640–8. [MEDLINE: 18633328]
Ioannidis 2008b
Ioannidis JP. Perfect study, poor evidence: interpretation of biases
preceding study design. Seminars in Hematology 2008;45:160–6.
[MEDLINE: 18582622]
Levi 2001
Levi M, de Jonge E, van der Poll T, ten Cate H. Advances in the
understanding of the pathogenetic pathways of disseminated
intravascular coagulation result in more insight in the clinical
picture and better management strategies. Seminars in Thrombrosis
and Hemostasis 2001;27:569–75. [MEDLINE: 11740680]
Levi 2007
Levi M. Disseminated intravascular coagulation. Critical Care
Medicine 2007;35:2191–5. [MEDLINE: 17855836]
Levi 2008
Levi M, van der Poll T. The role of natural anticoagulants in the
pathogenesis and management of systemic activation of coagulation
and inflammation in critically ill patients. Seminars in Thrombosis
and Hemostasis 2008;34:459–68. [MEDLINE: 18956286]
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Levi 2009a
Levi 2009. Disseminated intravascular coagulation (DIC) in
pregnancy and the peri-partum period. Thrombosis Research 2009;
123 (Suppl 2):63–4. [MEDLINE: 19217479]
Levi 2009b
Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the
diagnosis and management of disseminated intravascular
coagulation. British Committee for Standards in Haematology.
British Journal of Haematology 2009;145:24–33. [MEDLINE:
19222477]
Lurie 2000
Lurie S, Feinstein M, Mamet Y. Disseminated intravascular
coagulopathy in pregnancy: thorough comprehension of etiology
and management reduces obstetricians’ stress. Archives of Gynecology
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∗
Indicates the major publication for the study

APPENDICES

Appendix 1. LILACS search strategy

From 1982 to date
1) ((Pt ENSAYO CONTROLADO ALEATORIO OR Pt ENSAYO CLINICO CONTROLADO OR Mh ENSAYOS CONTRO-
LADOS ALEATORIOS OR Mh DISTRIBUCIÓN ALEATORIA OR Mh METODO DOBLE CIEGO OR Mh METODO SIM-
PLECIEGO OR Pt ESTUDIO MULTICÉNTRICO) or ((tw ensaio or tw ensayo or tw trial) and (tw azar or tw acaso or tw placebo
or tw control$ or tw aleat$ or tw random$ or (tw duplo and tw cego) or (tw doble and tw ciego) or (tw double and tw blind)) and tw
clinic$)) AND NOT ((Ct ANIMALES OR Mh ANIMALES OR Ct CONEJOS OR Ct RATÓN OR MH Ratas OR MH Primates
OR MH Perros OR MH Conejos OR MH Porcinos) AND NOT (Ct HUMANO AND Ct ANIMALES)) [Palavras]
2) Disseminated intravascular coagulation
3) pregnan$
4) 1 and 2 and 3

Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol) 8
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 2. WHO International Trials Registry Portal search
Advanced search
disseminated AND pregnan* (in the title field)
dic AND pregnan* (in the title field)
disseminated intravascular (in the condition field)

Appendix 3. Other website searches

We plan to search using simple search strings:
disseminated intravascular coagulopathy AND (pregnancy OR pregnant)
DIC AND (pregnancy OR pregnant)

HISTORY
Protocol first published: Issue 7, 2010

CONTRIBUTIONS OF AUTHORS
Arturo Martí-Carvajal (AMC) wrote the first draft of the protocol with subsequent input from Guiomar Peña-Martí and Gabriella
Comunián-Carrasco. AMC is guarantor for the review.

DECLARATIONS OF INTEREST
In 2004, Arturo Martí-Carvajal was employed by Eli Lilly to run a four-hour workshop on ’how to critically appraise clinical trials
on osteoporosis and how to teach this’. This activity was not related to his work with The Cochrane Collaboration or any Cochrane
review.
In 2007, Arturo Martí-Carvajal was employed by Merck to run a four-hour workshop ’how to critically appraise clinical trials and how
to teach this’. This activity was not related to his work with The Cochrane Collaboration or any Cochrane review.
Guiomar Peña-Martí and Gabriella Comunián-Carrasco: none known.

SOURCES OF SUPPORT

Internal sources
• Universidad de Carabobo, Venezuela.
Academic.

Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol) 9
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
External sources
• Iberoamerican Cochrane Center, Spain.
Academic.

Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum (Protocol) 10
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.