Low-molecular-weight heparin for prevention of placenta-mediated pregnancy complications: protocol for a systematic review and individual patient data meta-analysis (AFFIRM)
Low-molecular-weight heparin for prevention of placenta-mediated pregnancy complications: protocol for a systematic review and individual patient data meta-analysis (AFFIRM)
Marc A Rodger 0
Nicole J Langlois 2
Johanna IP de Vries 1
Timothy Ramsay 2
Ranjeeta Mallick 2
Dick Bezemer 1
Marion E van Hoorn 1
Carolien NH Abheiden 1
Paulien de Jong
0 The Ottawa Hospital, Centre for Practice-Changing Research , 501 Smyth Road, Box 201, Ottawa, ON K1H 8 L6 , Canada
1 Department of Obstetrics and Gynaecology
2 The Ottawa Hospital Research Institute, Centre for Practice-Changing Research , 501 Smyth Road, Box 201, Ottawa, ON K1H 8 L6 , Canada
Background: Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality in developed nations. Women who have experienced these complications are at an elevated risk of recurrence in subsequent pregnancies. However, despite decades of research no effective strategies to prevent recurrence have been identified, until recently. We completed a pooled summary-based meta-analysis that strongly suggests that low-molecular-weight heparin reduces the risk of recurrent placenta-mediated complications. The proposed individual patient data meta-analysis builds on this successful collaboration. The project is called AFFIRM, An individual patient data meta-analysis oF low-molecular-weight heparin For prevention of placenta-medIated pRegnancy coMplications. Methods/Design: We conducted a systematic review to identify randomized controlled trials with a low-molecularweight heparin intervention for the prevention of recurrent placenta-mediated pregnancy complications. Investigators and statisticians representing eight trials met to discuss the outcomes and analysis plan for an individual patient data meta-analysis. An additional trial has since been added for a total of nine eligible trials. The primary analyses from the original trials will be replicated for quality assurance prior to recoding the data from each trial and combining it into a common dataset for analysis. Using the anonymized combined data we will conduct logistic regression and subgroup analyses aimed at identifying which women with previous pregnancy complications benefit most from treatment with low-molecular-weight heparin during pregnancy. Discussion: The goal of the proposed individual patient data meta-analysis is a thorough estimation of treatment effects in patients with prior individual placenta-mediated pregnancy complications and exploration of which complications are specifically prevented by low-molecular-weight heparin. Systematic review registration: PROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD42013006249
Pregnancy; Placenta-mediated pregnancy complications; Low-molecular-weight heparin; Meta-analysis; Individual patient data meta-analysis; Pre-eclampsia; Small-for-gestational age; Placental abruption; Pregnancy loss; Systematic review
Placenta-mediated pregnancy complications include
preeclampsia (PE), late pregnancy loss, placental abruption
and the small-for-gestational age (SGA) newborn. We
completed a pooled summary-based meta-analysis that
strongly suggests that low-molecular-weight heparin
(LMWH) reduces the risk of placenta-mediated
complications in subsequent pregnancies [
A successful pregnancy requires the development of
adequate placental circulation. It has been hypothesized
that thrombosis in the placental bed is at least partially
responsible for placenta-mediated pregnancy
]. It has also been suggested that these
complications are the result of abnormal placental development
with underdeveloped placental vasculature or placental
]. These complications represent an
important health problem because they are common,
affecting more than one in six pregnancies , and often
have a devastating outcome for the affected women, their
unborn children, their families, and society. Specifically, PE
(characterized by a new onset of elevated blood pressure
and proteinuria during pregnancy) is one of the most
common causes of maternal mortality in the developed world
]. SGA newborns often suffer longterm effects
including developmental delay, poor school performance, and a
significantly lower likelihood of academic and professional
]. Fetal loss is a devastating event for
pregnant women and their families. Placental abruption
(separation of the placenta from the uterus before birth) can, in
the most severe cases, lead to maternal hemorrhage with
the risk of transfusion and both maternal and fetal death.
The risk of recurrent placenta-mediated pregnancy
complications in subsequent pregnancies is substantial.
For example, women with prior severe PE will have a 25
to 65% risk of recurrent PE, a 3% risk of placental
abruption, and a 10% risk of SGA (<10th percentile) [
These complications may be multiple (for example both
PE and SGA) and not isolated to the placenta-mediated
complication experienced in a prior pregnancy [
There are no highly effective preventative strategies that
can be used in subsequent pregnancies. Aspirin offers
small relative risk reductions in patients with prior PE
and SGA, however, it may be more effective at reducing
risk (approximately a 40% reduction) if started early in
the pregnancy (before 16 weeks) [
]. There are no
proven preventative strategies for the other complications.
It has been postulated that anticoagulants might prevent
placenta-mediated pregnancy complications by reducing
placental thrombosis and/or affecting maternal
coagulation activation or inflammation. Recent randomized
controlled trials (RCTs) conducted to determine if LMWH
can prevent recurrent placenta-mediated pregnancy
complications suggest an important treatment effect [
but this finding has not been universal .
Although it appears that LMWH is a promising
therapy in the prevention of placenta-mediated pregnancy
complications, there are disadvantages to the premature
adoption of this intervention without sufficient evidence
of benefit. If LMWH is used universally for all women
with prior placenta-mediated pregnancy complications,
we may be intervening unnecessarily and exposing women
to a risk of undesirable and potentially fatal, albeit rare,
side effects (major bleeding, heparin-induced
thrombocytopenia, osteoporotic fractures, withholding of epidural
analgesia due to fear of causing epidural hematoma, and
]. Less serious side effects including skin
reactions, minor bleeding, and transient elevations in liver
enzymes are more commonly experienced [
Therapy is also associated with cost and inconvenience since
the drug is expensive and is administered by injection
either once or twice a day. Therefore, it is necessary to
answer the question as to who benefits from LMWH
prophylaxis during pregnancy and to determine the nature
and magnitude of these benefits more precisely. The
individual patient data meta-analysis (IPDMA) has the
potential to answer these important questions and determine
the risk/benefit ratio of therapy for various subgroups
The composite outcome, including all
placenta-mediated pregnancy complications, that is used in many RCTs
is heterogeneous and not all individual outcomes can be
considered equally serious in terms of potential
consequences for the mother and newborn. For example, late
term pre-eclampsia is clinically less worrisome since the
symptoms tend to be less severe and generally resolve with
delivery. Conversely, women who develop pre-eclampsia
earlier in the pregnancy have more serious clinical
consequences including a greater risk of maternal and neonatal
death. Our pooled summary meta-analysis suggests that
LMWH may prevent severe pre-eclampsia and early
preeclampsia with less of an effect on late onset pre-eclampsia
]. Confirmation of these findings is extremely important
for clinicians treating these women and has direct relevance
for clinical practice worldwide.
There are many challenges associated with recruiting
pregnant women to RCTs with a drug intervention
including: the biases of clinicians either for or against the
therapy (based on insufficient evidence of benefit and lack
of knowledge about potential risk); the concerns of the
pregnant woman and her family about the health and
safety of the mother and baby; and the demands during
pregnancy of attending additional appointments and
investigations associated solely with study participation [
Furthermore, the pharmaceutical industry often excludes
pregnant women from trials due to liability concerns. As a
result, there is a dearth of RCTs evaluating LMWH in this
population compared to other patient groups (such as
oncology or orthopedic surgery). Those RCTs that do exist
are all academically driven and may not have the same
financial and human resources that are available to trials
that are sponsored by the pharmaceutical industry.
Therefore, meta-analysis is an essential tool that allows for greater
statistical power by pooling the existing small RCTs
evaluating LMWH for the prevention of placenta-mediated
Our recent pooled summary-based meta-analysis of six
RCTs (Table 1) included 848 pregnant women with a
history of pre-eclampsia, a SGA neonate (<10th percentile),
placental abruption, or late pregnancy loss (more than
12 weeks gestation) in a previous pregnancy [
primary finding was that 67 out of 358 (18.7%) women taking
LMWH during pregnancy had recurrent severe
placentamediated pregnancy complications, as compared with 127
out of 296 (42.9%) women with no LMWH (relative risk
reduction 48% (95% CI 14 to 68%; (I2 69%). However, since
the meta-analysis results apply to a heterogeneous group
of women with a mixture of placenta-mediated pregnancy
complications of varying prior severity and the primary
outcome for the meta-analysis was a composite of all
placenta-mediated complications (also of varying severity),
it is not clear which subgroups of women derive the most
benefit from LMWH (which outcomes are reduced and
which severity of outcomes are impacted). Before
recommendations for clinical practice can be advocated, it is
necessary to conduct more detailed analyses of the existing
data to determine potential benefits for subgroups of
women, to adjust for important baseline
characteristics of participants, and to explore other treatment-related
reasons for the reported heterogeneity (for example
specific LMWH drug (dalteparin, nadroparin or enoxaparin),
LMWH dose, gestational age when drug was initiated, and
co-interventions such as concomitant ASA use).
IPDMA has been proposed as an advantageous
methodological approach when subgroup analyses are
hypothesized to be clinically relevant. Analyzing original data from
individual patients makes use of a much richer dataset
and has greater statistical power than conventional
]. Furthermore, for this project, IPDMA will
allow for adjustment for covariates that are known to be
important in the recurrence of placenta-mediated
pregnancy complications. Such an analysis will also enable us
to explore clinical, methodological, and statistical
heterogeneity more robustly. IPDMA is an attractive method to
answer our study questions since it ‘dramatically and
consistently’ has more power to detect interactions between
risk groups .
The primary research question is: Which women with
previous placenta-mediated pregnancy complications have a
reduction in the risk of future complications when treated
with LMWH during pregnancy? Secondary research
questions are: Which of the placenta-mediated
pregnancy complications are avoided? Are severe and/or
early onset or non-severe and/or late onset
complications avoided? Does LMWH cause major bleeding in
women with prior placenta-mediated pregnancy
complications? And, are any other side effects increased by
LMWH use in women with prior placenta-mediated
pregnancy complications (thrombocytopenia, osteoporotic
fractures or allergic reactions)?
The proposed project is called AFFIRM (An individual
patient data meta-analysis oF low-molecular-weight
heparin For prevention of placenta-medIated
pRegnancy complications), PROSPERO registration number:
CRD42013006249. We will synthesize individual patient
data from RCTs of LMWH for the prevention of recurrent
placenta-mediated pregnancy complications. The overall
objective of the meta-analysis is to directly inform clinical
practice and the development of clinical practice guidelines.
The study is coordinated by the Clinical Epidemiology
Program at the Ottawa Hospital Research Institute.
Conceptually, the research approach involves four sequential
phases: a systematic review, knowledge synthesis planning,
data extraction and analysis, and interpretation of results
and knowledge translation. The first two phases have been
completed and are therefore described below in the past
tense. No data have been extracted or recoded for the
common dataset and no statistical analyses have been
performed; these steps are outlined in the future tense.
Electronic search strategies were developed and tested
through an iterative process by an experienced medical
information specialist in consultation with the review
team. The strategy was peer-reviewed prior to execution
by an experienced information specialist using the Peer
Review of Electronic Search Strategies (PRESS) checklist
]. The following search was conducted in May 2013:
using the OVID platform, we searched Ovid MEDLINE™,
Ovid MEDLINE™ In-Process & Other Non-Indexed
Citations, and EmbaseClassic + Embase (strategy included
as Additional file 1). We also searched the Cochrane
Library on Wiley (including CENTRAL, Cochrane
Database of Systematic Reviews, DARE, and HTA).
ClinicalTrials.gov and the WHO International Clinical Trials
Registry were searched to identify relevant in-process
and completed trials. Strategies utilized a combination
of controlled vocabulary (such as ‘hypertension,
pregnancyinduced,’ ‘placental insufficiency,’ ‘heparin,
low-molecularweight’) and keywords (pre-eclampsia, abruption, and
LMWH). Vocabulary and syntax were adjusted across
databases. Animal studies were excluded but there
were no language or date restrictions on any of the
searches. We sought additional references through
handASA = aspirin; GA = gestational age; IPDMA = individual patient data meta-analysis; IPDMA = individual patient data meta-analysis; PE = pre-eclampsia; RCT = randomized controlled trial; SB = stillbirth;
SGA = small-for-gestational age.
TIPPS = Thrombophilia In Pregnancy Prophylaxis Study *accepted for publication in the Lancet.
FRUIT = FRactionated heparin in pregnant women with a history of Utero-placental Insufficiency and Thrombophilia.
NOH-AP = Nîmes Obstetricians and HAematologist – abruptio placentae.
NOH-PE = Nîmes Obstetricians and HAematologist - pre-eclampsia.
HAPPY = Heparin in pregnant women with Adverse Pregnancy outcome to improve the rate of successful PregnancY.
Dalteparin 5000 IU + ASA vs ASA
PE prior to 34 weeks GA
Nadroparin 3800 IU vsno Nadroparin PE, Loss >15 weeks GA,
SGA <10thpercentile and/or abruption
Enoxaparin 4000 IU + ASA vs ASA
PE, SB, abruption, SGA <5th percentile Yes
Dalteparin 5000 IU+/−ASA vs +/−ASA
PE, SB, abruption, SGA <5th percentile Yes
Dalteparin 5000 IU vsno Dalteparin
PE, SGA <10th percentile
Unable to contact
searching the bibliographies of relevant items. Search
results are summarized in a preferred reporting items for
systematic reviews and meta-analyses (PRISMA) diagram
(Figure 1) and details of potentially eligible trials are
provided in Tables 2 and 3.
RCTs with an LMWH intervention for the prevention of
recurrent placenta-mediated pregnancy complications were
eligible. The study population of interest included currently
pregnant women with prior pregnancies complicated by
one or more of the following: PE, placental abruption, SGA
newborn (<10th percentile), pregnancy loss after 16 weeks
gestation or two losses after 12 weeks gestation. The
principal investigators of potentially eligible trials
identified by the systematic review (see Tables 1, 2 and 3) were
contacted via email to request additional information
about the study population. Once eligibility was
confirmed, investigators were invited to participate in the
IPDMA and attend the AFFIRM project planning
meeting. The lead investigators of the largest and most recently
completed trials agreed to contribute individual patient
data to this collaboration. Data from two small trials
] were not included because the investigators did
not respond; in one of these trials only a small proportion
of the total study population would have been eligible to
contribute data to AFFIRM . Some of the women in
the Scottish Pregnancy Intervention Study (SPIN) trial
would have been eligible for inclusion in AFFIRM,
however, the trial database does not include sufficient detail
about the timing of previous pregnancy losses to
determine the eligibility of individual participants [
Records iden fied through
(Cochrane = 56
Embase = 236
MEDLINE = 131)
Addi onal records iden fied
through trial registries
(ClinicalTrials.gov = 93
WHO registry = 1)
Records a er duplicates removed
(n =378 + 94 = 472)
Full-text ar cles or
registry records assessed
for eligibility (n=24)
Published = 14
Registered = 10
Poten ally eligible and
confirma on or invited to
par cipate in IPDMA
(n = 14)
Studies to be included in
(n = 9)
Iden fied in this review = 7
Previously iden fied = 2
Not relevant (n=447)
Published = 364
Registered = 83
Duplicate publica on = 5
Review ar cle = 1
Wrong popula on = 1
Wrong design = 2
Prematurely terminated = 1
Not included in IPDMA (n= 7)
Trial ongoing = 3
Wrong popula on = 2
No response from PI = 1
Unable to extract data from
only eligible par cipants = 1
Finland, Sweden, Women with Enoxaparin 40 mg vs
Netherlands N = 207 recurrent early Enoxaparin 40 mg +
or late miscarriage ASA vs ASA
IU + vitamins vs
Enoxaparin 40 mg vs
Enoxaparin 40 mg +
ASA vs ASA
Tinzaparin 4500 IU vs
Intact pregnancy at
24 wks GA; PE; IUGR <5th
Live birth rate; PE;
IUGR <2 SD; abruption
Enoxaparin 40 mg + ASA Pregnancy loss
GA of past losses
not available centrally
Nadroparin 2850 IU +
ASA vs ASA vs placebo
Dalteparin 5000 IU +
ASA vs ASA
SGA <10th percentile;
PE; HELLP; abruption
inclusion in IPDMA
(All losses <12
(All women with
ASA = aspirin; GA = gestational age; HELLP = HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count); IPDMA = individual patient data meta-analysis;
IUGR = intrauterine growth restriction; PE = pre-eclampsia; SB = stillbirth; SGA = small-for-gestational age.
SPIN = Scottish Pregnancy Intervention Study; HepASA = Low Molecular Weight Heparin and Aspirin in the Treatment of Recurrent Pregnancy Loss.
ALIFE = Anticoagulants for Living Fetuses.
HABENOX = Low Molecular Weight Heparin and/or Aspirin in Prevention of Habitual Abortion.
ETHIG II = Effectiveness of Dalteparin Therapy as Intervention in Recurrent Pregnancy Loss *final results in preparation for publication.
Knowledge synthesis planning
A crucial step in the success of the project was the
development of the knowledge synthesis and knowledge
translation plans. A full-day review team meeting was
held in Amsterdam on 4 July 2013. The purpose was to
allow for extensive discussion and consensus-reaching
on important study variables and outcomes and to
consider strategies for merging the existing datasets in a
centralized database. Participants included the principal
investigators of the included RCTs and statisticians with
in-depth knowledge of the trial data. The principal
investigators are all practising clinicians (obstetricians and
hematologists) who are also knowledge users in this
The detailed definitions for the IPDMA outcomes
were agreed upon by investigator consensus at the
face-to-face meeting. The definitions and diagnostic
criteria for each outcome variable are documented in
a data dictionary and the research protocol. These
definitions, which have been reviewed by all investigators, allow
standardization across studies and decrease the potential
ASA = aspirin; IPDMA = individual patient data meta-analysis; IUGR = intrauterine growth restriction; PE = pre-eclampsia; SGA = small-for-gestational age.
EPPI = Enoxaparin for the Prevention of Preeclampsia and Intrauterine growth restriction.
HEPEPE = Prevention of Maternal and Perinatal Complications by Enoxaparin in Women With Previous Severe Preeclampsia (original title is French).
HOPPE = Low Weight Heparin prOphylaxis for Placental Mediated Complications of PrEgnancy.
AFFIRM’s primary outcome is a composite outcome
including four pregnancy complications: early-onset or
severe pre-eclampsia, birth of a small-for-gestational age
newborn with a birth weight <5th percentile, placental
abruption, and late pregnancy loss. To qualify as a primary
outcome event, the pregnancy complication must satisfy
one or more predefined criteria. Early onset pre-eclampsia
is diagnosed at less than 34 weeks’ gestation. Severe
pre-eclampsia is characterized by at least one criterion
indicative of severe disease; these are, a systolic blood
pressure ≥ 160 mm Hg or diastolic blood pressure ≥110 mm
Hg, proteinuria > 0.5 g/24 hours, elevated liver enzymes
(more than two times the local upper range of normal),
platelets < 100 × 109/L, pulmonary edema, seizures
(eclampsia), headache or other neurological manifestations (stroke,
intracranial hemorrhage, cerebral edema, hyperreflexia, and
visual impairment), coagulopathy, oliguria (<30 ml/hr)
or HELLP syndrome (hemolysis, elevated liver enzymes,
low platelet count). Birth of a small-for-gestational age
newborn with a birth weight <5th percentile is
determined using local gender and gestational age specific birth
weight charts. The placental abruption outcome requires
a clinical diagnosis of placental abruption leading to
delivery. A late pregnancy loss occurs at or after 20 weeks of
gestation and cannot be explained by other factors,
including fetal chromosomal abnormalities, maternal infection,
cervical insufficiency or incompetence, or an intentional
termination of the pregnancy.
Nineteen secondary outcomes have been defined for
AFFIRM, including the four individual components of the
primary outcome: severe or early-onset pre-eclampsia,
birth of a small-for-gestational age newborn <5th
percentile, placental abruption and late pregnancy loss, all as
outlined above. Pre-eclampsia (non-severe) is characterized
by a systolic blood pressure ≥140 mm Hg or diastolic
blood pressure ≥90 mm Hg and proteinuria >0.3 g/
24 hours. A diagnosis of HELLP syndrome required 3
criteria, hemolysis [lactate dehydrogenase (LDH) > 600 IU/L
or serum bilirubin >1.2 mg/dl] an abnormal elevation of
liver enzymes (more than two times the local upper
range of normal), and platelets <100 × 109/L. Preterm
delivery <34 weeks and < 37 weeks are pre-specified
outcomes. A perinatal loss is any fetal or neonatal death
at over 20 weeks gestational age and less than or
equal to 28 days post-partum and neonatal mortality is
considered any neonatal death after birth and less than or
equal to 28 days post-partum. Birth of a
small-for-gestational age newborn <10th percentile is determined based
on local gender and gestational age specific birth weight
Adverse maternal outcomes include thrombocytopenia,
defined as a platelet count <75,000 × 109/L, and bleeding
outcomes at various time points. Antepartum major
bleeding is defined using the criteria proposed by the
International Society on Thrombosis and Haemostasis
]. That is, clinical or radiological evidence
of bleeding with at least one of the following criteria:
associated with a fall in hemoglobin of 2 g/dL (1.24 mmol/L)
or more; or a requirement for transfusion of two or more
units of red blood cells or whole blood; or symptomatic
bleeding occurring in a critical site: intracranial,
intraspinal, intraocular, pericardial, intra-articular,
intramuscular with compartment syndrome, or retroperitoneal, or
was considered to have contributed to maternal death.
Peripartum major bleeding is hemorrhage occurring after
the onset of labour or start of surgical delivery and within
24 hours postpartum that meets at least one of the
following: necessitating a surgical procedure, or associated with
a fall in hemoglobin of 4 g/dL (2.48 mmol/L) or more, or
a requirement for transfusion of two or more units of red
blood cells or whole blood, or estimated peripartum blood
loss >1000 ml, or considered to have contributed to
maternal death. Peripartum minor bleeding is hemorrhage
occurring after the onset of labour or start of surgical
delivery and within 24 hours postpartum that does not
meet any criterion above and with estimated peripartum
blood loss between 500 and 1000 ml. Postpartum major
bleeding is clinical or radiological evidence of bleeding
occurring between 24 hours and 6 weeks postpartum
and meeting at least one of the following ISTH
criteria: associated with a fall in hemoglobin of 2 g/dL
(1.24 mmol/L) or more, or a requirement for
transfusion of two or more units of red blood cells or whole
blood, or symptomatic bleeding occurring in a critical
site: intracranial, intraspinal, intraocular, pericardial,
intraarticular, intramuscular with compartment syndrome, or
retroperitoneal, or considered to have contributed to
An allergic reaction to LMWH is a reaction following
the administration of LMWH that results in anaphylaxis
or a rash requiring discontinuation of the allocated
LMWH. Heparin-induced thrombocytopenia (HIT) is
defined as a clinical diagnosis of HIT and a minimum of
a positive PF4 HIT ELISA assay. The venous
thromboembolism outcome includes deep vein thrombosis (DVT)
and/or pulmonary embolism. The criteria for diagnosis of
DVT are venography demonstrating a constant
intraluminal filling defect in the deep veins above the trifurcation
of the popliteal vein or compression ultrasound revealing
a non-compressibility of a venous segment above the
trifurcation of the popliteal vein. Diagnosis of distal, below
the knee DVT, is by either venography or compression
ultrasound. Diagnostic criteria for pulmonary embolism
are pulmonary angiography demonstrating a constant
intraluminal filling defect or a cutoff of a vessel more than
2.5 mm in diameter, or ventilation/perfusion (V/Q scan)
indicating high-probability, or pulmonary embolism found
Extraction and recoding of individual patient data
The definitions for each variable to be included in
AFFIRM’s common dataset are documented in a data
dictionary to allow standardization across studies and
decrease the potential for misclassification and bias. A
template for the common dataset has been developed
in Microsoft Excel and will be provided to the principal
investigator of each included trial. Recoded anonymized
individual patient data from each of the trials will populate
the Excel template. The recoded datasets for each of the
individual trials will be saved on an IronKey™ USB flash
drive and sent by courier to the coordinating center in
The AFFIRM common dataset will include individual
patient data in 10 pre-defined categories: administrative
and demographic data, thrombophilia, maternal medical
history, pregnancy history, current pregnancy and
delivery, infant data, pre-eclampsia outcome, other outcome
events, intervention and treatment during pregnancy,
and adverse events.
Data synthesis, validation and analysis
Once the individual participant data from the primary
studies have been merged in the common dataset,
descriptive analyses will be conducted to identify data outliers,
missing data, and unexpected inconsistencies. The project
coordinator will prepare data clarification reports and will
communicate with the principal investigators or their
delegates to resolve these queries. Next, we plan to conduct
preliminary analyses aimed at replicating the findings of
the individual published studies, to validate the centralized
database and data importation. Once the IPDMA team is
satisfied with the merged dataset, the database will be
locked and the planned analyses for the IPDMA synthesis
will be conducted.
The individual patient data will be analyzed in a
similar manner to an RCT, however, the analysis will account
for clustering at the study level. The primary analysis
will include all women who are eligible for AFFIRM and
will examine the risk of the primary composite outcome
in the treatment (LMWH) and control arms based on
intention-to-treat. Secondary univariate analyses will be
done for each of the pregnancy complications included
in the composite outcome. On-treatment sensitivity
analyses will be conducted for the primary and secondary
We have planned several subgroup analyses; these were
selected because they are clinically plausible and there is
evidence that they may be relevant. If certain subgroups
are found to be small (≤5 subjects) we will merge
subgroups as appropriate.
Women will be analyzed in subgroups according to the
previous pregnancy complications that were experienced.
Prior pre-eclampsia subgroups are any pre-eclampsia,
severe pre-eclampsia, early-onset pre-eclampsia, and
severe or early onset pre-eclampsia. Subgroups according to
prior SGA are SGA <10th percentile, SGA <5th percentile,
SGA <3rd percentile, prior pre-eclampsia and SGA <10th
percentile, prior pre-eclampsia and SGA <5th percentile,
prior pre-eclampsia and SGA <3rd percentile. Subgroups
of women with prior placental abruption are any
placental abruption, placental abruption leading to
delivery <37 weeks’ gestation, placental abruption leading
to delivery < 34 weeks’ gestation, and placental abruption
with pre-eclampsia. Participants will be grouped for
analysis according to the gestational age of prior
pregnancy loss: >12 weeks’ gestation, >16 weeks’ gestation,
and >20 weeks’ gestation. Demographic subgroups are
according to maternal age (<35 years or ≥35 years) and
ethnic group (Caucasian, Black, Asian or other).
Women will be grouped according to personal
characteristics and risk factors. For thrombophilia the subgroups are
women with weak thrombophilia (Factor V Leiden [FVL]
or prothrombin gene mutation [PGM]); moderate
thrombophilia (protein C deficiency, protein S deficiency); strong
thrombophilia (antithrombin deficiency, antiphospholipid
antibodies, combined thrombophilia ≥1 type, homozygous
FVL or PGM); or no thrombophilia. Participants will be
grouped according to personal history of venous
thromboembolism (VTE), family history of VTE, and no VTE
Quality assessment will be conducted for all eligible
studies using the tool for assessing risk of bias from the
Cochrane Handbook for reviews of interventions [
and reported on a study level. These assessments will
also be used to inform subgroup analyses and sensitivity
analyses to explore whether these biases may have affected
the IPDMA analysis. We plan to examine the
randomization integrity once the data from the original trials have
been combined. We will endeavour to compare the
original randomization lists with actual randomization to
test the integrity of the allocation concealment. We will
also compare the baseline characteristics of participants
who have been randomized to the LMWH and no
LMWH groups at the study level and aggregate level to
see if there are imbalances between the groups that may
suggest a lack of integrity in randomization processes.
Once the results of the analyses are available, they will
be circulated to all investigators and collaborators and a
teleconference will be scheduled to discuss the findings
and their interpretation. Regardless of the IPDMA results,
they will be disseminated. Dr Shannon Bates is the
principal knowledge user for this project. She will provide input
throughout the project and will be a leader for the
knowledge translation phase of the study. The
principal investigators of the identified eligible RCTs (Drs Rey,
Martinelli, de Vries, Gris, Rodger, Middeldorp, Schleussner,
and Kaaja) are all experienced researchers and also
practicing physicians who are knowledge users. Furthermore,
these team members are all involved in leadership roles in
their institutions and countries, including practice
guideline development, and have the potential to considerably
influence the international community of healthcare
providers in a variety of settings.
The strategies for knowledge translation will rely heavily
on the input from all involved knowledge users and will
take into consideration the suitability of proposed media
and/or approach for different practice settings and
international contexts. Traditional methods, such as
publication in a peer-reviewed journal, geared towards either a
generalist or specialist audience, will be employed. Results
will also be presented at international meetings; it is
anticipated that knowledge users (clinicians) in
hematology, obstetrics, and family medicine will be targeted. In
addition, patient advocacy and education groups (such
as the Pre-eclampsia Foundation, the North American
Thrombosis Forum, and Thrombosis Canada) will be
provided with the results in a language and format
suitable to a non-medical audience.
This IPDMA will permit the investigators to explore
which women within the heterogeneous group of patients
with placenta-mediated complications benefit and which
women do not benefit from low-molecular-weight heparin
injections throughout pregnancy.
Ethics, privacy and security
The subjects in each of the RCTs all provided informed
consent to participate in the original trial. We will not
be seeking individual consent for the secondary use of
the data for the following reasons: the objectives of the
IPDMA are consistent with the original trials, there are
no risks or benefits associated with this analysis, no
identifying information will be transferred, and it would
be logistically time consuming and, in some cases,
impossible to contact the women who participated. In order to
ensure patient confidentiality any identifying information
will be removed from the original dataset before it is
transferred. The IronKey™ flash drive includes numerous
security features including hardware-based encryption, a
random password generator, two-factor authentication,
and a self-destruct mechanism which make it extremely
unlikely that the dataset can be accessed by anyone other
than the intended recipient. Once the data are merged in
Ottawa in the common database, they will be stored on
the research institute’s network which has multiple
security features and regular backup procedures in place.
Limitations and challenges
One relevant potential drawback of IPDMA is biased
pooling of data. Bias can be introduced when eligible
studies are missed, when authors do not provide their data for
the analysis, when the outcomes are different across
studies, and when outcome and covariate data are missing
from included studies [
]. Our recently completed pooled
summary meta-analysis was a successful collaboration of
five principal investigators [
]. In addition to the team
members from these five trials, the principal investigators
of four additional trials have committed to provide data
for the AFFIRM meta-analysis. These are the largest and
most robust trials completed in this area.
The multinational research team has representation
from Canada, the Netherlands, France, Italy, Germany,
and Finland. Almost all review team members attended
the face-to-face IPDMA planning meeting. To protect
against the misclassification of outcomes, the AFFIRM
review team discussed each outcome at this meeting
until consensus on detailed definitions and diagnostic
criteria was reached. Definitions for all variables to be
included in the IPDMA common dataset are
documented in a data dictionary that was reviewed, revised
according to team feedback, and finalized. Despite this,
we recognize that challenges will be encountered due to
variability in how the variables were originally defined
and collected in each of the nine trials. In some cases it
will be necessary to consult the original clinical records
to obtain complete information for the IPDMA which
will be a labor-intensive process. Another challenge is
the diversity in language of the original datasets (English,
French, Dutch, Italian, and German) that will necessitate
translation when the data are recoded. Attention to detail,
careful documentation, and excellent communication
will be instrumental to the successful completion of
Additional file 1: Search strategy.
ASA: Acetylsalicylic acid; ACCP: American college of chest physicians;
DARE: Database of abstracts of reviews of effects; GA: Gestational age;
HELLP: HELLP syndrome (hemolysis, elevated liver enzymes, low platelet
count); HIT: Heparin-induced thrombocytopenia; HTA: Health technology
assessment database; IPDMA: Individual patient data meta-analysis;
ISTH: International society on thrombosis and hemostasis; IUGR:
Intrauterine growth restriction; LMWH: Low-molecular-weight heparin;
PE: Pre-eclampsia; RCT: Randomized controlled trial; SB: Stillbirth;
SGA: Small-for-gestational age.
Dr Marc Rodger received grant funding of more than $10,000 from Pfizer
and Leo Pharma and has served on advisory boards for Sanofi Aventis but
not been paid. Dr Johanna de Vries received grant funding for a two-year
investigator period between 2000 and 2001 on behalf of the FRUIT-RCT by
Pfizer, formerly Pharmacia. Sponsorship was obtained from Pfizer for the
AFFIRM investigators’ meeting in 2013. Grant funding was obtained from
Pfizer in December 2013 for a single year, to be used from January 2014 to
January 2015. Dr Évelyne Rey received travel grants from Leo Pharma for the
4th International Symposium on Women’s Health Issues in Thrombosis and
Hemostasis, February 4-6 2011, Berlin, Germany. She also received consultant
honorariums from Leo Pharma for the information booklet ‘Anticoagulation
pendant la grossesse’, 2010 to 2011, and for CME presentations, 2009 to
2010. Dr Jean-Christophe Gris holds board membership for Sanofi, LFB, and
Stago. He is also a consultant for Sanofi, Stago, Leo Pharma, and LFB. He has
received grants from Sanofi, Stago, Leo Pharma, LFB, and Baxter Healthcare
Corporation. He has received payment for lectures including service on
speakers bureaus forSanofi, Stago, Leo Pharma, LFB, Bristol-Myers Squibb
Pfizer, Bayer, and Boehringer Ingelheim. Dr. Shannon Bates received an
honoraria from Leo Pharma and Pfizer, Canada for various presentations.
Dr Saskia Middeldorp: GSK supported the ALIFE trial with a grant (until 2010).
GSK currently supports the Highlow trial (has been taken over by Aspen in
2014). She has also received consulting fees and lecture honoraria from
Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo and
research support from GSK, Bristol-Meyers Squibb/Pfizer and Sanquin.
Dr Ekkehard Schleussner: Pfizer, Germany and Merck, Germany supported the
ETHIG II trial (until 2013). He also received an honoraria from Pfizer, Ferring,
Bayer-Jenapharm for various presentations.
MR, lead IPDMA investigator; conceived of the study concept; wrote the first
draft of the protocol and first draft of the manuscript; developed the IPDMA
variable definitions. RM, contributed to study design, particularly data
analysis (coordinating statistician); reviewed and approved of the final
manuscript. TR, contributed to study design, particularly data analysis (lead
statistician); critical revision of the manuscript and approval of the final
manuscript. ER, JDV, MVH, ES and DP, contributed to study design;
developing detailed definitions for study outcomes and eligibility; provided
input on IPDMA variable definitions; critical revision of the manuscript and
approval of the final manuscript. JCG, DB, AP and PDJ, contributed to study
design; developing detailed definitions for study outcomes and eligibility;
reviewed and approved of the final manuscript. CA, IM and SM, contributed
to study design; developing detailed definitions for study outcomes and
eligibility; critical revision of the manuscript and approval of the final
manuscript. NL, project coordinator: AFFIRM; assisted in writing the first draft
of the protocol and first draft of the manuscript; developed first draft of the
data dictionary and template for the IPDMA common dataset. SB,
contributed to study design, particularly knowledge translation planning;
critical revision of the manuscript and approval of the final manuscript.
RK, approved the methodology for the study; reviewed and approved of the
final manuscript. BS, designed and conducted the electronic search strategy
for the systematic review; reviewed and approved of the final manuscript.
All authors read and approved the final manuscript.
This collaborative meta-analysis based on individual patient data is funded
by a Knowledge Synthesis Grant from the Canadian Institutes of Health
Research (CIHR), reference number KRS 126593. The authors would like to
acknowledge the contribution of David Moher who provided methodological
advice during the conception and design of the project. The Knowledge
Synthesis Group at the Ottawa Hospital Research Institute also played an
important role during the systematic review: Raymond Daniel downloaded the
records from the searches, removed duplicates, and obtained the full-text
articles and Kavita Singh screened the titles and abstracts of citations to assess
VU University Medical Center, PO Box 7057, Amsterdam MB 1007, The
Netherlands. 4CHU Ste-Justine, 3175 chemin de la Côte-Sainte-Catherine,
local 4804, Montreal, QC H3T 1C5, Canada. 5Consultations et Laboratoire
d'Hématologie & Délégation à la Recherche Clinique et à l'Innovation, Place
du Pr. Robert Debré, Nîmes cédex 09 F-30029, France. 6Department of
Internal Medicine and Medical Specialties, A. Bianchi Bonomi Hemophilia and
Thrombosis Center, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore
Policlinico, University of Milan, Via Pace 9, Milan 20122, Italy. 7Department of
Obstetrics and Gynaecology, Jena University Hospital, Bach Street 18, Jena
07743, Germany. 8Independent information specialist, 3104 Apple Hill Drive,
Ottawa, ON K1T 3Z2, Canada. 9Department of Vascular Medicine, Academic
Medical Center, Meibergdreef 9, Amsterdam F4-276, 1105 AZ, The
Netherlands. 10Department of Medicine, McMaster University Room HSC
3 W11, 1280 Main Street West, Hamilton, ON L8S 4 K1, Canada. 11Clinical Trial
Centre, University of Leipzig, Haertelstr 16-18, Leipzig 04107, Germany.
12Laboratorio di Biostatistica, Centro di Ricerche Cliniche per le Malattie Rare
Aldo e Cele Daccò, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri,
Villa Camozzi - via G. Camozzi 3, Ranica BG 24020, Italy. 13Academic Medical
Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The
Netherlands. 14Turku University and Satakunta Central Hospital, Helsinki
University Hospital, Sairaalantie 3, 28500 Pori, Finland.
1. Rodger MA , Carrier M , Le Gal G , Martinelli I , Perna A , Rey E , De Vries JI , Gris JC : Meta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications . Blood 2014 , 123 : 822 - 828 .
2. van der Molen EF , Verbruggen B , Novakova I , Eskes TK , Monnens LA , Blom HJ : Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopathy . BJOG 2000 , 107 : 785 - 791 .
3. Weiner Z , Younis JS , Blumenfeld Z , Shalev E : Assessment of uterine placental circulation in thrombophilic women . Semin Thromb Hemost 2003 , 29 : 213 - 218 .
4. Arias F , Romero R , Joist H , Kraus FT : Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta . J Matern Fetal Med 1998 , 7 : 277 - 286 .
5. Sood R , Kalloway S , Mast AE , Hillard CJ , Weiler H : Fetomaternal cross talk in the placental vascular bed: control of coagulation by trophoblast cells . Blood 2006 , 107 : 3173 - 3180 .
6. Steegers EA , Von DP , Duvekot JJ , Pijnenborg R : Pre-eclampsia . Lancet 2010 , 376 : 631 - 644 .
7. Berg CJ , Atrash HK , Koonin LM , Tucker M : Pregnancy-related mortality in the United States, 1987 - 1990 . Obstet Gynecol 1996 , 88 : 161 - 167 .
8. Khan KS , Wojdyla D , Say L , Gulmezoglu AM , Van Look PF : WHO analysis of causes of maternal death: a systematic review . Lancet 2006 , 367 : 1066 - 1074 .
9. Department of Health WO, Scottish Department of Health: Why mothers die . Report on confidential enquiries into maternal deaths in the United Kingdom 1994 -1996. London: Her Majesty's Stationary Office; 1998 .
10. Atrash HK , Koonin LM , Lawson HW , Franks AL , Smith JC : Maternal mortality in the United States, 1979 - 1986 . Obstet Gynecol 1990 , 76 : 1055 - 1060 .
11. Rusen ID , Liston R , Wen SW , Bartholomew S : Special Report on Maternal Mortality and Severe Morbidity in Canada. Enhanced Surveillance . The Path to Prevention. Canada: Minister of Public Works and Government Services; 2004 .
12. Strauss RS : Adult functional outcome of those born small for gestational age: twenty-six-year follow-up of the 1970 British Birth Cohort . JAMA 2000 , 283 : 625 - 632 .
13. Strauss RS , Dietz WH : Effects of intrauterine growth retardation in premature infants on early childhood growth . J Pediatr 1997 , 130 : 95 - 102 .
14. Strauss RS , Dietz WH : Growth and development of term children born with low birth weight: effects of genetic and environmental factors . J Pediatr 1998 , 133 : 67 - 72 .
15. Van Rijn BB , Hoeks LB , Bots ML , Franx A , Bruinse HW : Outcomes of subsequent pregnancy after first pregnancy with early-onset preeclampsia . Am J Obstet Gynecol 2006 , 195 : 723 - 728 .
16. Sibai BM , Mercer B , Sarinoglu C : Severe preeclampsia in the second trimester: recurrence risk and long-term prognosis . Am J Obstet Gynecol 1991 , 165 : 1408 - 1412 .
17. Hnat MD , Sibai BM , Caritis S , Hauth J , Lindheimer MD , MacPherson C , VanDorsten JP , Landon M , Miodovnik M , Paul R , Meis P , Thurnau G , Dombrowski M : Perinatal outcome in women with recurrent preeclampsia compared with women who develop preeclampsia as nulliparas . Am J Obstet Gynecol 2002 , 186 : 422 - 426 .
18. Askie LM , Duley L , Henderson-Smart DJ , Stewart LA : Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data . Lancet 2007 , 369 : 1791 - 1798 .
19. Bujold E , Roberge S , Lacasse Y , Bureau M , Audibert F , Marcoux S , Forest JC , Giguere Y : Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis . Obstet Gynecol 2010 , 116 : 402 - 414 .
20. De Vries JIP , Van Pampus MG , Hague WM , Bezemer PD , Joosten JH : Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT . J Thromb Haemost 2012 , 10 : 64 - 72 .
21. Gris JC , Chauleur C , Molinari N , Mares P , Fabbro-Peray P , Quere I , Lefrant JY , Haddad B , Dauzat M : Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia. The pilot randomised controlled NOH-PE trial . Thromb Haemost 2011 , 106 : 1053 - 1061 .
22. Mello G , Parretti E , Fatini C , Riviello C , Gensini F , Marchionni M , Scarselli GF , Gensini GF , Abbate R : Low-molecular-weight heparin lowers the recurrence rate of preeclampsia and restores the physiological vascular changes in angiotensin-converting enzyme DD women . Hypertension 2005 , 45 : 86 - 91 .
23. Rey E , Garneau P , David M , Gauthier R , Leduc L , Michon N , Morin F , Demers C , Kahn SR , Magee LA , Rodger M : Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial . J Thromb Haemost 2009 , 7 : 58 - 64 .
24. Gris JC , Chauleur C , Faillie JL , Baer G , Mares P , Fabbro-Peray P , Quere I , Lefrant JY , Haddad B , Dauzat M : Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae. The pilot randomised controlled NOH-AP trial . Thromb Haemost 2010 , 104 : 771 - 779 .
25. Martinelli I , Ruggenenti P , Cetin I , Pardi G , Perna A , Vergani P , Acaia B , Facchinetti F , La Sala GB , Bozzo M , Rampello S , Marozio L , Diadei O , Gherardi G , Carminati S , Remuzzi G , Mannucci PM : Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial . Blood 2012 , 119 : 3269 - 3275 .
26. Huhle G , Geberth M , Hoffmann U , Heene DL , Harenberg J : Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin . Gynecol Obstet Invest 2000 , 49 : 67 - 69 .
27. Greer IA , Nelson-Piercy C : Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy . Blood 2005 , 106 : 401 - 407 .
28. Bank I , Libourel EJ , Middeldorp S , van der Meer J , Buller HR : High rate of skin complications due to low-molecular-weight heparins in pregnant women . J Thromb Haemost 2003 , 1 : 859 - 861 .
29. Rodger MA : Thrombophilia and placenta-mediated pregnancy complications: from the bench to bedside to policy . Thromb Res 2008 , 123 : S96 - S100 .
30. Rodger MA , Kahn SR , Cranney A , Hodsman A , Kovacs MJ , Clement AM , Lazo-Langner A , Hague WM : Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial . J Thromb Haemost 2007 , 5 : 1600 - 1606 .
31. Sud S , Douketis J : ACP Journal Club . The devil is in the details…or not? A primer on individual patient data meta-analysis . Ann Intern Med 2009 , 151 : JC1 - JC3 .
32. Clarke MJ : Individual patient data meta-analyses . Best Pract Res Clin Obstet Gynaecol 2005 , 19 : 47 - 55 .
33. Lambert PC , Sutton AJ , Abrams KR , Jones DR : A comparison of summary patient-level covariates in meta-regression with individual patient data meta-analysis . J ClinEpidemiol 2002 , 55 : 86 - 94 .
34. Sampson M , McGowan J , Cogo E , Grimshaw J , Moher D , Lefebvre C : An evidence-based practice guideline for the peer review of electronic search strategies . J Clin Epidemiol 2009 , 62 : 944 - 952 .
35. Schleussner E , Kamin G , Seeliger G , Rogenhofer N , Toth B , for the ETHIG Investigator Group: Low-molecular-weight heparin in recurrent pregnancy loss - Results of the ETHIG II study [abstract] . Thromb Res 2013 , 131 : S73 .
36. Giancotti A , La TR , Spagnuolo A , D'Ambrosio V , Cerekja A , Piazze J , Chistolini A : Efficacy of three different antithrombotic regimens on pregnancy outcome in pregnant women affected by recurrent pregnancy loss . J Matern Fetal Neonatal Med 2012 , 25 : 1191 - 1194 .
37. Salman SA , Shaaban OM , Zahran KM , Fathalla MM , Anan MA : Low molecular weight heaprin (LMWH) for treatment of recurrent miscarriage negatively tested for antiphospholipid antibodies: a randomized controlled trial [abstract] . Fertil Steril 2012 , 98 : S191 .
38. Visser J , Ulander VM , Helmerhorst FM , Lampinen K , Morin-Papunen L , Bloemenkamp KW , Kaaja RJ : Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial . Thromb Haemost 2011 , 105 : 295 - 301 .
39. Clark P , Walker ID , Langhorne P , Crichton L , Thomson A , Greaves M , Whyte S , Greer IA : SPIN: the Scottish Pregnancy Intervention Study: a multicentrerandomised controlled trial of low molecular weight heparin and low dose aspirin in women with recurrent miscarriage . Blood 2010 , 115 : 4162 - 4167 .
40. Kaandorp SP , Goddijn M , van der Post JA , Hutten BA , Verhoeve HR , Hamulyak K , Mol BW , Folkeringa N , Nahuis M , Papatsonis DN , Papatsonis DN , Buller HR , van der Veen F , Middeldorp S : Aspirin plus heparin or aspirin alone in women with recurrent miscarriage . N Engl J Med 2010 , 362 : 1586 - 1596 .
41. Laskin CA , Spitzer KA , Clark CA , Crowther MR , Ginsberg JS , Hawker GA , Kingdom JC , Barrett J , Gent M : Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial . J Rheumatol 2009 , 36 : 279 - 287 .
42. Schulman S , Kearon C : Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients . J Thromb Haemost 2005 , 3 : 692 - 694 .
43. Higgins JPT , Green S : Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011 ]. The Cochrane Collaboration: 2011 [www.cochrane-handbook .org]