Articles

Antepartum dalteparin versus no antepartum dalteparin for

the prevention of pregnancy complications in pregnant
women with thrombophilia (TIPPS): a multinational
open-label randomised trial
Marc A Rodger, William M Hague, John Kingdom, Susan R Kahn, Alan Karovitch, Mathew Sermer, Anne Marie Clement, Suzette Coat,
Wee Shian Chan, Joanne Said, Evelyne Rey, Sue Robinson, Rshmi Khurana, Christine Demers, Michael J Kovacs, Susan Solymoss, Kim Hinshaw,
James Dwyer, Graeme Smith, Sarah McDonald, Jill Newstead-Angel, Anne McLeod, Meena Khandelwal, Robert M Silver, Gregoire Le Gal,
Ian A Greer, Erin Keely, Karen Rosene-Montella, Mark Walker, Philip S Wells, for the TIPPS Investigators

Summary
Background Thrombophilias are common disorders that increase the risk of pregnancy-associated venous Published Online
thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated pregnancy complications July 25, 2014
http://dx.doi.org/10.1016/
(severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum S0140-6736(14)60793-5
dalteparin would reduce these complications in pregnant women with thrombophilia.
See Online/Comment http://
dx.doi.org/10.1016/S0140-
Methods In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled 6736(14)60850-3
consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous Thrombosis Program, Division
placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either of Hematology, Department of
Medicine, University of
antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks’ gestation, and twice daily
Ottawa, Ottawa, ON, Canada
thereafter until at least 37 weeks’ gestation) or to no antepartum dalteparin (control group). Randomisation was done (Prof M A Rodger MD); Ottawa
by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a Hospital Research Institute,
permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation Ottawa, ON, Canada
(Prof M A Rodger,
number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed
A M Clement RN,
study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the Prof G Le Gal MD,
outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early- Prof E Keely MD, M Walker MD,
onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous Prof P S Wells MD); Obstetric
Medicine, Robinson Institute,
thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov,
University of Adelaide,
number NCT00967382, and with Current Controlled Trials, number ISRCTN87441504. Women’s and Children’s
Hospital, Adelaide, South
Findings Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned Australia, Australia
(Prof W M Hague MD); Division
to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum
of Maternal-Fetal Medicine,
dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned Department of Obstetrics and
to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on- Gynecology, Mount Sinai
treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Hospital, University of Toronto,
Toronto, ON, Canada
Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (Prof J Kingdom MD,
(dalteparin 25/146 [17·1%; 95% CI 11·4–24·2%] vs no dalteparin 27/143 [18·9%; 95% CI 12·8–26·3%]; risk difference Prof M Sermer MD); Centre for
−1·8% [95% CI –10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 [19·6%] vs no dalteparin 24/141 Clinical Epidemiology, Jewish
[17·0%]; risk difference +2·6% [95% CI –6·4 to 11·6%]). In safety analysis, the occurrence of major bleeding did not General Hospital, Montreal, QC,
Canada (Prof S R Kahn MD);
differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 [19·6%]) Department of Medicine,
than in the no dalteparin group (13/141 [9·2%]; risk difference 10·4%, 95% CI 2·3–18·4; p=0·01). University of Ottawa/Ottawa
Hospital, Ottawa, ON, Canada
Interpretation Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, (A Karovitch MD, Prof G Le Gal,
Prof E Keely, Prof P S Wells);
pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk Robinson Institute, University
of these complications and is associated with an increased risk of minor bleeding. of Adelaide, Adelaide, South
Australia, Australia
Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn. (S Coat PhD); Department of
Medicine, University of British
Columbia, Vancouver, BC,
Introduction women.2 Thrombophilia acts synergistically with Canada (W S Chan MD);
Thrombophilias are common acquired or genetic pregnancy to increase further the risk of venous Maternal Fetal Medicine,
NorthWest Academic Center,
predispositions to develop venous thromboembolism.1 thromboembolism during pregnancy.3
University of Melbourne,
Venous thromboembolism, which comprises deep vein Placenta-mediated pregnancy complications, comprising Melbourne, Australia
thrombosis and pulmonary embolism, is more frequent pre-eclampsia, birth of a small-for-gestational-age infant, (J Said MBBS); Departments of
in pregnant women than in non-pregnant age-matched placental abruption, or pregnancy loss, are also common4,5 Medicine and Obstetrics and

www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60793-5 1

 Articles
Gynecology, University of
Montreal, and CHU Sainte-
Justine Research Center,
Montreal, QC, Canada
(E Rey MD); Department of
Medicine, Dalhousie University,
Halifax, NS, Canada
(Prof S Robinson MD);
Departments of Medicine and
Obstetrics and Gynecology,
University of Alberta, Royal
Alexandra Hospital, Edmonton,
AB, Canada (R Khurana MD);
Department of Medicine,
Université de Laval, Quebec, QC,
Canada (C Demers MD);
Department of Medicine,
London Health Sciences Centre,
University of Western Ontario,
London, ON, Canada
(Prof M J Kovacs MD);
Department of Medicine, McGill
University, St Mary’s Hospital
Center, Montreal, QC, Canada
(S Solymoss MD); Department of
Obstetrics, Sunderland Royal
Hospital, Sunderland, Tyne and
Wear, UK (K Hinshaw MBBS);
Department of Obstetrics and
Gynaecology, York Hospital,
York, UK (J Dwyer MBBS);
Department of Obstetrics and
Gynecology, Queen’s University,
Kingston, ON, Canada
(Prof G Smith MD); Division of
Maternal-Fetal Medicine,
Department of Obstetrics and
Gynecology, Department of
Radiology, and Department of
Clinical Epidemiology and
Biostatistics, McMaster
University, Hamilton, ON,
Canada (S McDonald MD);
Department of Medicine,
University of Saskatchewan,
Saskatoon, SK, Canada
(J Newstead-Angel MD);
Department of Medicine,
Sunnybrook Health Sciences
Centre, Toronto, ON, Canada
(A McLeod MD); Department of
Obstetrics and Gynecology,
Cooper Medical School of
Rowan University/Cooper
Hospital, Camden, NJ, USA
(Prof M Khandelwal MD);
Department of Obstetrics and
Gynecology, University of Utah
Health Sciences Center, Salt Lake
City, UT, USA
(Prof R M Silver MD); Faculty of
Health and Life Sciences,
University of Liverpool,
Liverpool, UK (Prof I A Greer MD);
and Department of Medicine,
The Warren Alpert Medical
School of Brown University,
Women’s Medicine
Collaborative, Providence, RI,
USA (Prof K Rosene-Montella MD)
2 www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60793-5
and lead to substantial maternal and fetal or neonatal
morbidity and mortality.4 Placental microvascular and
macrovascular thrombosis is a frequent, overlapping,
pathophysiological link in many affected pregnancies.5
Patients with previous placenta-mediated pregnancy
complications have a raised risk of both recurrent
placenta-mediated pregnancy complications6 and venous
thromboembolism during subsequent pregnancies.7,8
Similarly, evidence suggests that women with previous
venous thromboembolism have a raised risk of placenta-
mediated pregnancy complications in subsequent
pregnancies.9
Thrombophilias are consistently associated with early
and late pregnancy loss10,11 and can also be related to
severe pre-eclampsia, birth of a small-for-gestational-age
infant below the third percentile of birthweight, and
placental abruption.10 Since the initial discovery of an
association between thrombophilia and placenta-
mediated pregnancy complications more than 15 years
ago,12 clinicians, patients, guideline developers, and policy
makers have struggled to address the question of whether
pregnant women with thrombophilia should receive
antepartum thromboprophylaxis.13
Low-molecular-weight heparin is the thrombo-
prophylactic drug of choice in pregnancy because, unlike
oral anticoagulants, it does not cross the placenta and has a
favourable maternal safety profile with a low risk of major
bleeding, heparin-induced thrombocytopenia, and
heparin-induced osteoporosis.14 Nonetheless, the drug
needs to be administered by burdensome daily or twice
daily subcutaneous injections, is expensive, and can
complicate regional anaesthetic options if not discontinued
within 12–24 h of labour onset.
In the Thrombophilia in Pregnancy Prophylaxis Study
(TIPPS) we aimed to establish whether antepartum
prophylactic dalteparin, a low-molecular-weight heparin,
would reduce the risk of venous thromboembolism and
placenta-mediated pregnancy complications in pregnant
women with thrombophilia at high risk of pregnancy
complications.
Methods
Study design and participants
We enrolled pregnant women with thrombophilia who
were at increased risk of placenta-mediated pregnancy
complications, venous thromboembolism, or both in a
randomised trial to compare prophylactic dose antepartum
dalteparin with no antepartum dalteparin. Between
Feb 28, 2000, and Sept 14, 2012, the study was initiated in
36 tertiary care centres in Canada, Australia, the USA, the
UK, and France. 26 of these 36 centres screened patients
for eligibility (the other ten did not because they were
either unable to implement local trial operations or get
referrals to screen potentially eligible patients) and
21 centres recruited at least one patient. We obtained
appropriate regulatory approvals from Health Canada
(Canada), the US Food and Drug Administration (USA),
the Therapeutic Goods Administration (Australia), or the
Medicines and Healthcare Product Regulatory Agency
(UK), and local research ethics board approvals before we
began the study. All women participating in the study
provided written informed consent.
We screened 3022 women with previous pregnancy
complications, venous thromboembolism risk factors, or
thrombophilia for eligibility. Women were eligible for
inclusion if they had a confirmed thrombophilia (panel 1),
were at raised risk of placenta-mediated pregnancy
complications or venous thromboembolism (panel 1),
were pregnant, and had provided written informed
consent. Women were excluded if they were 21 weeks or
more gestational age at the time of randomisation, had a
contraindication to heparin treatment (panel 1), were
geographically inaccessible, needed anticoagulant therapy
as judged by the local investigator (panel 1), had already
previously participated in the study, or were younger than
the legal lower age limit to provide consent according to
country-specific regulations. We maintained screening
records to detail any reason for ineligibility in all patients
approached for the study.
Randomisation and masking
After confirming eligibility and obtaining consent, research
coordinators at each centre randomly assigned eligible
patients in a 1:1 ratio to antepartum dalteparin or no
antepartum dalteparin by a web-based randomisation
system. The computer-generated randomisation schedule
was stratified by country and gestational age at
randomisation day (<8 weeks, 8–12 weeks, and 12–20 weeks)
and had a permuted block design (block sizes 4 and 8). At
the time of randomisation, site pharmacists (or delegates)
received a randomisation number and treatment allocation
(by fax and/or e-mail) from the central web randomisation
system. The site pharmacist (or delegate) then dispensed
study drug to the local coordinator who taught the study
participants how to self-administer the study drug and
explained the trial procedures. Patients and study personnel
were not masked but outcome adjudicators were masked to
treatment assignment.
Procedures
We randomly assigned 292 women to receive either
antepartum dalteparin 5000 international units (IU)
once daily by subcutaneous self-injection from the day
of randomisation until 20 weeks of gestation followed
by 5000 IU twice daily from 20 weeks until at least
37 weeks gestational age, or no antepartum dalteparin.
The dose of dalteparin was doubled at 20 weeks’
gestation on the basis of pharmacokinetic studies
suggesting that the dose requirement increases in most
women after this point.15 During the initial 26 months
of the study, the control group received matching,
identically supplied and formulated placebo in prefilled
syringes. Owing to poor recruitment (only 19 participants
were recruited in 26 months), on June 25, 2002, the trial

Panel 1: Specific inclusion and exclusion criteria
Inclusion criteria (1, 2, 3, and 4 must have been met for
inclusion):
1 Thrombophilia confirmed by one or more of the following:
1·1 Factor V Leiden: one positive DNA based assay for factor V
Leiden (homozygous or heterozygous), or documented
activated protein C resistance and a first-degree relative
testing positive once for factor V Leiden in a DNA-based assay
1·2 Prothrombin gene mutation (homozygous or heterozygous) in
a DNA-based assay
or
Two abnormal tests, and no normal tests, for one or more of
the following:
1·3 Protein C deficiency
1·4 Protein S deficiency: at least one test done outside
pregnancy or the 6 week post-partum period, or, in addition
to two abnormal tests in pregnancy, one abnormal test
obtained in a first-degree relative
1·5 Antithrombin deficiency
or
1·6 Anti-phospholipid antibody confirmed by two positive tests
for one or more of the following: anticardiolipin IgG
(>30 U/ml), anticardiolipin IgM (>30 U/ml), anti-β2
glycoprotein IgG (>20 U/ml), anti-β2 glycoprotein IgM
(>20 U/ml), or positive Lupus anticoagulant
2 One or more of the following high-risk criteria for
pregnancy complications (venous thromboembolism,
pregnancy loss, or placenta-mediated complications):
2·1 Previous history of pre-eclampsia (including late-onset and
non-severe pre-eclampsia)
2·2 Previous unexplained birth of a small-for-gestational-age
infant (birthweight <10th percentile, corrected for sex and
gestational age)
2·3 Previous major placental abruption, defined as an abruption
associated with: vaginal bleeding or concealed
haemorrhage, and uterine tenderness, and fetal distress,
maternal shock, or maternal coagulopathy
2·4 Previous pregnancy loss* defined as:
2·4·1 Three or more unexplained pregnancy losses at
less than 10 weeks’ gestation, or
2·4·2 Two or more unexplained pregnancy losses between
10 and 16 weeks’ gestation, or
2·4·3 One or more unexplained pregnancy losses at or more
than 16 weeks’ gestation
2·5 Women with a history of one or more of the following
thromboembolic events/risk factors:
2·5·1 Previous documented provoked proximal† venous
thromboembolism
2·5·2 Previous documented calf vein‡ thrombosis
2·5·3 Previous superficial phlebitis
2·5·4 A first-degree relative with a history of pulmonary
embolism or deep vein thrombosis treated with
anticoagulants (more than 1 month of heparin or
warfarin)
www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60793-5
Articles
Correspondence to:
Prof Marc A Rodger, Ottawa
Hospital, General Campus,
3 Pregnancy confirmed by a positive serum, or urine 501 Smyth Road, Box 201A,
βhCG, or by ultrasound Ottawa, ON, K1H 8L6, Canada
4 Signed informed consent mrodger@ohri.ca
Exclusion criteria (any one criterion met led to exclusion):
1 21 weeks or more gestational age at time of randomisation
2 Contraindication to heparin therapy, including:
2·1 History of heparin-induced thrombocytopenia
2·2 Platelet count lower than 100 000 × 106/L
2·3 History of osteoporosis or steroid use (potential
increased risk of osteoporosis and osteoporotic
fracture with heparin therapy)
2·4 Actively bleeding
2·5 Documented peptic ulcer within 6 weeks
(contraindication to anticoagulation)
2·6 Heparin, bisulphite, or fish allergy
2·7 Severe hypertension (systolic blood pressure
>200 mm Hg and/or diastolic blood pressure
>120 mm Hg: contraindication to anticoagulation)
2·8 Severe hepatic failure (international normalised ratio
>1·8): increased likelihood of bleeding
2·9 Women with serum creatinine level greater than
80 μmol/L (1·3 mg/dL) and 24-h creatinine clearance
less than 30 mL/min. However, women with serum
creatinine clearance of 80 μmol/L (1·3 mg/dL) or less
did not require a normal 24-h creatinine clearance to
be eligible.
3 Geographical inaccessibility (less likely to comply with
necessary follow-up visits and care)
4 Need for anticoagulants as judged by the local
investigator, including (but not limited to):
4·1 Women with recurrent pregnancy loss with
antiphospholipid antibody syndrome
4·2 Women with previous unprovoked§ proximal¶
venous thromboembolism, whose pulmonary
embolism or deep vein thrombosis was treated with
anticoagulants (more than 1 month of heparin or
warfarin) or inferior vena cava interruption
4·3 Women with mechanical heart valves
4·4 Women on long-term anticoagulants before
pregnancy
5 Previous participation in the TIPPS trial
6 Below the legal age limit to provide informed consent
according to country-specific regulations
*Examples of explained miscarriage or fetal loss include loss associated with severe congenital
malformations, chromosomal abnormalities, neonatal alloimmune haemolytic anaemia,
recent cytomegalovirus infection, positive fetal or placental listeria cultures, and women with
known abnormal uterine anatomy. †Proximal venous thromboembolism includes pulmonary
embolism or deep vein thrombosis occurring at or above the trifurcation of the popliteal vein.
‡Calf vein thrombosis is a deep vein thrombosis that occurs below the trifurcation of the
popliteal vein. §Unprovoked refers to a venous thromboembolism that occurs outside all of
the following periods: surgery, immobilisation, cast, and/or malignancy. ¶Proximal refers to a
venous thromboembolism that occurs above the trifurcation of the popliteal vein.
3
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3022 women assessed for eligibility

2730 excluded
2378 did not meet eligibility criteria
175 had ≥1 exclusion criteria
177 refused to participate
292 randomised

148 initially allocated to antepartum dalteparin 144 initially allocated to no antepartum dalteparin

2 excluded for ineligibility 1 excluded for ineligibility

146 allocated to antepartum dalteparin 143 allocated to no antepartum dalteparin

12 crossed over to the control group 14 crossed over to the antepartum

dalteparin group

14 patients crossed over from other group 12 patients crossed over from other group

148 received antepartum dalteparin 141 received no antepartum dalteparin

0 lost to follow-up (note: 3 patients did not
have a 6-week post-partum visit)
15 non-compliant with dalteparin
1 had <80% antepartum doses
10 had <80% post-partum doses
4 had <80% doses in both periods
0 lost to follow-up (note: 6 patients did not
have a 6-week post-partum visit)
14 non-compliant with post-partum
dalteparin (<80% post-partum doses)

146 women in intention-to-treat analysis 143 women in intention-to-treat analysis

143 women in on-treatment and safety analyses* 141 women in on-treatment and safety analyses

Figure 1: Trial profile

*The five patients who were non-compliant with antepartum dalteparin were excluded from the on-treatment and safety analyses.

steering committee changed the study design to an
open-label trial comparing antepartum open-label
dalteparin with no antepartum dalteparin control. Post
partum, all participants were prescribed dalteparin at a
dose of 5000 IU once daily by subcutaneous self-
injection from day 1 (administered 6–28 h after delivery)
until day 42. All participants received otherwise similar
obstetrical care (according to local practices) and study
follow-up.
We defined crossovers as participants who switched
study groups within 10 days of randomisation.
Participants who discontinued dalteparin after 10 days
were labelled as non-compliant. Throughout study
follow-up, we recorded cointerventions (eg, aspirin) and
concomitant use of other medications.
Patients attended clinic follow-up visits within
7–9 days of randomisation and then at 12, 20, 28, 32,
36 weeks’ gestation and at 6 weeks post partum. These
visits included assessments of outcome and adverse
events, measurement of weight and blood pressure,
study drug compliance diary review, urine dipstick
assessment for protein and blood, complete blood
count, and serum creatinine and liver function tests.
Bone mineral density was measured at the 6-week post-
partum visit. Additionally, follow-up visits, either in
person or on the telephone, were done at 8, 16, 24, 30,
34, 35, 37, 38, 39, and 40 weeks’ gestation. We assessed
outcomes and adverse events at the time of labour and
delivery by review of participants’ medical records and
any gaps were resolved at the 6 weeks post-partum
follow-up visit.
Outcomes
The primary endpoint was a composite outcome that
included any of the following events: objectively
documented symptomatic major venous thrombo-
embolism (deep vein thrombosis proximal to the calf
trifurcation, pulmonary embolism, or sudden maternal
death); severe or early-onset (<32 weeks) pre-eclampsia
(defined as severe if accompanied by blood pressure
≥160/110 mm Hg or liver function tests three-times
above normal limits, platelet count <100 000 × 10⁶/L,

4 www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60793-5

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oliguria [<30 mL/h urine output in a 24 h period], Hemostasis17) and minor bleeding (non-major bleeding),
pulmonary oedema [on chest x-ray], coagulopathy bone mineral density measured at 6 weeks post partum,
[partial thromboplastin time >1·5 ×baseline, preterm delivery, placental abruption, heparin-induced
international normalised ratio >1·5 ×baseline, or thrombocytopenia, and symptomatic fracture.
fibrinogen <1·0 g/dL], proteinuria >5 g/24 h, or All suspected primary and secondary outcome events
seizures); birth of a small-for-gestational-age infant were adjudicated independently and blindly by at least
(birthweight <10th percentile);16 or pregnancy loss. two physicians in a panel that included experts in
Placental abruption was not included in the composite obstetrics and thrombosis.
primary outcome because of the hypothetical possibility
that dalteparin might increase the frequency of this
Antepartum No
bleeding complication. dalteparin antepartum
Secondary outcomes included major bleeding (as group dalteparin
defined by the International Society of Thrombosis and (n=146) group (n=143)
(Continued from previous column)
Antepartum No High-risk inclusion criteria
dalteparin antepartum
Previous pregnancy complications 92 (63%) 84 (59%)
group dalteparin
(any of those listed below)
(n=146) group (n=143)
Pre-eclampsia 20 (14%) 25 (18%)
Age (years) 31·9 (4·7) 31·6 (5·1)
Eclampsia 3 (2%) 3 (2%)
Gestational age at randomisation 12·0 (4·5) 11·7 (4·7)
(weeks) SGA infant (<10th percentile) 26 (18%) 19 (13%)

Ethnic origin Major placental abruption 16 (11%) 10 (7%)

White 133 (91%) 129 (90%) Three or more miscarriages at 24 (16%) 20 (14%)
<10 weeks’ gestation
Black 3 (2%) 3 (2%)
Two or more fetal losses at 11 (8%) 14 (10%)
Asian 8 (6%) 4 (3%) 10–16 weeks’ gestation
Native Canadian 0 3 (2%) One or more fetal losses at 27 (19%) 33 (23%)
Other 2 (1%) 4 (3%) ≥16 weeks’ gestation
Smoking status VTE risk factors/events (any of the 67 (46%) 61 (43%)
Ever smoker 56 (38%) 51 (36%) following)

Current smoker 5 (3%) 4 (3%) Family history of VTE in first- 45 (31%) 46 (32%)
degree relatives
BMI (kg/m²)
Mean number of first-degree 1·1 1·1
Pre-pregnancy 26·3 (6·6) 27·0 (6·8) relatives with VTE, per participant
At time of randomisation 27·7 (6·8) 27·8 (6·5) Previous secondary VTE 11 (8%) 9 (6%)
Baseline blood pressure (mm Hg) Previous calf deep vein thrombosis 10 (7%) 6 (4%)
Systolic 112·3 (12·0) 114·4 (12·6) Previous superficial phlebitis 7 (5%) 5 (4%)
Diastolic 67·9 (8·9) 69·6 (9·5) Concurrent medications during study
Obstetrical history pregnancy
Gravidity 3·1 (1·8) 3·3 (1·9) Aspirin (all participants) 43 (30%) 57 (40%)
Parity 1·0 (1·2) 1·0 (1·0) Aspirin (participants with previous 15/37 (41%) 19/28 (68%)
Preterm deliveries 0·33 (0·54) 0·32 (0·53) pre-eclampsia or SGA infants)

Spontaneous abortions 1·1 (1·48) 1·2 (1·5) Vitamins including folic acid 136 (93%) 142 (99%)

Therapeutic abortions 0·2 (0·58) 0·2 (0·45) Analgesic use in pregnancy 67 (46%) 49 (34%)

Living children 0·7 (1·0) 0·6 (0·75) Antibiotic use in pregnancy 45 (31%) 40 (28%)

Multiple pregnancies (ie, twins, 0·01 (0·1) 0·03 (0·18) Labour and delivery of study pregnancy
triplets) Induced 64 (44%) 55 (39%)
Outcomes after previous livebirths Epidural use 80 (55%) 82 (57%)
Neonatal death 13 (9%) 14 (10%) Caesarean section 61 (42%) 53 (37%)
Infant death 5 (3%) 4 (3%) Emergency caesarean section 25 (17%) 19 (13%)
Thrombophilia inclusion criteria Peri-partum haemorrhage 6 (4%) 9 (6%)
Factor V Leiden* 94 (64%) 82 (57%) Major 2 (1%) 2 (1%)
Prothrombin gene mutation 30 (21%) 33 (23%) Minor 4 (3%) 7 (5%)
Protein S deficiency 11 (8%) 13 (9%) Estimated blood loss at delivery (mL) 467·4 (201·0) 470·4 (237·1)
Protein C deficiency 6 (4%) 11 (8%)
Data are mean (SD) or n (%), unless otherwise indicated. SGA=small for
Antithrombin deficiency 2 (1%) 1 (1%) gestational age. VTE=venous thromboembolism. *Four patients with
Antiphospholipid antibody 12 (8%) 10 (7%) homozygous Factor V Leiden.
(Table continues in next column)
Table 1: Baseline characteristics

www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60793-5 5

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expected minimal clinically important difference of 16%

Antepartum No antepartum Difference (95% CI) p
dalteparin dalteparin value (ie, 33% relative risk reduction), we aimed for a sample size
(n=146) (n=143) of 284 to achieve 80% power with a two-tailed α of 0·05.
Primary analysis The data safety monitoring board reviewed study
Patients with one or more of major 25 (17·1%) 27 (18·9%) −1·8% (−10·6 to 7·1) 0·70 performance and safety outcomes regularly. The board
VTE, severe or early onset also did a single planned formal blinded interim analysis
pre-eclampsia, SGA (<10%), or after 50% of study participants completed follow-up.
pregnancy loss
All data analyses were done according to a pre-
Stratified by gestational age at
randomisation
established analysis plan, with an intention-to-treat
approach. Intention-to-treat analysis was supplemented
<8 weeks 9/33 (27·3%) 12/32 (37·5%) −10·2% (−32·9 to 12·4) 0·38
by an on-treatment sensitivity analysis to assess the
8–12 weeks 9/33 (27·3%) 3/32 (9·4%) 17·9% (−0·3 to 36·1) 0·06
robustness of our findings.
12–20 weeks 7/80 (8·8%) 12/79 (15·2%) −6·4% (−16·5 to 3·6) 0·21
For the primary analysis, we compared the proportion
Stratified by location
of patients experiencing one or more of the composite
Australia 8/38 (21·0%) 8/36 (22·2%) −1·2% (−19·9 to 17·6) 0·90
outcome events between the dalteparin group and the
Canada 17/102 (16·7%) 19/104 (18·3%) −1·6% (−12·0 to 8·8) 0·76
control group using an unadjusted χ² test of proportions.
Europe 0/3 0/1 NA NA
We did prespecified subgroup analyses, in which we
USA 0/3 0/1 NA NA
analysed treatment effects in subgroups based on
Secondary analysis: efficacy outcomes
stratification variables (country and gestational age at
Symptomatic major VTE 1 (0·7%) 2 (1·4%) −0·7 (−3·1 to 1·6) 0·62
recruitment), thrombophilia, previous history of specific
Pre-eclampsia 8 (5·5%) 5 (3·5%) 2·0 (−2·8 to 6·8) 0·42 placenta-mediated pregnancy complications, and history
Severe or early onset pre- 7 (4·8%) 4 (2·8%) 2·0 (−2·4 to 6·4) 0·38 of venous thromboembolism events or risk factors.
eclampsia
In secondary analyses, for each of the binary outcomes
Small-for-gestational-age infant 9 (6·2%) 12 (8·4%) −2·2 (−8·2 to 3·8) 0·47
(<10%) (major bleeding, minor bleeding, preterm delivery,
SGA (<5%) 2 (1·4%) 3 (2·1%) −0·7 (−3·7 to 2·3) 0·68 heparin-induced thrombocytopenia, and fractures), we
SGA (<3%) 3 (2·0%) 0 2·0 (−0·2 to 4·4) 0·25
used an unadjusted χ² test of proportions to compare the
Pregnancy loss (any) 12 (8·2%) 10 (7·0%) 1·2 (−4·9 to 7·3) 0·69
proportion of patients with these outcomes between the
Early (≥3 at <10 weeks) 4 (2·7%) 5 (3·5%) 0·8 (−4·8 to 3·2) 0·75
dalteparin group and the control group. We compared
mean bone mineral density, gestational age at delivery,
Late (≥2 at >10 weeks or ≥1 at 6 (4·1%) 2 (1·4%) 2·7 (−1·0 to 6·5) 0·28
>16 weeks) and birthweight in the dalteparin and control groups with
Any pre-eclampsia, SGA, or loss 27 (18·5%) 28 (19·6%) −1·1 (−10·1 to 8·0) 0·81 independent t tests. We also did on-treatment sensitivity
or abruption analyses for the primary and secondary analyses.
Placental abruption 4 (2·7%) 3 (2·1%) 0·6 (−2·9 to 4·2) 0·72 Descriptive data are presented as percentages or means
Preterm delivery (<37 weeks) 23 (15·8%) 17 (11·9%) 3·9 (−4·1 to 11·8) 0·34 (SDs). All statistical tests were two-sided and significance
Birthweight of livebirths (g) 3186·2 (758) 3241·4 (764) −55·2 (−238·6 to 0·55 was set at p<0·05. SAS version 9.3 was used for all
128·1) analyses. This trial is registered with ClinicalTrials.gov,
Gestational age at delivery (weeks) number NCT00967382, and with Current Controlled
Of livebirths 38·1 (2·84) 38·2 (3·1) −0·13 (−0·86 to 0·59) 0·72 Trials, number ISRCTN87441504.
Of pregnancy loss 16·8 (8·2) 10·8 (5·3) 6·0 (−0·09 to 12·11) 0·06
Secondary analysis: safety outcomes (on-treatment analysis) (n=143 in dalteparin group, n=141 in Role of the funding source
control group) The funders of the study had no role in the design or
Major bleeding 3 (2·1%) 2 (1·4%) 0·7 (−2·4 to 3·7) 1·0 conduct of the study; in the collection, analysis, and
Minor bleeding (non-major) 28 (19·6%) 13 (9·2%) 10·4 (2·3 to 18·4) 0·01 interpretation of the data; or in the preparation, review, or
Heparin-induced 0 0 ·· ·· approval of the report. MAR, TR, RM, DF, and AMC had
thrombocytopenia
complete access to all the data in the study, and MAR,
Osteoporotic fracture 0 0 ·· ··
PSW, AK, JK, MS, WMH, SRK, WSC, and AMC had final
Bone mineral density measured at 2·16 (0·35) 2·23 (0·42) −0·07 (−0·19 to 0·04) 0·21
6 weeks post partum (g/cm³)
responsibility for the decision to submit for publication.

Data are n (%) or mean (SD), unless otherwise indicated. VTE=venous thromboembolism. SGA=small for gestational
age. NA=not applicable.
Table 2: Primary and secondary analysis
Statistical analysis
A priori, based on the prediction that venous
thromboembolism, severe or early onset pre-eclampsia,
small-for-gestational-age infants, or pregnancy loss would
occur in 49% of the control participants12,18–20 and an
Results
Between Feb 28, 2000, and Sept 14, 2012, we approached
469 eligible women to participate in the study, of whom
292 consented and were randomly allocated to either
antepartum dalteparin (n=148) or no antepartum
dalteparin (n=144; figure 1). Three women were excluded
post-randomisation because of ineligibility (two in the
antepartum dalteparin group [who received the drug but
were not eligible to participate] and one in the control

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Events/total (n/N) Risk ratio (95% CI) p value

Dalteparin Control
Subgroup
Maternal age <35 years 14/109 17/98 0·70 (0·4–1·4) 0·37
Maternal age <40 years 22/135 26/136 0·90 (0·5–1·4) 0·54
Previous pregnancy loss 14/69 17/74 0·90 (0·5–1·6) 0·70
Previous early loss 7/24 4/20 1·50 (0·5–4·3) 0·49
Previous late loss 9/37 12/44 0·90 (0·4–1·9) 0·76
Previous pre-eclampsia 7/20 6/25 1·50 (0·6–3·6) 0·42
Previous severe/early pre-eclampsia 6/13 2/9 2·10 (0·5–8·1) 0·29
Previous SGA <10% 7/26 5/19 1·02 (0·4–2·7) 0·96
Previous SGA <5% 1/3 0/1 1·50 (0·1–22·6) 0·77
Previous SGA <3% 3/13 3/11 0·80 (0·2–3·4) 0·81
Previous abruption 0/16 4/10 0·10 (0·004–1·2) 0·07
Previous secondary VTE 2/11 0/9 4·20 (0·2–77·1) 0·34
Previous calf deep vein thrombosis 0/10 3/6 0·10 (0·01–1·5) 0·09
Family history of VTE 5/45 6/46 0·80 (0·3–2·6) 0·78
Factor V Leiden 17/94 13/82 1·10 (0·6–2·2) 0·70
Prothrombin gene mutation 3/30 4/33 0·80 (0·2–3·4) 0·79
APLA 4/12 3/10 1·10 (0·3–3·8) 0·87
Protein C/protein S/antithrombin 1/19 7/25 0·20 (0·03–1·4) 0·10
Aspirin users 3/43 12/57 0·30 (0·1–1·1) 0·07
Aspirin non-users 22/103 15/86 1·20 (0·7–2·2) 0·50

0·01 0·1 1 10 100

Favours dalteparin Favours control

Figure 2: Subgroup analysis forest plot with risk ratio (95% CI) for the primary composite outcome
The primary composite outcome was major VTE or severe/early-onset pre-eclampsia, SGA infant (<10th percentile), or pregnancy loss. SGA=small for gestational age.
VTE=venous thromboembolism. APLA=anti-phospholipid antibodies.

group), leaving 146 patients assigned to antepartum
dalteparin and 143 to no antepartum dalteparin.
Therefore, for the intention-to-treat analyses, there were
146 women in the antepartum dalteparin group and
143 in the control group. However, 26 women crossed
over within 10 days of randomisation (12 from dalteparin
to no dalteparin, and 14 from no dalteparin to dalteparin),
and an additional five patients in the treatment group
were non-compliant with antepartum dalteparin and
were excluded from on-treatment and safety analyses.
Therefore, there were 143 women on antepartum
dalteparin and 141 women on no antepartum dalteparin
for the on-treatment and safety analyses (figure 1).
The baseline characteristics of the two groups were
similar (table 1). Overall, the mean age of the women was
31·8 years (SD 4·9), mean gestational age at randomisation
was 11·9 weeks (4·6), and most participants were white
(91% [262/289]). Most women had either the factor V
Leiden (60% [176/289]) or prothrombin gene mutation
(22% [63/289]). During a mean of 2·2 previous pregnancies
(SD 1·8) and a mean of 1·0 (1·0) previous deliveries, 61%
(176/289) of the study population had experienced
pregnancy complications. 44% (128/289) of participants
had a risk factor for venous thromboembolism, most of
whom (79% [101/128]) had a first-degree relative with the
disorder. During the study pregnancy, aspirin use was
slightly more common in the control group (difference
+10·4% [95% CI −0·5% to 21·3%]) whereas analgesic use
was slightly more frequent in the antepartum dalteparin
group (difference +11·6% [−0·4% to 22·8%]).
The proportions of patients undergoing a caesarean
section or experiencing peri-partum haemorrhage (a
>40 g/L decrease in haemoglobin at 24 h post-partum)
were similar between groups, as was estimated blood loss
at delivery (table 1).
No participants were lost to follow-up during the
antepartum period or at labour and delivery. Five of
146 women (3·4%) in the antepartum dalteparin group
were non-compliant with antepartum dalteparin (ie, they
took <80% of the prescribed doses). In the post-partum
period, non-compliance with post-partum dalteparin was
similar between the groups (9·6% [14/146] in the
antepartum dalteparin group vs 9·8% [14/143] in the
control group).
Overall, 52 of 289 randomised women experienced one
or more components of the primary composite outcome
measure (symptomatic major venous thromboembolism,
severe or early onset pre-eclampsia, birth of a small-for-
gestational-age infant [<10th percentile], or pregnancy
loss). 25 of 146 (17·1% [95% CI 11·4–24·2%]) had the
primary composite outcome in the antepartum dalteparin
group compared with 27 of 143 (18·9% [12·8–26·3]) in the
no antepartum dalteparin group (p=0·70), with a difference
of −1·8% in favour of dalteparin (95% CI of difference
–10·6% to 7·1%) (table 2). None of the component
outcomes of the primary composite outcome measure
differed between the two groups (table 2). There were also
no between-group differences with alternate severity
definitions for these component outcomes (table 2). Three
patients had symptomatic major venous thromboembolism
while on dalteparin (two with previous calf deep vein
thrombosis had venous thromboembolism during the
post-partum period and one patient with previous
provoked proximal deep vein thrombosis and anti-

www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60793-5 7

 Articles
phospholipid antibodies had venous thromboembolism at
11 weeks’ gestation while on antepartum dalteparin). Mean
birthweight and gestational age at delivery of livebirths
were similar between the groups.
Our prespecified subgroup analyses showed no
significant differences between groups in terms of
thrombophilia, previous pregnancy complications,
previous venous thromboembolism events or risk
factors, aspirin use, gestational age at enrolment or
country, in both intention–to-treat and on-treatment
See Online for appendix analyses (table 2, figure 2, and appendix).
Although we recorded no differences in major bleeding
events, more minor bleeding events occurred in the ante-
partum dalteparin group (19·6% [28/143]) than in the no
antepartum dalteparin group (9·2% [13/141]; p=0·01)
(table 2). No patients had heparin-induced thrombo-
cytopenia, changes in bone mineral density, or clinical
fracture.
One patient who received antepartum dalteparin had a
left parieto-occipital transient ischaemic attack (expressive
aphasia and right visual field loss for 1 h) at 27 weeks’
gestation with no thrombocytopenia. One participant in
the control group had a severe allergic reaction (lip/
tongue swelling) after a first dose of post-partum
dalteparin. Allergic-type skin reactions were noted in
15 participants on dalteparin (nine antepartum and six
post partum) and in four participants not on dalteparin
(three antepartum and one post partum in a non-
compliant participant). Raised levels of liver enzymes
(aspartate aminotransferase or alanine transaminase)—
defined as two-times normal values—were recorded in
11 participants on dalteparin (ten antepartum and one
post partum) and in none of the control participants.
Three neonatal deaths occurred in infants born
prematurely. One of these deaths occurred in the
antepartum dalteparin group (preterm rupture of
membranes at 24 weeks’ gestation) and two were in the
control group (preterm rupture of membranes at 24 weeks’
gestation and pre-eclampsia at 30 weeks). Six children in
pregnancies exposed to antepartum dalteparin had
congenital anomalies (ankyloglossia [n=2], ectopic kidney,
trisomy, strawberry haemangioma, and cataract). Two
children in the control group had congenital anomalies
(hemi-vertebrae/scoliosis and duplex renal collecting
system).
Discussion
In our trial, antepartum dalteparin did not reduce the
risk of either pregnancy loss, venous thromboembolism,
or placenta-mediated pregnancy complications in
pregnant women with thrombophilia at high risk of
pregnancy loss, venous thromboembolism, or placenta-
mediated pregnancy complications.
This trial addresses a key therapeutic question in a large
and vulnerable patient group. The absence of benefit is an
important finding. The discovery of an association between
thrombophilia and pregnancy complications in the
8 www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60793-5
mid-1990s led to widespread off-label use of low-molecular-
weight heparin in pregnant women—both with and
without thrombophilia—who had previous pregnancy
complications. This off-label use has been fuelled by the
emotional consequences of these complications21
combined with expert opinion,22,23 consensus panels,24,25
and small non-randomised studies suggesting benefit.26–28
Antepartum low-molecular-weight herparin is not a
benign intervention; it can be complicated by heparin-
induced thrombocytopenia29,30 (albeit rarely), withholding
of epidural analgesia, and, as shown in our trial, increased
minor bleeding,14 allergic reactions,14 skin reactions,14 raised
liver transaminase concentrations, and the risk of
induction of labour. Additionally, up to 400 subcutaneous
injections of the drug per term of pregnancy is both a
personal and financial burden. Clinicians and patients can
be reassured that dalteparin use throughout the
antepartum period does not lead to significant changes in
bone mineral density. Finally, the continued belief in
ineffective therapy hampers further research for efficacious
treatments for women at risk of venous thromboembolism
and pregnancy complications.
We designed the trial to detect a minimal clinically
important difference of 16% in the composite primary
outcome (severe or early-onset pre-eclampsia, small-for-
gestational-age infants <10th percentile, pregnancy loss, or
major venous thromboembolism). This 16% absolute
difference translates into a number needed to treat of six—
ie, six women would need to inject up to 400 needles per
pregnancy at a drug cost of more than US$8000 per
pregnancy to prevent one outcome. The lower bound of
the 95% CI of the difference in composite event rates
between groups in our intention-to-treat analysis (−1·8%
favouring dalteparin [95% CI of difference –10·6% to
7·1%) and in our on-treatment analysis (+2·6% favouring
control [95% CI –6·4 to 11·6%]), excludes a 16% difference
favouring dalteparin; therefore, we can conclude that
important treatment effects have been excluded. Although
our trial was not designed to detect important differences
in each individual component of our composite outcome,
our secondary analyses do not support important treatment
effects in these outcomes. We noted that in the relevant
subgroups of women with thrombophilia, such as those
with previous pregnancy loss, previous pre-eclampsia,
previous birth of a small-for-gestational-age infant, and a
family history of venous thromboembolism, antepartum
dalteparin did not seem to reduce the risk of pregnancy
loss, placenta-mediated pregnancy complications, or
venous thromboembolism. Although these secondary and
subgroup analyses should be interpreted with caution,
they suggest that women with thrombophilia should not
be prescribed low-molecular-weight heparin to prevent
these complications unless further research suggests
benefit in these subgroups or individual outcomes.
The strengths of our trial include its generalisability
provided by the multinational design, the strategies used
to protect against bias (including allocation concealment

from central web randomisation, masked independent
adjudication of all outcome events, and no loss of patients
to follow-up), and a dosing regimen that ensured
prophylactic dose anti-factor Xa activity throughout
pregnancy in most women.15 Our primary composite
outcome measure included events that are all clinically
important, and equal weighting of these events was judged
appropriate by the investigators and grant reviewers a
priori. In view of the fact that women with thrombophilia
who have had previous complications seem to be at higher
risk of all of these complications in subsequent
pregnancies, and that these complications often overlap, to
study a composite outcome measure in this therapeutic
area also seemed to be a sensible and pragmatic approach.
Our trial has some limitations. Crossover and non-
compliance might have led to a reduction in detectable
treatment effect. However, crossover was balanced, non-
compliance was negligible (3·4% of participants
administered <80% of antepartum dalteparin doses), and
our on-treatment sensitivity analysis did not change the
conclusions of the study. Recruitment challenges led to
the trial being completed after more than 12 years of
enrolment and introduce the possibility of time trend or
cohort effects. The characteristics of participants, co-
interventions, or both, might have varied over time and
led to changes in participants’ risk for outcomes. A
plausible notion is that the combination of dalteparin with
aspirin is effective whereas dalteparin alone is not
effective. Indeed, in our subgroup analysis in aspirin
users, antepartum dalteparin trended toward a treatment
effect but did not reach significance. Ideally, all patients
would have been randomised in early pregnancy to
maximise the possibility that dalteparin could positively
affect placental development. Our subgroup analysis of
treatment effect by gestational age at enrolment did not
suggest differential effect but had low power to explore
this hypothesis. Future research into higher doses of low-
molecular-weight heparin with and without aspirin, or
trials that start treatment with low-molecular-weight
heparin earlier in pregnancy, might be warranted.
Our findings need to be considered in the context of
previous trials exploring the benefit of low-molecular-
weight heparin to prevent pregnancy-associated venous
thromboembolism, recurrent pregnancy loss, and late
placenta-mediated pregnancy complications. Our study is
the first randomised trial to assess the risks and benefits of
low-molecular-weight heparin to prevent pregnancy-
associated venous thromboembolism in women with
thrombophilia (panel 2). None of the pregnant women
with thrombophilia without previous distal or provoked
venous thromboembolism had symptomatic major
antepartum venous thromboembolism in the control
group (0%, 95% CI 0–2·8%). This result affirms consensus
guidelines that suggest that women with thrombophilia
without previous venous thromboembolism can have
antepartum anticoagulant prophylaxis withheld.13
However, all three women who had venous
www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60793-5
Articles
Panel 2: Research in context
Systematic review
We did a systematic review and meta-analysis following a systematic review protocol
previously published39 and updated in January, 2014, to explore the benefit of
low-molecular-weight heparin in preventing placenta-mediated pregnancy complications
and pregnancy loss. We also added the search terms “venous thrombosis”, “deep vein
thrombosis”, and “pulmonary embolism” to explore the benefit of antepartum low-
molecular-weight heparin to prevent venous thromboembolism in thrombophilic women.
The latter search identified no trials. We assessed the quality of the evidence with the
Cochrane Handbook’s risk of bias assessment tool.
Interpretation
Our findings are consistent with previously published high-quality evidence that suggests
no benefit of antepartum low-molecular-weight heparin in women with previous
pregnancy loss, women with previous non-severe or late-onset pre-eclampsia, or women
with previous small-for-gestational-age birth between the 5th and 10th percentile. Our
randomised trial is the first to show that thrombophilic women without previous venous
thrombosis do not benefit from antepartum low-molecular-weight-heparin. Our meta-
analysis shows that lower quality evidence suggests that low-molecular-weight heparin
might prevent recurrent severe placenta-mediated pregnancy complications (severe or
early-onset pre-eclampsia, small-for–gestational-age birth <5th percentile, and placental
abruption) but we did not record this benefit in the subgroup analyses of our trial.
thromboembolism in our trial had a history of calf deep
vein thrombosis or provoked venous thromboembolism.
All three women had venous thromboembolism while on
prophylactic dalteparin (one antepartum and two post-
partum), and the overall event rate was 3 of 36 (8·3%;
95% CI 1·7–22·5%) in the subgroup with previous calf
deep vein thrombosis or previous provoked venous
thromboembolism. This finding suggests that these
patients might need more aggressive prophylaxis.13
Our subgroup analysis in women with thrombophilia
and previous pregnancy loss suggesting no improvement
in livebirth rate with low-molecular-weight heparin is
consistent with other multicentre trials that have shown no
increase in livebirth rate with this treatment in unselected
patients,31–34 women without thrombophilia,34 and in
women with thrombophilia.35 This finding contrasts with
the results of three single-centre trials, with a higher risk of
bias, suggesting benefit in women with thrombophilia36
and without thrombophilia.37,38 Overall, the existing
evidence does not support the use of low-molecular-weight
heparin to prevent recurrent pregnancy loss.
To analyse the cumulative evidence assessing the use of
low-molecular-weight heparin to prevent recurrent late
placenta-mediated pregnancy complications (late
pregnancy loss, pre-eclampsia, abruption, or small-for-
gestational-age infants <10th percentile), we updated our
recently published meta-analysis39 with our present
findings (figure 3). This updated meta-analysis suggests a
benefit in reducing recurrent late placenta-mediated
complications (RR 0·57, 95% CI 0·36–0·91) but showed
substantial heterogeneity (I²=68%). We did subgroup
analyses to assess the causes of this heterogeneity. When
we explored the summary effects and heterogeneity in
9
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multicentre trials,40–42 including TIPPS (RR 0·86 [95% CI
0·53–1·41]; I²=47%) compared with single-centre trials43–45
(0·36 [0·24–0·52]; I²=0%), we noted a reduction in overall
heterogeneity and no clear treatment effect from the
results of multicentre trials. When we explored trials
registered in a clinical trials registry before completion,40,42
including TIPPS (RR 1·08 [95% CI 0·74–1·60]; I²=0%)
compared with trials not registered before completion41,43–45
(0·35 [0·25–0·50]; I²=0%), we also noted an important
reduction in heterogeneity and no clear treatment effect
in registered trials. Conversely, when we analysed trials
that included only women with previous severe late
placenta-mediated pregnancy complications, at a study
level41,44,45 (RR 0·37 [95% CI 0·25–0·55]; I²=0%) compared
with trials that included women with previous non-severe
late placenta-mediated pregnancy complications, at a
study level,40,42,43 including TIPPS (RR 0·80 [95% CI
0·44–1·46]; I²=68%), we also noted a reduction in
heterogeneity and no clear treatment effect in trials
including women with non-severe late placenta-mediated
pregnancy complications. In summary, higher quality
evidence suggests that low-molecular-weight heparin
does not prevent recurrent non-severe placenta-mediated
pregnancy complications, whereas lower quality evidence
suggests that low-molecular-weight heparin might
prevent recurrent severe placenta-mediated pregnancy
complications. However, given that the latter evidence is
mainly driven by single-centre unregistered trials, the
quality of evidence dictates that further research is needed
to explore this hypothesis. Meanwhile, women with and
without thrombophilia, with previous late-onset and non-
severe pre-eclampsia and previous mildly small-for-
gestational-age infants (birthweight between 5th and 10th
percentile) should not be offered low-molecular-weight
heparin to prevent recurrent pregnancy complications.
In conclusion, antepartum prophylactic dose
dalteparin in women with thrombophilia at increased risk
of pregnancy loss, placenta-mediated pregnancy
Relative risk
(95% CI)
Rey et al (2009) 0·35 (0·15–0·79)
Gris et al (2010) 0·39 (0·21–0·68)
Gris et al (2011) 0·36 (0·18–0·69)
Mello et al (2005) 0·30 (0·14–0·60)
Martinelli et al (2012) 1·10 (0·55–2·21)
de Vries et al (2012) 1·10 (0·63–1·93)
Rodger et al (2014) 1·05 (0·50–2·25)
Combined (random effects) 0·57 (0·36–0·91)
0·1 0·2 0·5 1 2 5 3
Relative risk (95% CI)
Figure 3: Meta-analysis of published randomised trials assessing the relative risk reduction (random effects)
of recurrent placenta-mediated pregnancy complications with low-molecular-weight heparin in women
with previous placenta-mediated pregnancy complications
Recurrent placenta-mediated complications were defined as any pre-eclampsia, placental abruption, birth of a
small-for-gestational-age infant (birthweight <10th percentile), or pregnancy loss at more than 20 weeks.
Previous placenta-mediated complications were pre-eclampsia, birth of a small-for-gestational-age infant
(birthweight <10th percentile), late pregnancy loss (>12 weeks), or placental abruption.
10 www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60793-5
complications, or venous thrombosis does not reduce the
occurrence of these complications. Further research is
needed to establish whether low-molecular-weight heparin
reduces the risk of recurrent severe pre-eclampsia,
severely small-for-gestational-age infants (birthweight
<5th percentile), or placental abruption.
Contributors
MAR and PSW participated in study design, data collection and
interpretation, writing and critical review of the report, and approval of
the final version. WMH, JK, SRK, AK, EK, and MW participated in study
design, data collection, critical review of the report, and approval of the
final version. DF* and TR* contributed to study design, data analysis, data
interpretation, critical review of the report, and approval of the final
version. AMC and GLG participated in data collection, data analysis, data
interpretation, writing and critical review of the report, and approval of
the final version. RM participated in data analysis and interpretation,
critical review of the report, and approval of the final version. MS, SC,
WSC, JS, ER, SR, RK, CD, MJK, SS, KH, JD, GS, SM, JN-A, AM, MK,
RMS, IAG, KR-M, BM*, NT*, JM*, LO*, MB*, WF*, LM*, PvD*, MP*,
MC*, HC*, PC*, AT*, CC*, and SM* participated in data collection,
critical review of the report, and approval of the final version. CN*
(deceased), PG* (deceased), and RL* (deceased) participated in study
design and data collection. *Denotes members of the TIPPS investigators
not listed in main author list.
The TIPPS investigators
M A Rodger, W M Hague, J Kingdom, S R Kahn, A Karovitch, M Sermer,
A M Clement, S Coat, W S Chan, J Said, E Rey, S Robinson, R Khurana,
C Demers, M J Kovacs, S Solymoss, K Hinshaw, J Dwyer, G Smith,
S McDonald, J Newstead-Angel, A McLeod, M Khandelwal, R Silver,
G Le Gal, I A Greer, E Keely, K Rosene-Montella, M Walker, P S Wells,
B McCarron, N Thomas, J Martel, C Nimrod (deceased), L Opatrny,
M Blostein, L Magee, P von Dadelszen, M Carrier, R Mallick, T Ramsay,
E Pasquier, D Fergusson, and M Paidas. Data Safety Monitoring Board:
M Cushman (Chair 2007–12), H Clark (Chair 2003–06), P Garner
(deceased) (Chair 2000–02), R Lee (deceased), P Callas, A Tinmouth,
C Code, and S McFaul.
Declaration of interests
AM has received honoraria for educational activities from Leo Pharma,
Sanofi, and Bayer. The other authors declare no competing interests.
Acknowledgments
This study was funded by the Canadian Institutes of Health Research
(MCT 82205) and the Heart and Stroke Foundation of Canada (NA 4849).
Partial start-up funding (US$150 000) and initial study drug were provided
by Pharmacia and UpJohn (2000–02). MR was supported by a Heart and
Stroke Foundation of Ontario Career Investigator Award (CI6225 and
CI7441) and a University of Ottawa Faculty of Medicine Clinical Research
Chair in Venous Thrombosis and Thrombophilia. SRK is supported by a
National Research Scientist award from the Fonds de la Recherche en Santé
du Québec. SM is supported by a Canadian Institutes of Health Research
New Investigator Award. JK was supported by the Rose Torno Chair.
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11

TIPPing practice away from anticoagulation in pregnancy
Clinical management of women with a history of adverse
pregnancy outcomes (ie, recurrent early pregnancy
loss, severe pre-eclampsia, placental abruption, and
unexplained fetal growth restriction or stillbirth) is a
challenging area in obstetrics because of the paucity
of evidence-based preventive therapies. In the face
of emotionally charged requests for preventive treat-
ment by women with adverse pregnancy outcomes,
clinicians are often tempted to provide non-evidence-
based therapies that might seem to be both biologically
plausible and of minimum harm.
In the 1990s, epidemiological data emerged showing an
association between genetic thrombophilias and adverse
pregnancy outcomes.1,2 The proposed pathophysiological
mechanism linking maternal prothrombotic tendencies
with adverse pregnancy outcomes is through placental
insufficiency caused by microvascular or macrovascular
thrombosis of this crucial maternal–fetal interface. This
concept led researchers to investigate low-molecular-
weight heparin as a potential treatment to reduce
placental thrombosis and thereby reduce adverse
pregnancy outcomes. Early studies showed promising
results3,4 and, despite the absence of high-quality
evidence, clinicians and guideline committees5 quickly
adopted use of these drugs. However, subsequent higher
quality randomised clinical trials6,7 were unable to replicate
the success of earlier research.
The Thrombophilia in Pregnancy Prophylaxis Study
(TIPPS),8 undertaken by Marc Rodger and colleagues
and reported in The Lancet, is the first large international
randomised controlled trial designed to resolve the
clinical equipoise of the effect of antepartum low-
molecular-weight heparin (dalteparin) on adverse
pregnancy outcomes in women at the highest risk of
these outcomes (ie, women with both thrombophilia
and a history of either adverse pregnancy outcomes or
venous thromboembolism). The results of this study
are convincingly negative: following randomisation
of 292 women, antepartum dalteparin did not
significantly reduce the incidence of adverse pregnancy
outcomes, the trial’s primary outcome, recorded in
25 of 146 women (17·1%) in the dalteparin group versus
27 of 143 (18·9%) in the control group (risk difference
–1·8%, 95% CI –10·6 to 7·1). The results were consistent
across the wide range of clinically important events that
www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60850-3
Comment
comprised the composite primary outcome (severe or
early-onset pre-eclampsia, small-for-gestational-age
infants [<10th percentile], pregnancy loss, or venous
thromboembolism); in both intention-to-treat and on-
treatment analyses; and across pre-planned subgroup
analyses. From a patient safety perspective, although
Science Photo Library
no differences in major bleeding or bone mineral density
were recorded, dalteparin was associated with an
increase in minor bleeding, abnormal liver enzymes, and
local skin reactions. Published Online
July 25, 2014
The TIPPS study design was methodologically http://dx.doi.org/10.1016/
rigorous. The investigators used pragmatic eligibility S0140-6736(14)60850-3
criteria (which make the results broadly generalisable See Articles
http://dx.doi.org/10.1016/
to pregnant women with thrombophilias), event S0140-6736(14)60793-5
adjudication was masked, there was no loss to follow-
up for the primary outcome, participant adherence to
dalteparin was high, and crossover rates were similar
in the two study groups. The study limitations include
the low event rates (18·9% events observed vs 49%
anticipated in the control group), differential use of
aspirin between the study groups, slow recruitment
rate, and the small subgroup sizes. However, several
important points should be noted. First, the lower than
anticipated event rate of adverse pregnancy outcomes
is consistent with recent prospective observational data
showing lower (and often non-significant) associations
between thrombophilias and adverse pregnancy
outcomes.9 The difference in event rates in TIPPS still
reliably excludes the trial’s prespecified minimally
clinically significant difference of 16% (ie, resulting in a
number needed to treat of six).
Second, the rate of aspirin use was higher in the
non-dalteparin group (40%) than in the dalteparin
group (30%), especially in women with previous pre-
eclampsia or small-for-gestational-age infants (68%
control vs 41% dalteparin). This finding probably
represents the clinicians’ perceived need to intervene
(because the study was unmasked), but aspirin use is
unlikely to have significantly biased the trial results,
since other large studies have not shown a benefit of
aspirin in reducing adverse pregnancy outcomes10,11
apart from a minor reduction in pre-eclampsia.12
Third, although the 12-year recruitment period was
extremely long, treatments for prevention of adverse
pregnancy outcomes did not change substantially
1
 Comment
during this period. Fourth, despite the small subgroup
sizes, TIPPS showed no statistically significant benefit
across any of these subgroups, which is consistent
with the investigators’ updated systematic review
and meta-analysis.8 Finally, caution should be used in
interpretation of the subgroup analysis that showed
an apparent non-significant benefit of low-molecular-
weight heparin in patients who used aspirin, in view of
the high number of subgroups compared and the small
subgroup size. Nonetheless, this latter finding might
merit further research.
TIPPS emphasises other important messages for
clinicians and researchers. Despite vigorous recruitment
efforts, it took more than 12 years to recruit 292 women
at 36 centres in five countries. 15 centres did not recruit
any participants at all, mainly because the use of low-
molecular-weight heparin had already become local
standard practice. This situation draws attention to the
fact that clinicians’ altruistic intentions to treat these
high-risk women might have inadvertently caused them
minor harm, potentially increased the rates of labour
induction, reduced access to regional anaesthetics,
increased health-care costs (because of the high cost of
low-molecular-weight heparin), and slowed the research
momentum in this area. Importantly, TIPPS also shows
that withholding of antepartum low-molecular-
weight heparin in women with thrombophilias
did not significantly increase rates of venous
thromboembolism, which supports recent guidelines
that advise only post-partum thromboprophylaxis for
women with anything but the most serious cases of
thrombophilia.13
The TIPPS investigators should be congratulated for
completing this much needed, rigorous trial, which, along
with their updated systematic review and meta-analysis,
clearly shows that low-molecular-weight heparin is
ineffective in preventing a wide range of clinically
important adverse pregnancy outcomes in women with
thrombophilia. Hopefully, these results will finally tip
clinicians away from using the drug in this setting and
motivate researchers to pursue other potentially effective
preventive interventions.
2 www.thelancet.com Published online July 25, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60850-3
*Paul S Gibson, Kara A Nerenberg
Departments of Medicine and Obstetrics and Gynecology,
University of Calgary, Calgary, AB, T3L 2Y3, Canada (PSG); and
The Ottawa Hospital Research Institute, University of Ottawa,
Ottawa, ON, Canada (KAN)
gibsonp@ucalgary.ca
PSG receives an unrestricted educational grant from Sanofi. KN declares no
competing interests.
1 Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic
thrombophilia in women with complications of pregnancy. N Engl J Med
1999; 340: 9–13.
2 Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss:
a meta-analysis. Lancet 2003; 361: 901–08.
3 Gris JC, Mercier E, Quéré I, et al. Low-molecular-weight heparin versus
low-dose aspirin in women with one fetal loss and a constitutional
thrombophilic disorder. Blood 2004; 103: 3695–99.
4 Brenner B, Hoffman R, Carp H, Dulitsky M, Younis J. Efficacy and safety of
two doses of enoxaparin in women with thrombophilia and recurrent
pregnancy loss: the LIVE-ENOX study. J Thromb Haemost 2005; 3: 227–29.
5 Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents
during pregnancy: the Seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest 2004; 126: 627S–44S.
6 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.
7 Martinelli I, Ruggenenti P, Cetin I, et al. Heparin in pregnant women with
previous placenta-mediated pregnancy complications: a prospective,
randomized, multicenter, controlled clinical trial. Blood 2012;
119: 3269–75.
8 Rodger MA, Hague WM, Kingdom J, et al. Antepartum dalteparin versus no
antepartum dalteparin for the prevention of pregnancy complications in
pregnant women with thrombophilia (TIPPS): a multinational open-label
randomised trial. Lancet 2014; published online July 25. http://dx.doi.
org/10.1016/S0140-6736(14)60793-5.
9 Rodger MA, Betancourt MT, Clark P, et al. The association of factor V Leiden
and prothrombin gene mutation and placenta-mediated pregnancy
complications: a systematic review and meta-analysis of prospective
cohort studies. PLoS Med 2010; 7: e1000292.
10 Kaandorp SP, Goddijn M, van der Post JA, et al. Aspirin plus heparin or
aspirin alone in women with recurrent miscarriage. N Engl J Med 2010;
362: 1586–96.
11 Clark P, Walker ID, Langhorne P, et al, on behalf of the Scottish Pregnancy
Intervention Study (SPIN) collaborators. SPIN (Scottish Pregnancy
Intervention) study: a multicenter, randomized controlled trial of
low-molecular-weight heparin and low-dose aspirin in women with
recurrent miscarriage. Blood 2010; 115: 4162–67.
12 Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for
prevention of preeclampsia: a meta-analysis of individual patient data.
Lancet 2007; 369: 1791–98.
13 Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO.
VTE, thrombophilia, antithrombotic therapy, and pregnancy.
Antithrombotic Therapy and Prevention of Thrombosis, 9th edn: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Chest 2012; 141 (2 suppl): e691S–736S.