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Rodger MA, et al. "Antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia". Lancet. 2014. 384(9955):1673-1683.
PubMedFull text

Clinical Question

Among pregnant women with thrombophilia, does antepartum prophylactic deltaparin reduce the risk of pregnancy complications including venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications?

Bottom Line

Antepartum prophylactic dalteparin in pregnant women with thrombophilia does not decrease the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications. Deltaparin has a greater risk of minor bleeding.

Major Points



  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=284
    • Antepartum dalteparin (n=143)
    • Standard (n=141)
  • Setting: 36 centers in 5 countries
  • Enrollment: Feb 2000 to September 2012
  • Mean follow-up:
  • Analysis: Intention-to-treat


Inclusion Criteria

One or more of the following:

  • Previous preeclampsia
  • Previous unexplained intra-uterine growth restriction
  • Previous recurrent miscarriage:
    • Three (3) or more unexplained miscarriage at less than 10 weeks gestation;
    • Two (2) or more unexplained fetal loss between 10 and 16 weeks gestation;
    • One (1) or more unexplained fetal loss at or greater than 16 weeks gestation
  • Previous abruptio placenta
  • Previous personal history of VTE:
    • Previous documented secondary proximal VTE,
    • Previous documented calf-vein thrombosis (idiopathic or secondary),
    • Previous superficial phlebitis
  • First degree relative with symptomatic thrombophilia
  • Pregnancy: between 4 and 20 weeks of gestation
  • Thrombophilia
  • Two abnormal tests, and no normal tests:
    • Protein S
    • Protein C
    • Antithrombin
  • Two positive tests:
    • Anticardiolipin immunoglobulin M (IgM) (>30 U/ml)
    • Anticardiolipin immunoglobulin G (IgG) (>30 U/ml)
    • Anti-b2 glycoprotein IgG (>20 U/ml)
    • Anti-b2 glycoprotein IgM (>20 U/ml)
    • Lupus anticoagulant
  • One positive test:
    • Factor V Leiden (heterozygous or homozygous)
    • Prothrombin gene defect (heterozygous or homozygous)

Exclusion Criteria

  • Less than 4 weeks gestation or greater than 20 weeks gestation
  • No confirmed thrombophilia
  • Contraindication to heparin therapy including:
    • History of heparin induced thrombocytopenia
    • Platelet count less than 100,000 109/L
    • History of osteoporosis or steroid use
    • Actively bleeding
    • Documented peptic ulcer within 6 weeks
    • Heparin, bisulfite or fish allergy
    • Severe hypertension (Systolic Blood Pressure >200mmhg and/or Diastolic Blood Pressure >120mmHg)
    • Serum creatinine greater than 80 umol/L (1.3mg/dl) and an abnormal 24 hour urine creatine clearance (<30ml/min)
    • Severe hepatic failure (INR >1.8)
  • Geographic inaccessibility
  • Need for anticoagulants, discretion of the investigator such as but not limited to:
    • Recurrent fetal loss and phospholipid antibody syndrome
    • Prior idiopathic proximal VTE:
    • History of idiopathic deep venous thrombosis (DVT) or pulmonary embolism (PE) treated with anticoagulants (> 1 month of heparin or warfarin) or inferior vena cava (IVC) interruption
    • Idiopathic is a VTE occurring outside all of the following periods: antepartum, postpartum, oral contraceptive use, surgery, immobilization, cast, and malignancy
    • Mechanical heart valve
  • Legal lower age limitations (country specific)
  • Prior participation in TIPPS
  • Unable/unwilling to provide informed consent

Baseline Characteristics

  • Mean age: 72 years
  • Mean BMI: 28
  • Mean HbA1c: 8.8%
  • Units of insulin: 14 units/day


  • Randomized to intensive (targeting HbA1c <6%) or standard (HbA1c 7-7.9%) glycemic therapy

    • Then 46% were randomized to intensive (SBP <120) vs. standard (SBP <140) blood pressure therapy
    • Remaining 54% randomized to fenofibrate vs. placebo; all received statin
  • Intensive glycemic control group attended monthly visits for 4 months, then every 2 months, with additional visits and telephone calls as needed
  • Standard therapy group had glycemic control visits every 4 months


Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Composite of VTE, pre-eclampsia, IUGR, and fetal loss
2.11% vs. 2.29% (HR 0.90; 95% CI 0.78-1.04; P=0.16)

Secondary Outcomes

Composite of rates of pregnancy induced hypertension, preterm labor and abruptio placenta
1.41% vs. 1.14% (HR 1.22; 95% CI 1.01-1.46; P=0.04)
Safety including rates of bleeding, thrombocytopenia, and fractures
0.79% vs. 0.56% (HR 1.35; 95% CI 1.04-1.76; P=0.02)
Bone mineral density

Subgroup Analysis

Adverse Events



The trial was funded by Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.

Further Reading