Intervention Review

You have free access to this content

Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction

  1. Jodie M Dodd1,*,
  2. Anne McLeod2,
  3. Rory C Windrim3,
  4. John Kingdom3

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 24 JUL 2013

Assessed as up-to-date: 24 OCT 2012

DOI: 10.1002/14651858.CD006780.pub3


How to Cite

Dodd JM, McLeod A, Windrim RC, Kingdom J. Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD006780. DOI: 10.1002/14651858.CD006780.pub3.

Author Information

  1. 1

    The University of Adelaide, School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia

  2. 2

    University of Toronto, Department of Medicine, Toronto, Canada

  3. 3

    University of Toronto, Department of Obstetrics and Gynaecology, Toronto, Canada

*Jodie M Dodd, School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Women's and Children's Hospital, 72 King William Road, Adelaide, South Australia, 5006, Australia. jodie.dodd@adelaide.edu.au.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 24 JUL 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Gris 2010

MethodsTrial conducted in France between January 2000 and 2009.


Participants160 women with placental abruption in a previous pregnancy.


InterventionsWomen were randomised to (1) subcutaneous enoxaparin or (2) no treatment.


OutcomesPerinatal mortality; pre-eclampsia; preterm birth less than 37 and 34 weeks; NICU admission.


NotesMethod of randomisation: computer-generated.
Allocation concealment: sealed opaque envelopes.
Blinding of participants, caregivers: no; outcome assessors: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated.

Allocation concealment (selection bias)Low riskSealed opaque envelopes.

Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding of participants, caregivers: no.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessors: not stated.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAppears complete.

Selective reporting (reporting bias)Low riskAppears complete.

Other biasLow riskNo other potential bias identified.

Gris 2011

MethodsTrial conducted in France between January 2000 and 2010.


Participants224 women with severe pre-eclampsia in a previous pregnancy.


InterventionsWomen were randomised to (1) subcutaneous enoxaparin and aspirin or (2) aspirin alone.


OutcomesPerinatal mortality; pre-eclampsia; preterm birth less than 37 and 34 weeks; NICU admission.


NotesMethod of randomisation: computer-generated.
Allocation concealment: sealed opaque envelopes.
Blinding of participants, caregivers: no; outcome assessors: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated.

Allocation concealment (selection bias)Low riskSealed opaque envelopes.

Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding of participants, caregivers: no.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessors: not stated.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAppears complete.

Selective reporting (reporting bias)Low riskAppears complete.

Other biasLow riskNo other potential bias identified.

Kincaid-Smith 1995

MethodsTrial conducted in Australia.


Participants21 women with primary glomerulonephritis or reflux nephropathy who were considered on clinical grounds to be at high risk of developing pre-eclampsia; randomised from 14 weeks' gestation.


InterventionsWomen were randomised to (1) subcutaneous heparin and dipyridamole or (2) no treatment.


OutcomesPerinatal mortality; pre-eclampsia; length of antenatal stay; preterm birth less than 37 weeks; infant birthweight < 2500 g; infant birthweight less than 10th centile for gestational age.


NotesMethod of randomisation: stated "randomized by the envelope method".
Allocation concealment: "envelope method".
Blinding of participants, caregivers and outcome assessors: no.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStated "randomized by the envelope method".

Allocation concealment (selection bias)Low risk"Envelope method."

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants, caregivers, or outcome assessors.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding of participants, caregivers, or outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAppears complete.

Selective reporting (reporting bias)Low riskAppears complete.

Other biasLow riskNo other potential bias identified.

Kingdom 2011

MethodsTrial conducted in Toronto, Canada between March 2007 and May 2010.


Participants32 women with a singleton pregnancy and negative thrombophilia screen, who had 2 or more of the following: abnormal first or second trimester maternal serum screening (in the absence of a chromosomal fetal anomaly); abnormal placental morphology detected on ultrasound; abnormal maternal uterine artery Doppler waveform prior to 24 weeks' gestation.


InterventionsWomen were randomised to (1) subcutaneous heparin 7500 IU twice daily and medical surveillance or (2) medical surveillance only.

8 of 16 women in the control group received low-dose aspirin alone.


OutcomesPrimary outcomes related to feasibility of recruitment and maternal emotional wellbeing.


NotesMethod of randomisation: computer-generated.
Allocation concealment: central telephone randomisation.
Blinding of participants, caregivers and outcome assessors: no.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated.

Allocation concealment (selection bias)Low riskCentral telephone randomisation.

Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding of participants, caregivers and outcome assessors: no.

Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of participants, caregivers and outcome assessors: no.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported.

Selective reporting (reporting bias)Low riskExpected outcomes reported.

Other biasLow riskNo.

Martinelli 2012

MethodsTrial conducted in 8 centres in Italy, between April 2007 and April 2010.


Participants135 women with a history of pre-eclampsia, eclampsia, HELLP syndrome, previous fetal loss or fetal growth restriction, with gestational age less than 12 weeks' gestation.


InterventionsWomen were randomised to (1) low molecular weight heparin and medical surveillance or (2) medical surveillance only.


OutcomesPre-eclampsia; eclampsia, HELLP syndrome, placental abruption, fetal growth restriction, or fetal death.


NotesMethod of randomisation: computer-generated random number sequence.
Allocation concealment: central telephone randomisation.
Blinding of participants and caregivers: no; outcome assessors: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation sequence.

Allocation concealment (selection bias)Low riskCentral telephone randomisation.

Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding of participants and caregivers: no.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessors: not stated.

Incomplete outcome data (attrition bias)
All outcomes
Low risk135 women randomised; 128 women analysed.

Selective reporting (reporting bias)Low riskAppears complete.

Other biasHigh riskTrial stopped after 135 women randomised due to futility (estimated sample size 266 women).

Mello 2005

MethodsTrial conducted in Italy, between January 2001 and December 2002.


Participants80 women with a history of pre-eclampsia who were negative on thrombophilia testing; treatment was started as soon as pregnancy was confirmed.


InterventionsWomen were randomised to (1) low molecular weight heparin or (2) no treatment.


OutcomesPre-eclampsia; infant birthweight less than 10th centile for gestational age.


NotesMethod of randomisation: computer-generated random number sequence.
Allocation concealment: not stated.
Blinding of participants, caregivers, and outcome assessors: no.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random number sequence.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants, caregivers, or outcome assessors.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding of participants, caregivers, or outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAppears complete.

Selective reporting (reporting bias)Low riskAppears complete.

Other biasLow riskNo other potential bias identified.

Nieder 1995

MethodsTrial conducted in Germany.


Participants160 women at increased risk of developing pre-eclampsia, between 22 and 38 weeks' gestation.


InterventionsWomen were randomised to (1) triazolopyrimidine or (2) placebo.


OutcomesRate of pre-eclampsia; rate of preterm birth.


NotesMethod of randomisation: not stated.
Allocation concealment: not stated.
Blinding of participants, caregivers, and outcome assessors: not stated.
Study stated to be "randomised, double blind, placebo control".


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot stated.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnable to assess.

Selective reporting (reporting bias)Unclear riskUnable to assess.

Other biasLow riskNo other potential bias identified.

Rey 2009

MethodsTrial conducted in Canada between August 2000 and June 2007.


Participants116 women with past history of severe pre-eclampsia, fetal growth restriction (infant birthweight less than 5th centile), unexplained fetal death or abruption, in the absence of a known thrombophilia; women randomised from 17 weeks' gestation.

Original sample size 276 women; trial stopped after an interim analysis due to slow recruitment.


InterventionsWomen were randomised to (1) low molecular weight heparin or (2) no treatment.


OutcomesPrimary composite of severe pre-eclampsia, infant birthweight less than 5th centile, abruption requiring birth less than 34 weeks' gestation, or fetal death after 20 weeks.


NotesMethod of randomisation: computer-generated random number table.
Allocation concealment: sealed opaque envelopes.
Blinding of participants and caregivers: no.
Blinding of outcome assessors: yes.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random number table.

Allocation concealment (selection bias)Low riskSealed opaque envelopes.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo blinding of participants or caregivers.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAppears complete.

Selective reporting (reporting bias)Low riskAppears complete.

Other biasHigh riskTrial stopped early after interim analysis due to slow recruitment.

Yu 2004a

MethodsTrial conducted in China.


Participants107 women with established fetal growth restriction.


InterventionsWomen were randomised to (1) standard heparin infusion, (2) low molecular weight heparin, or (3) dextran infusion.


OutcomesMajor neurodevelopmental handicap at child follow-up; antepartum haemorrhage, thrombocytopaenia, preterm birth less than 37 weeks' gestation, infant birthweight less than 10th centile.


NotesMethod of randomisation: stated "women were randomised into three groups".
Allocation concealment: not stated.
Blinding of participants, caregivers, and outcome assessors: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of randomisation: stated "women were randomised into three groups".

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot stated.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnable to assess.

Selective reporting (reporting bias)Unclear riskUnable to assess.

Other biasLow riskNo other potential bias identified.

Yu 2010

MethodsTrial conducted in China.


Participants104 women, 73 with established fetal growth restriction, and 31 with established pre-eclampsia.


InterventionsWomen were randomised to (1) standard heparin infusion, or (2) the control group (no details provided as to what this comprised).


OutcomesUltrasound and haematological measures; no prespecified review outcomes were reported.


NotesMethod of randomisation: not stated.
Allocation concealment: not stated.
Blinding of participants, caregivers, and outcome assessors: not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated.

Allocation concealment (selection bias)Unclear riskNot stated.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot stated.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnable to assess.

Selective reporting (reporting bias)Unclear riskUnable to assess.

Other biasLow riskNo other potential bias identified.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Airoldi 1988Not a randomised controlled trial.

Eid 2006Not a randomised controlled trial.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Bonnar 1980

MethodsStudy conducted in Ireland.

Participants40 women at high risk of fetal growth restriction.

InterventionsTreatment with heparin and dipyridamole or no treatment.

OutcomesInfant growth restriction.

NotesThere is insufficient information presented in the abstract to evaluate study methodology; no data are presented.

Ferrier 2000

MethodsTrial conducted in Switzerland.

Participants24 women with a history of pre-eclampsia, renal disease, or hypertension.

InterventionsTreatment with heparin and low-dose aspirin or low-dose aspirin alone.

OutcomesHypertension, fetal loss, uric acid renal clearance.

NotesThere is insufficient information presented in the abstract to evaluate study methodology.

Yu 2004b

MethodsTrial conducted in China.

ParticipantsWomen with established fetal growth restriction.

InterventionsWomen were randomised to (1) standard heparin infusion, (2) low molecular weight heparin, or (3) dextran infusion.

OutcomesDoppler ultrasound parameters reported.

NotesMethod of randomisation: stated "women were randomised into three groups".
Allocation concealment: not stated.
Blinding of participants, caregivers, and outcome assessors: not stated.

This could be an additional report of Yu 2004a. Awaiting further clarification from authors.

 
Comparison 1. Heparin (alone or with other medication) versus no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal mortality6653Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.20, 0.78]

 2 Preterm birth less than 34 weeks' gestation3494Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.29, 0.73]

 3 Major neurodevelopmental delay at child follow-up1107Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Pre-eclampsia7761Risk Ratio (M-H, Random, 95% CI)0.47 [0.22, 1.03]

 5 Eclampsia1135Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Placental abruption4551Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.10, 1.40]

 7 Antepartum haemorrhage (after 20 weeks requiring hospitalisation)1107Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Mean length of antenatal hospital stay120Mean Difference (IV, Fixed, 95% CI)-9.0 [-15.14, -2.86]

 9 Thrombocytopaenia2242Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Preterm birth less than 37 weeks' gestation5621Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.58, 0.90]

 11 Infant birthweight less than 2500 grams1110Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.37, 1.82]

 12 Infant birthweight less than 10th centile for gestational age7710Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.27, 0.61]

 13 Apgar score less than 7 at 5 minutes age3519Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.29, 0.60]

 14 NICU admission3416Risk Ratio (M-H, Random, 95% CI)0.62 [0.25, 1.53]

 15 Fetal death3519Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.23, 1.46]

 16 Neonatal death2384Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.06, 1.36]

 
Comparison 2. Triazolopyrimidine (Trapidil) versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pre-eclampsia1160Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.12, 1.16]

 
Comparison 3. Unfractionated heparin versus low molecular weight heparin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Major neurodevelopmental delay at child follow-up168Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Antepartum haemorrhage (after 20 weeks and requiring hospitalisation)168Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Thrombocytopaenia168Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Preterm birth prior to 37 weeks' gestation168Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.22, 7.05]

 5 Infant birthweight less than 10th centile for gestational age168Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.13, 5.61]