The Relationship between Use of Low Molecular Weight Heparin during Pregnancy and Risk of Peripartum Adverse Events: A Meta-Analysis

  

    

    
Study Location
    
Type of study
    
Study features
    
Indication for LMWH use
    
Study duration
    
Funding agencies
  
  

    
[16]
    
Italy
    
A single center retrospective cohort study
    

      
Number of included women: 88
      
LMWH type: Unknown
      
LMWH dose: Preventive dose: LMWH 40mg/d, If body weight > 60kg, 60mg/d; Treatment dose:    the dose was adjusted according to patient’s weight and was given twice daily
    
    
Women with type I antithrombin deficiency
    
Between Jan 1, 1980 and Jan 1, 2018
    
No
  
  

    
[4]
    
Russia
    
A multi-center retrospective cohort study
    

      
Number of included women: 68
      
Group: Group I (n=50) received prophylaxis with LMWH±aspirin (50-100 mg/day) in preconception    period or from the 1st trimester, during pregnancy and at least    6 weeks postpartum. Group II (n=18) received LMWH±aspirin from the II to III trimester.
      
LMWH type: Enoxaparin
      
LMWH dose: The dose was adjusted    according to patient’s weight (<50kg: 20mg LMWH, 50-70 kg: 40mg LMWH, 71-90kg:    60mg LMWH, 91-110 kg: 80mg LMWH, >110kg: 0.6mg/kg LMWH). The last dose of    LMWH was used the day before of labor, at least 12h before the c/s or onset    of labor and resumed in 6-8 h after delivery for a minimum of    6 weeks under the control of the hemostasis system.
    
    
Women with thrombophilia and a history of    thrombosis
    
From 2009 to 2016
    
Unknown
  
  

    
[10]
    
Denmark
    
A cohort study
    

      
Number of included women:166
      
Group: 1. LMWH-treated:166; 2.    LMWH-untreated:18020
      
LMWH type: Tinzaparin (95.2%), dalteparin (4.8%)
      
LMWH dose: The majority (86.1%) was    treated with tinzaparin 4,500 IU subcutaneously once daily or dalteparin    5,000 IU subcutaneously once daily.
      
LMWH usage: In half the cases (50.9%),    treatment was commenced in the first trimester, but the time of initiation    varied from 3rd to 39th gestational week. Treatment was    discontinued at induction or onset of spontaneous labor, resumed 12 hours    after delivery and generally continued until six weeks postnatally (75.3%; n=125).
    
    

      
Prior    or current VTE with or without thrombophilia;
      
Prior    adverse obstetric event and thrombophilia;
      
Thrombophilic    disorder;
      
Habitual    abortion and thrombophilia;
      
Other    reasons for treatment (prolonged immobilization, elevated D-dimer, impaired    venous function and/or prior, adverse obstetric outcome).
    
    
From January 1, 2001 to December 31, 2005
    
Research grant from Hillerød Hospital
  
  

    
[14]
    
Turkey
    
A single-center retrospective cohort study
    

      
Number of included women: 57; Number of pregnancies: 72;
      
Groups: 1) OAC warfarin (1-6w)-LMWH (6-12w)-OAC (12-36w)-LMWH    (36-38w); 2) OAC warfarin + ASA (1-36w); 3) No anticoagulation; 4) LMWH treatment throughout pregnancy.
    
    
Pregnant women who underwent mechanical heart    valve replacement
    
From January 1990 to December 2015
    
No
  
  

    
Carolina Arbuthnot. 2016
    
UK
    
A single-center retrospective cohort study
    

      
Number of pregnancies: 16469.
      
Group: 1) Using LMWH (n=115): among them, 66 women received    a prophylaxis dose of LMWH and 47 received a therapeutic dose of LMWH; 2) Control group (n=16415): no anticoagulant or    antiplatelet therapy.
      
LMWH usage: LMWH was stopped 12h (for    prophy-lactic LMWH) and 24h (for therapeutic LMWH) prior to delivery.
    
    

      
VTE;
      
Thrombophilia;
      
Recurrent    miscarriage
      
Recurrent    VTE;
      
Multiple    risk factors
    
    
From 2009 to 2013
    
No
  
  

    
[13]
    
Netherlands
    
A single-center retrospective cohort study
    

      
Group: 1) LMWH treatment: 88; 2) No LMWH treatment: 352;
      
LMWH type: Fondaparinux, danaparoid or    acenocoumerol;
      
LMWH usage: LMWH or another preparation    was stopped at the start of spontaneous or induced labor and restarted 4-8    hours after delivery (when blood loss was normal) and stopped six weeks    postpartum.
    
    

      
History    of VTE
      
Recurrent    fetal loss
      
Asymptomatic    Thrombophilic defects
      
VTE in    current pregnancy
    
    
From 1999 to 2009
    
No
  
  

    
[17]
    
Netherlands
    
A single-center retrospective cohort study
    

      
Group: 1) LMWH treatment: 95; 2) No LMWH treatment: 524
      
LMWH type: Enoxaparin, Dalteparin,    Nadroparin, Danaparoid, Tinzaparin;
      
LMWH usage: Discontinue LMWH as soon as    either contractions started, membranes ruptured or to administer the last    injection the morning before the day that induction of labour or a caesarean    section was planned
    
    

      
Current    or history of VTE and thrombophilia;
      
Recurrent    thrombophlebitis and thrombophilia;
      
Antiphospholipid    syndrome;
      
Preeclampsia;
      
Prosthetic    heart valve with or without heart thrombosis;
      
Current    cerebrovascular accident.
    
    
From 1995 to 2008
    
No
  
  

    
[15]
    
UK
    
A case-control study
    

      
Group: 1) LMWH treatment: 55; 2) No    LMWH treatment: 110;
      
LMWH type: Enoxaparin;
      
LMWH usage: Twice daily
    
    

      
Current    or history of DVT and/or PE and a thrombophilia;
      
Prophylaxis    for a thrombophilia;
      
Mitral    valve replacement;
      
History    of sagittal sinus thrombosis and a thrombophilia
      
Coronary    aneurysm and nephrotic syndrome
    
    
From 2001 to 2005
    
No
  
  

    
[19]
    
Finland
    
A single-center retrospective cohort study
    

      
Group: 1) LMWH treatment: 648; 2) No LMWH treatment: 626;
      
LMWH dose: 1) Normal prophylactic doses were    enoxaparin 40mg/day or dalteparin 5000IU/day; 2) Intermediate    (50% of treatment doses, i.e. enoxaparin 1mg/kg/day or dalteparin    100IU/kg/day); 3) Adjusted doses were defined as weight adjusted full    treatment doses of LMWH (dalteparin 200IU/kg once daily or enoxaparin 1 mg/kg    twice daily); 
      
LMWH usage: Women with hereditary thrombophilias    (Factor V Leiden mutation, prothrombin mutation, protein C/S deficiencies) and    APLAs without a history of VTE received LMWH prophylaxis from the late third    trimester (gestational weeks 34–36) until 6 weeks postpartum ; Women with    combined thrombophilias or antithrombin (AT) deficiency, even without a    history of VTE, received LMWH prophylaxis from gestational week 6 until 6    weeks postpartum; The median time of LMWH initiation was 17 gestational weeks    and the mean duration was 22 weeks.
    
    

      
Prior    or current VTE;
      
Prior    adverse obstetric outcome;
      
Mechanical    heart valve;
      
Prior    stroke;
      
Thrombophilia    without any other indication;
      
Other    reasons (immobilization, impaired venous function, cardiac disease etc.).
    
    
From February 1994 to January 2007
    
No
  
  

    
Joyce Lai. 2017
    
Canada
    
A single-center retrospective cohort study
    

      
Group: 1) Anticoagulation with heparin: 137; 2) No anticoagulation: 1233
    
    

      
Thrombosis    history;
      
Hereditary    thrombophilia;
      
Medical    disorders associated with thrombosis
    
    
From March 2013 to March 2014
    
An educational grant from Sanofi.
  
  

    
HENRIK. 2000
    
Denmark
    
A population-based cohort study
    

      
Group: 1) LMWH anticoagulation: 66; 2) No    LMWH anticoagulation: 17259;
      
LMWH type: Enoxaparin, dalteparin,    tinzaparin
    
    
Unknown
    
From 1991 to 1998
    
Danish Medical Research Council (grant no.    9700677) and EU BIOMED program (Contract No. BMH4-CT97–2430); Danish National    Research Foundation
  

Table 1: Characteristics of included studies.