Low-molecular-weight Heparin (LMWH) Versus Unfractionated Heparin (UFH) in Pregnant Women With Recurrent Abortion Secondary to Antiphospholipid Syndrome

Low-molecular-weight Heparin Versus Unfractionated Heparin in Pregnant Women With History of Recurrent Abortion Secondary to Antiphospholipid Syndrome. A Randomized Controlled Trial

The aim of this study is to compare the efficacy and safety of Low molecular weight heparin (LMWH) plus low dose aspirin (LDA) with unfractionated heparin(UFH) plus LDA in women with recurrent pregnancy loss associated with antiphospholipid syndrome (APS).

Study Overview

• Status: Completed
• Conditions: Recurrent Abortion
• Intervention / Treatment: Drug: enoxaparin 40mg plus low dose aspirin; Drug: Heparin calcium5,000 U twice daily plus low dose aspirin

Detailed Description

Women with antiphospholipid syndrome (APS) have live birth rates as low as 10% in pregnancies without pharmacological treatment. Low dose aspirin (LDA) ,unfractionated heparin(UFH) , Low molecular weight heparin (LMWH) , prednisone, and intravenous immunoglobulin (IVIG) have been used either alone or in combination in order to improve the live birth rate in APS positive women with recurrent miscarriage. A Cochrane review of 13 randomized or quasi-randomized, controlled trials of various management options of pregnant women with a history of pregnancy loss and APL, revealed that combined UFH and aspirin was the treatment of choice which reduced pregnancy loss by 54% .

During the past decade , low molecular weight heparins were widely used in the prophylaxis and treatment of patients with venous or arterial thrombosis ,with an efficacy and safety superior or at least equivalent to that of UFH .Although recent studies reported the use of LMWH in the management of patients recurrent pregnancy loss secondary to antiphospholipid syndrome resulted in encouraging results . It is not clear whether the efficacy and safety of LMWH is equivalent to that of UFH .

Although LMWH is more expensive than UFH . LMWH has longer half life , greater bioavailability , more stable dose-response relationship than UFH and therefore can be administered once daily. Furthermore, LMWH requires less frequent monitoring than UFH and and has less adverse effect on bone mineral density and platelet count .These advantages make LMWH more attractive for the patients and physicians than UFH .

There are only two studies which compared the efficacy of LMWH plus LDA with that of UFH plus LDA in the management of pregnant women with recurrent pregnancy loss secondary to APS. In addition ,no randomized controlled study has yet compared the efficacy of LMWH plus LDA with UFH plus LDA.

The aim of this study is to compare the efficacy and safety of Low molecular weight heparin (LMWH) plus low dose aspirin (LDA) with unfractionated heparin(UFH) plus LDA in women with recurrent pregnancy loss associated with antiphospholipid syndrome (APS).

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Cairo University Hospital
  • Cairo, Egypt
    • Ahmed Elgazzar hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 37 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Patients with a minimum of three consecutive pregnancy losses before 10 weeks gestation
• Positive lupus anticoagulant and/or anticardiolipin antibodies (IgG and IgM) on at least two occasions twelve weeks apart .
• Age between 19 - 37 years,
• Body mass index between 19-30

Exclusion Criteria:

• Parental chromosomal abnormalities
• Uterine abnormalities
• Luteal phase defect
• Systemic lupus erythematosus
• Previous thromboembolism
• Sensitivity to aspirin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: enoxaparin 40 mg plus low dose aspirin	Drug: enoxaparin 40mg plus low dose aspirin; Enoxaparin 40mg/day by subcutaneous injection ( Clexane 40 mg, Aventis international, Sanofi-aventis France ) is started when the serum pregnancy test become positive. Enoxaparin is stopped 2 days before planned induction of labor or cesarean section and twice-daily unfractionated heparin (UFH) is initiated. The evening UFH dose is cancelled before planned caesarean section . The patients are asked to stop enoxaparin or UFH with the beginning of labor pains . Low dose aspirin (75 mg/day)(Aspocid Paediatric ,Chemical Industries Development (CID)) is started before conception and continued until 36 weeks gestation.; Other Names: Clexane 40 mg
Active Comparator: Heparin calcium 5,000 U twice daily plus low dose aspirin	Drug: Heparin calcium5,000 U twice daily plus low dose aspirin; Heparin Calcium 5,000 U twice daily (Cal-Heparine, Amoun Pharmaceutical Co, Egypt) by subcutaneous injection is started when the serum pregnancy test become positive. The evening UFH dose is cancelled before planned caesarean section . The patients are asked to stop UFH with the beginning of labor pains . Low dose aspirin (75 mg/day)(Aspocid Paediatric ,Chemical Industries Development (CID))is started before conception and continued until 36 weeks gestation .; Other Names: Cal-Heparine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live Birth Rate = (Number of Live Births / Total Number of Pregnancies)	Live birth occurs when a fetus (> 24 weeks ) , exits the maternal body and subsequently shows signs of life, such as voluntary movement, heartbeat, or pulsation of the umbilical cord.	pregnancy > 24weeks gestation

Secondary Outcome Measures

Outcome Measure	Time Frame
Minor and Major Bleeding	Duration of pregnancy and puerperium
Thrombocytopenia	Duration of pregnancy and puerperium
Preeclampsia	Pregnancy > 20 weeks gestation
IUFD	Pregnancy >24 weeks gestation
Preterm Delivery	24 weeks gestation<Pregnancy <37weeks gestation
Spontaneous Osteoporotic Fractures	Duration of pregnancy and puerperium

Collaborators and Investigators

• Sponsor: Cairo University
• Collaborators: Ahmed Elgazzar Hospital
• Investigators: Principal Investigator: Usama M Fouda, Lecturer of obstetrics and Gynecology , Cairo university; Principal Investigator: Ahmed M Sayed, Assistant professor of obstetrics and Gynecology , Cairo university.

Publications and helpful links

General Publications

• Hamulyak EN, Scheres LJ, Marijnen MC, Goddijn M, Middeldorp S. Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss. Cochrane Database Syst Rev. 2020 May 2;5(5):CD012852. doi: 10.1002/14651858.CD012852.pub2.
• Noble LS, Kutteh WH, Lashey N, Franklin RD, Herrada J. Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin. Fertil Steril. 2005 Mar;83(3):684-90. doi: 10.1016/j.fertnstert.2004.11.002.
• Stephenson MD, Ballem PJ, Tsang P, Purkiss S, Ensworth S, Houlihan E, Ensom MH. Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated heparin. J Obstet Gynaecol Can. 2004 Aug;26(8):729-34. doi: 10.1016/s1701-2163(16)30644-2.
• Fouda UM, Sayed AM, Abdou AM, Ramadan DI, Fouda IM, Zaki MM. Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome. Int J Gynaecol Obstet. 2011 Mar;112(3):211-5. doi: 10.1016/j.ijgo.2010.09.010. Epub 2011 Jan 19.

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): November 1, 2009
• Study Completion (Actual): December 1, 2009

Study Registration Dates

• First Submitted: January 19, 2010
• First Submitted That Met QC Criteria: January 19, 2010
• First Posted (Estimate): January 20, 2010

Study Record Updates

• Last Update Posted (Estimate): August 29, 2011
• Last Update Submitted That Met QC Criteria: July 29, 2011
• Last Verified: January 1, 2010

More Information

Terms related to this study

• Keywords: Antiphospholipid syndrome; unfractionated heparin; Low Molecular Weight Heparin; Recurrent abortion
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Disease Attributes; Pregnancy Complications; Abortion, Spontaneous; Recurrence; Abortion, Habitual; Antiphospholipid Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Calcium-Regulating Hormones and Agents; Anticoagulants; Aspirin; Heparin; Calcium; Enoxaparin; Calcium heparin
• Other Study ID Numbers: Aps/UFH/enox40