Effects and effectiveness of heparin in assisted reproduction
Introduction
Maternal hypercoagulability due to the presence of acquired or hereditary thrombophilic disorders has been associated with a number of pregnancy complications such as recurrent early miscarriages, late miscarriage, intrauterine fetal death, pre-eclampsia, intrauterine growth restriction and placental abruption (Kupferminc et al., 1999, Rey et al., 2003).
Despite significant improvements in treatment protocols and laboratory techniques the baby take-home rate after assisted reproduction is disappointing, e.g. an average of 20% in Germany (German IVF Register, 2009). Thus, it is highly comprehensible that various approaches are undertaken in attempts to improve the pregnancy and delivery rates after IVF/ICSI (Bohlmann et al., 2009). In recent years, the use of heparin in various forms has become a widespread approach in assisted reproduction. It is the aim of this manuscript to summarise the current knowledge of effects of various forms of heparins in assisted reproduction, to analyze its application and consider its effectiveness in improving the outcome (the baby take-home rate), and to take into account the possible side-effects of such a therapeutic approach.
However, when considering the effectiveness of heparin in assisted reproduction, specific effects of heparin on the coagulation system, during implantation and on the interaction with the placenta must be taken into account as well.
Section snippets
Materials and methods
A systematic literature search of the PubMed/Medline database was performed assessing all articles published up to November 2010. All retrieved articles were evaluated and cross-checked for references on the topic. “IVF”, “ICSI”, “assisted reproduction”, “heparin”, “side effect”, “coagulation”, “thrombosis”, “thrombophilia”, “thrombophilic disorder”, “implantation”, “implantation failure” and “placenta” were used as key-words. Clinical studies were restricted to findings in humans.
Changes in the coagulation system during controlled ovarian stimulation
It is generally accepted that significant changes in the coagulation system occur during ovarian stimulation. The procoagulatory changes in coagulation and fibrinolysis during ovarian stimulation are considered to be comparable to those occurring in pregnancy (Table 1) (Clark et al., 1998, Nelson and Greer, 2008). More pronounced procoagulatory changes are found if the ovarian hyperstimulation syndrome (OHSS) occurs (Rogolino et al., 2003), which in itself is associated with a decreased chance
Heparin in the treatment of the ovarian hyperstimulation syndrome
Although being part of treatment protocols for OHSS (The Practice Committee of the ASRM, 2008b) no prospective trials have yet answered the question which heparin should be given, for how long, and at which dosage in patients suffering from OHSS. Thus, the application of heparin is based on biological plausibility rather than on prospective randomised trials.
Prevention and treatment of thrombosis in ART patients
No prospective trials to compare the effects of unfractionated or different low-molecular weight heparins during ART in patients at high
A word of caution
A 38-year-old nulliparous woman with positive APAs died from complications of a cerebral haemorrhage after she had been given a combination of heparin and aspirin to improve her ART outcome. She had no history of thromboembolic events (CDC, 1998). However, other side effects of heparin therapy, such as genital bleedings, increased rates of swelling and itching at the injection sites (Kaandorp et al., 2010), osteopenia and potentially heparin-induced thrombocytopenia, have to be taken into
References (57)
- et al.
Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy
Chest
(2008) - et al.
More on: the ‘ART’ behind the clot: solving the mystery
J. Thromb. Haemost.
(2007) - et al.
Ovarian stimulation for ovulation induction and in vitro fertilization in patients with systemic lupus erythematosus and antiphospholipid syndrome
Fertil. Steril.
(2009) - et al.
Unfractionated heparin, low molecular weight heparins, and pentasaccharide: basic mechanism of actions, pharmacology, and clinical use
Hematol. Oncol. Clin. North. Am.
(2005) - et al.
A review of upper extremity deep vein thrombosis in pregnancy: unmasking the ‘ART’ behind the clot
J. Thromb. Haemost.
(2006) - et al.
SPIN: the Scottish Pregnancy Intervention Study: a multicentre randomised controlled trial of low molecular weight heparin and low dose aspirin in women with recurrent miscarriage
Blood
(2010) - et al.
Heparin and low-molecular-weight heparins modulate the decidualization of human endometrial stromal cells
Fertil. Steril.
(2010) - et al.
Thrombotic risk during pregnancy: a population study
Obstet. Gynecol.
(1999) - et al.
A case of forearm amputation after ovarian stimulation for in vitro fertilization–embryo transfer
Fertil. Steril.
(2001) - et al.
Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review
J. Thromb. Haemost.
(2010)
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)
J. Thromb. Haemost.
Involvement of heparanase in early pregnancy losses
Thromb. Res.
Thrombophylaxis with low-molecular weight heparin (Dalteparin) in pregnancy
Thromb. Res.
Heparin/aspirin therapy for implantation failure in IVF cycles
Fertil. Steril.
Thrombophilic disorders and fetal loss: a meta-analysis
Lancet
Management of 273 cases of recurrent implantation failure: results of a combined evidence-based protocol
Reprod. BioMed. Online
A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies
Fertil. Steril.
Management of patients with antiphospholipid antibodies undergoing in vitro fertilization
J. Autoimmun.
Intravaginal and intracervical application of seminal plasma in in vitro fertilization or intracytoplasmic sperm injection treatment cycles: a double-blind, placebo-controlled, randomized pilot study
Fertil. Steril.
Safety of IVF under anticoagulant therapy in patients at risk for thrombo-embolic events
Reprod. Biomed. Online
Treatment of ovarian hyperstimulation syndrome
Semin. Reprod. Med.
Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women
Thromb. Haemost.
Current concepts of efficient diagnosis and therapeutic options in patients with recurrent early abortions
Geburtsh. Frauenheilk.
Anticoagulation and assisted reproduction, improved pregnancy and birth rates through additional therapy with aspirin and heparin?
Gynäkol. Endokrinol.
Pregnancy-related death associated with heparin and aspirin treatment for infertility, 1996
MMWR Morb. Mortal. Wkly. Rep.
Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy
Thromb. Haemost.
Methylenetetrahydrofolate reductase C677T and A1298C variants do not affect ongoing pregnancy rates following IVF
Hum. Reprod.
Heparanase expression and function during early pregnancy in mice
Biol. Reprod.
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