Effects and effectiveness of heparin in assisted reproduction

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Abstract

Despite significant improvements in treatment protocols and laboratory techniques, the baby take-home rate after assisted reproduction (ART) is disappointing, e.g. 20% in Germany. It is therefore understandable that various approaches are undertaken to improve the pregnancy and delivery rates after IVF and ICSI. Among others, the application of heparin is suggested to avoid implantation failure – partially irrespective of maternal thrombophilia. The applications of heparin for various indications are presented in this manuscript and critically discussed, taking into account current studies and meta-analyses. Furthermore, possible effects of heparin on the embryo-maternal dialogue and indications for heparin to prevent and treat thromboembolic disease during ART are summarized. A systematic literature search of the PubMed/Medline database was performed assessing all articles published before November 2010. “IVF”, “ICSI”, “assisted reproduction”, “heparin”, “side effect”, “coagulation”, “thrombosis”, “thrombophilia”, “thrombophilic disorder”, “implantation”, “implantation failure” and “placenta” were used as keywords. The available studies on heparin in assisted reproduction are characterized by heterogeneous inclusion criteria and a lack of proven effectiveness in special constellations. In conclusion, the application of heparin to improve ART outcome rates is not justified.

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

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