Low-Molecular-Weight-Heparin (LMWH) has been used empirically in patients undergoing in-vitro fertilization embryo transfer (IVF-ET) with the purpose to aid in improving pregnancy outcomes. The potential mechanism is that LMWH could exert its anticoagulant effect by inhibiting factor Xa, reducing the risk of insufficiency blood supply in the very early stage of pregnancy. Moreover, LMWH is supposed to play a role in manipulating blastocyst supposition, adhesion, and implantation, as well as trophoblast differentiation and invasion. However, limited high-quality clinical trials focus on the effectivity of LMWH in IVF-ET, and the published evidence is not consensus, leading to considerable controversy in the clinical application of LMWH in IVF-ET patients. Here, investigators try to evaluate the effect of LMWH on pregnancy outcome in women with multiple failures of IVF-ET via a multi-center randomized controlled trial.

Implantation failure seems to be inevitable in some couples undergoing IVF-ET treatment, despite transferred with high-quality embryos. There are several factors, including coagulation, are supposed to contribute to the implantation failure. Several groups reported that inherited and acquired coagulation is highly prevalent in women with recurrent implantation failure (RIF). Besides, women undergoing assisted reproduction are more likely to expose to thrombotic risks because high-dose exogenous gonadotrophins are given to harvest more oocytes for the fertilization. Given the risk of thrombosis, patients are often recommended to receive thromboprophylaxis with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in many clinics empirically.

LMWH is generated by depolymerization from UFH. Compared with UFH, LWMH exerts its anticoagulant effect mainly by inhibiting factor Xa rather than factor IIa. LMWH has a more predictable antithrombotic response and allows the administration to patients themselves without the laboratory monitoring. Also, it substantially reduces the risk of heparin-induced thrombocytopenia (HIT).

Beyond its anticoagulant effects, heparin is supposed to improve pregnancy outcomes by modulating blastocyst supposition, adhesion and implantation and as well as trophoblast differentiation and invasion through interactions with several adhesion molecules, growth factors, cytokines, and enzymes. Also, complement activation induced by aPL antibodies in mice is inhibited, and pregnancy complications are attenuated when treated with heparin.

Unfortunately, the use of LMWH in IVF/ET seems based on biological plausibility rather than evidence of efficacy. The high-quality studies (randomized controlled trials or prospective controlled trials) are limited, and the results are controversial. A meta-analysis (including 2 RCT and 1 quasi-RCT) reported that there is no difference in implantation rate in women with ≥3 recurrent implantation failure when treated with LMWH. Although live birth rate (LBR) and miscarriage rates are improved, investigators are still concerned because limited studies and patients were included in this analysis. Even in the non-RIF patients with or without thrombophilia defects, no consensus results could be achieved.

Given the burden of daily injection, skin irritation at injection site and other potential side-effects, the effectivity of LMWH in IVF/ET should be carefully examined even though LMWH is regarded as safe thromboprophylaxis. Hence, investigators propose a multi-center randomized study to evaluate the efficacy of Heparin in IVF-ET.

Inclusion Criteria:

• ≥2 consecutive IVF/ICSI-ET without clinical pregnancy
• ≥2 oocytes retrieval cycles
• 19<BMI≤25
• Normal ovarian reserve ( AMH> 1, FSH <10 )
• Willing and able to sign the informed consent.

Exclusion Criteria:

• Uterine abnormalities confirmed by hysterosalpingography or hysteroscopy
• Parental chromosomal abnormalities
• PCOS
• Anti-phospholipid Syndrome
• Endocrine disorder
• Endometriosis
• Hydrosalpinx
• Chronic disease (liver, renal, thyroid, and thrombocytopenia)
• Regular anticoagulation or antiplatelet treatment
• Patients who had contraindication for unfractionated heparin therapy
• History of tuberculosis, HIV, HBV, HCV or tests indicating carriage of HBV or HCV, or positive interferon-gamma release assay in any of the couple
• Enrollment in another clinical trial