Effect of LMWH on Pregnancy Outcome in Women With Multiple Failures of IVF-ET

Effect of Low-Molecular-Weight-Heparin (LMWH) on Pregnancy Outcome in Women With Multiple Failures of IVF-ET

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.

Study Overview

• Status: Unknown
• Conditions: Infertility
• Intervention / Treatment: Drug: Low Molecular Weight Heparin (enoxaparin sodium)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 240
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China, 518045
      • Recruiting
      • Clinical Research Center for Reproductive Medicine, Fertility Center, Shenzhen Zhongshan Urology Hospital
      • Contact: Lianghui Diao, Ph.D.; Phone Number: 9723 +86-755-88361001
      • Contact: Songchen Cai, M.Phil; Phone Number: 9726 +86-755-88361001
      • Sub-Investigator: Ruochun Lian, MD/PhD
  • Hubei
    • Wuhan, Hubei, China, 430060
      • Not yet recruiting
      • Renmin Hospital of Wuhan University
      • Contact: Jie Li, MD/PhD; Phone Number: +86-27-88042292
  • Jiangsu
    • Nanjing, Jiangsu, China, 210008
      • Not yet recruiting
      • The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
      • Contact: Lijun Ding, Ph.D.; Phone Number: +86-25-83106666
      • Contact: Jie Mei, Ph.D.; Phone Number: +86-25-83106666

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 38 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

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: Experimental Arm; Low Molecular Weight Heparin (enoxaparin sodium) + routine luteal phase support	Drug: Low Molecular Weight Heparin (enoxaparin sodium); enoxaparin sodium 40mg/day subcutaneously after oocyte collection, and routine luteal phase support after embryo transfer until clinical pregnancy confirmed by ultrasound
No Intervention: Control Arm; routine luteal phase support

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth rate	Birth of liveborn	Time of delivery up to 42 weeks gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Embryo implantation rate	Gestational sacs are seen by ultrasound	4 weeks
Clinical pregnancy rate	Fetal heartbeat is seen by ultrasound	7-8 weeks
Miscarriage rate	After clinical pregnancy confirmed, before 28 weeks	Up to 28 weeks
Ovarian hyperstimulation syndrome (OHSS) rate	Ovarian hyperstimulations syndrome after COH	Up to 3 weeks after COH

Collaborators and Investigators

• Sponsor: Shenzhen Zhongshan Urology Hospital
• Collaborators: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School; Renmin Hospital of Wuhan University
• Investigators: Principal Investigator: Haixiang Sun, M.D. Ph.D, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School; Principal Investigator: Jing Yang, M.D. Ph.D, Renmin Hospital of Wuhan University; Principal Investigator: Ruochun Lian, M.D. Ph.D, Shenzhen Zhongshan Urology Hospital

Publications and helpful links

General Publications

• Urman B, Ata B, Yakin K, Alatas C, Aksoy S, Mercan R, Balaban B. Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer cycles: a randomized open-labeled pilot trial. Hum Reprod. 2009 Jul;24(7):1640-7. doi: 10.1093/humrep/dep086. Epub 2009 Apr 8.
• Noci I, Milanini MN, Ruggiero M, Papini F, Fuzzi B, Artini PG. Effect of dalteparin sodium administration on IVF outcome in non-thrombophilic young women: a pilot study. Reprod Biomed Online. 2011 Jun;22(6):615-20. doi: 10.1016/j.rbmo.2011.03.016. Epub 2011 Mar 22.
• Stern C, Chamley L, Norris H, Hale L, Baker HW. 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. 2003 Aug;80(2):376-83. doi: 10.1016/s0015-0282(03)00610-1.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2018
• Primary Completion (Anticipated): October 31, 2021
• Study Completion (Anticipated): October 31, 2022

Study Registration Dates

• First Submitted: October 7, 2018
• First Submitted That Met QC Criteria: October 8, 2018
• First Posted (Actual): October 10, 2018

Study Record Updates

• Last Update Posted (Actual): July 29, 2020
• Last Update Submitted That Met QC Criteria: July 27, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: IVF; Assisted Reproductive Technology; pregnancy; LMWH; Implantation; Low Molecular Weight Heparin
• Additional Relevant MeSH Terms: Infertility; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Enoxaparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Enoxaparin sodium
• Other Study ID Numbers: szuh-2018-CT001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No