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

NCT ID: NCT03701750

Last Updated: 2020-07-29

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 240 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-01
• Study Completion Date: 2022-10-31

Brief Summary

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.

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.

Conditions

Infertility

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental Arm

Low Molecular Weight Heparin (enoxaparin sodium) + routine luteal phase support

Group Type: EXPERIMENTAL

Low Molecular Weight Heparin (enoxaparin sodium)

Intervention Type: DRUG

enoxaparin sodium 40mg/day subcutaneously after oocyte collection, and routine luteal phase support after embryo transfer until clinical pregnancy confirmed by ultrasound

Control Arm

routine luteal phase support

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 38 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

OTHER

Sponsor Role: collaborator

Renmin Hospital of Wuhan University

OTHER

Sponsor Role: collaborator

Shenzhen Zhongshan Urology Hospital

OTHER_GOV

Sponsor Role: lead

Responsible Party

Yong Zeng

Head of Hospital

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Haixiang Sun, M.D. Ph.D

Role: PRINCIPAL_INVESTIGATOR

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Jing Yang, M.D. Ph.D

Role: PRINCIPAL_INVESTIGATOR

Renmin Hospital of Wuhan University

Ruochun Lian, M.D. Ph.D

Role: PRINCIPAL_INVESTIGATOR

Shenzhen Zhongshan Urology Hospital

Locations

Clinical Research Center for Reproductive Medicine, Fertility Center, Shenzhen Zhongshan Urology Hospital

Shenzhen, Guangdong, China

Site Status: RECRUITING

Renmin Hospital of Wuhan University

Wuhan, Hubei, China

Site Status: NOT_YET_RECRUITING

The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Nanjing, Jiangsu, China

Site Status: NOT_YET_RECRUITING

Countries

China

Central Contacts

Lianghui Diao, Ph.D.

Role: CONTACT

diaolianghui@gmail.com

+86-755-88361001 ext. 9723

Songchen Cai, M.Phil.

Role: CONTACT

szcaisc@gmail.com

+86-755-88361001 ext. 9726

Facility Contacts

Lianghui Diao, Ph.D.

Role: primary

+86-755-88361001 ext. 9723

Songchen Cai, M.Phil

Role: backup

+86-755-88361001 ext. 9726

Jie Li, MD/PhD

Role: primary

+86-27-88042292

Lijun Ding, Ph.D.

Role: primary

+86-25-83106666

Jie Mei, Ph.D.

Role: backup

+86-25-83106666

References

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.

Reference Type: BACKGROUND

PMID: 19357135 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21498125 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12909502 (View on PubMed)

Other Identifiers

szuh-2018-CT001

Identifier Type: -

Identifier Source: org_study_id