Akhtar, Muhammad A. (2015) Peri-implantation heparin improves implantation and the clinical pregnancy rate and live birth rate in subfertile women. PhD thesis, University of Warwick.

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Abstract

The clinical success of assisted reproductive technology (ART) is measured by the clinical pregnancies (implantation success) and the live births rates.

Following ART live birth rates vary from 20-40% and are dependent upon a variety of factors. Various adjunct therapies are being used with ART to improve implantation and pregnancy outcomes. The effectiveness of these adjuvant therapies remains unclear and requires further evaluation. One group of medical adjuvant therapies widely used in clinical practice are thromboprophylactic agents, including heparin. Heparin can potentially modulate many of the mechanisms of implantation including successful apposition, adhesion and penetration of the developing embryo into the endometrium. This is independent of its anticoagulant function for which it is used routinely in clinical practice.

Following completion of a literature review, it became evident that heparin could potentially improve decidualisation and implantation. It improves function of various growth factors and cytokines in the endometrium promoting and facilitating implantation in laboratory models. From this initial research, we postulated that heparin used as adjunct to ART should improve the clinical pregnancy and the live birth rates via these mechanisms described. Bleeding is a known side effect of systemic heparin due to its effect on the coagulation cascade.

A systematic review and meta-analysis protocol was devised and peer-reviewed to assess the published data. The aim of this was to establish whether using the currently available evidence, peri-implantation heparin improves pregnancy outcomes in women undergoing ART. A secondary aim was to determine if there were any significant side effects. The meta-analysis was performed in accordance with the protocol. This demonstrated that peri-implantation systematic heparin does improve clinical pregnancy rates and live birth rates in these women. Nevertheless, there were only three randomised control trials (RCTs) included in the review that met the inclusion criteria and there was significant heterogeneity amongst the participants in the included studies. Systemic side effects of heparin including bleeding and bruising were also identified in this review.

As the proposed mechanism of improving implantation by heparin is improvement of endometrial cytokines and growth factors. It was hypothesised that direct endometrial administration of heparin should improve decidualisation thus improving implantation. To confirm or refute this hypothesis, initially a phase 1 study is required to be undertaken for direct endometrial administration of heparin as currently it is only licenced as a systemic injectable formulation.

We developed a protocol to assess the feasibility of intrauterine flushing for direct endometrial administration of low molecular weight heparin (LMWH) with a prospective randomised placebo controlled pilot study. This novel study was approved by National Research Ethics Service (NRES), Medicine & Healthcare products Regulatory Authority (MHRA), UK. Sponsorship was obtained from the University of Warwick and local Research & Development (R&D) approval was obtained. The study was undertaken at University Hospitals Coventry and Warwickshire NHS Trust (UHCW). It demonstrated the acceptability of intrauterine flushing of heparin to women. The concept of the trial was popular with patients making recruitment unproblematic. Minimal side effects were reported, no serious adverse events occurred. Most women recruited underwent ART following the study, with many achieving a clinical pregnancy and live birth. Our hypothesis for primary outcome measure, uterine natural killer (uNK) cell density, as a marker of decidualisation was refuted.

Item Type:	Thesis (PhD)
Subjects:	R Medicine > RG Gynecology and obstetrics
Library of Congress Subject Headings (LCSH):	Heparin, Fertility human, Infertility, Female
Official Date:	May 2015
Dates:	Date Event May 2015 Submitted
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Quenby, Siobhan
Extent:	192, [78] leaves : illustrations (colour)
Language:	eng

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