Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: a systematic review and meta-analysis

Abstract

BACKGROUND Poor fertility outcomes in women with recurrent implantation failure (≥ RIF) present significant challenges in assisted reproduction, and various adjuncts, including heparin, are used for potential improvement in pregnancy rates. We performed this systematic review and meta-analysis to evaluate the effect of low-molecular-weight heparin (LMWH) on live birth rates (LBRs) and implantation rates (IRs) in women with RIF and undergoing IVF. METHODS Studies comparing LMWH versus control/placebo in women with RIF were searched for on MEDLINE, EMBASE, Cochrane Library, conference proceedings and databases for registered and ongoing trials (1980-2012). Statistical analysis was performed using Review Manager 5.1. The main outcome measure was LBR per woman. RESULTS Two randomized controlled trials (RCTs) and one quasi-randomized trial met the inclusion criteria. One study included women with at least one thrombophilia ( Qublan et al., 2008) and two studies included women with unexplained RIF ( Urman et al., 2009; Berker et al., 2011). Pooled risk ratios in women with ≥ 3 RIF (N = 245) showed a significant improvement in the LBR (risk ratio (RR) = 1.79, 95% confidence interval (CI) = 1.10-2.90, P = 0.02) and a reduction in the miscarriage rate (RR = 0.22, 95% CI = 0.06-0.78, P = 0.02) with LMWH compared with controls. The IR for ≥ 3 RIF (N = 674) showed a non-significant trend toward improvement (RR = 1.73, 95% CI 0.98-3.03, P = 0.06) with LMWH. However, the beneficial effect of LMWH was not significant when only studies with unexplained RIF were pooled. The summary analysis for the numbers needed to be treated with LMWH showed that approximately eight women would require treatment to achieve one extra live birth. CONCLUSIONS In women with ≥3 RIF, the use of adjunct LMWH significantly improves LBR by 79% compared with the control group; however, this is to be considered with caution, since the overall number of participants in the studies was small. Further evidence from adequately powered multi-centered RCTs is required prior to recommending LMWH for routine clinical use. This review highlights the need for future basic science and clinical research in this important field.

A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications

“…The effect of heparin treatment in assisting some pregnancies could lie in its ability to block the heparin binding site of HPV, 47 and HPV status may provide clarity to the heparin therapy debate. 48 Similarly, salicylic acid is widely prescribed and appears effective in pre-eclamptic pregnancies. 49 Salicyclic acid is also used as an inexpensive treatment for cutaneous warts, possibly affecting HPV E6 and E7 protein action on cyclooxygenase-2 transcription.…”

Obstetric outcome in pregnancy with thrombophilia: a comparative study of two different thromboprophylaxis regimes

“…3,4,8,[10][11][12] It has also been seen that the treatment with LMWH has been preferred to unfractionated heparin. 3,4,8,11,[13][14][15][16][17][18][19][20] The recommendations for anticoagulation therapy for acquired thrombophilia are very well defined and have found to have a significant positive impact on pregnancy outcome. 2,4,8,12,15,22,23 Heparin is a glycosaminoglycan that binds to antithrombin thereby inactivating thrombin, Factor IXa and Factor Xa resulting in expression of anticoagulant response.…”

“…The ease of administration and better bioavailability of low molecular weight heparin has resulted in conduct of various trials favouring its use over unfractionated heparin in treatment of pregnant women with thrombophilia. 3,4,8,[13][14][15][16][17][18][19][20] Low dose ecosprin acts by blocking the conversion of arachdonic acid to thromboxane A2. Hence, there is reduction in synthesis of Thromboxane A2.…”

Adjuvants Therapies for Women Undergoing IVF: Is There Any Evidence of their Safety and Efficacy? An Updated Mini-Review

“…On the contrary, a systematic review and a meta-analysis including two RCTs and one quasi-randomized trial showed a significant improvement in the LBR (risk ratio (RR) ¼ 1.79, 95% confidence interval (CI) ¼ 1.10-2.90, P ¼ 0.02) and a reduction in the miscarriage rate (RR ¼ 0.22, 95% CI ¼ 0.06-0.78, P ¼ 0.02) with LMWH compared with controls. However, the beneficial effect of LMWH was not significant when only studies with unexplained RIF were pooled [28]. Finally, a recent Cochrane review [33] including three RCTs, of which two consisted of women with 3 RIF and one consisted of women with unexplained infertility undergoing their first IVF cycles, reported similar findings: when a fixed effect analysis was used as a statistical model, peri-implantation heparin was associated with an improvement in live birth rate compared with placebo or no heparin (odds ratio (OR) 1.77, 95% confidence interval (CI) 1.07 to 2.90) and also an improvement in the clinical pregnancy rate (OR 1.61, 95% CI 1.03 to 2.53) but authors noted low quality of evidence.…”

“…In the last decade it has been proposed also as an adjunct in assisted reproduction since it has been speculated that heparin may improve the intrauterine environment in sub-fertile women. The proposed mechanism is that heparin may improve decidualization with an associated activation of growth factors such as IGF-1, heparinbinding epidermal growth factor and cytokine expression in the endometrium promoting embryo implantation through trophoblast invasion and proliferation, promoting successful pregnancy [28,29]. Heparin is administered trans-dermally in the form of unfractionated or low-molecular-weight heparin (LMWH) which is derived from heparin by depolymerization, showing similar activity but with increased bioavailability and half-life.…”