Low-molecular-weight-heparin increases Th1- and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomised controlled trial

E Rasmark Roepke,R Boij,J Ernerudh,E Nedstrand,G Berg,C Petersson Strid,E Piccione,M Rubér,J Svensson-Arvelund,V Bruno,V Bruno,M C Jenmalm

doi:10.1038/s41598-019-48799-6

E Rasmark Roepke, R Boij + Show 10 more

Open Access

https://doi.org/10.1038/s41598-019-48799-6

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Abstract

Low-molecular-weight heparin (LMWH) is widely used to treat recurrent pregnancy loss (RPL) because of its anti-coagulant effects. Although in vitro studies have suggested additional immunological effects, these are debated. We therefore investigated whether LMWH could modulate immune responses in vivo during pregnancy of women with unexplained RPL. A Swedish open multi-centre randomised controlled trial included 45 women treated with tinzaparin and 42 untreated women. Longitudinally collected plasma samples were obtained at gestational weeks (gw) 6, 18, 28 and 34 and analysed by multiplex bead technology for levels of 11 cytokines and chemokines, chosen to represent inflammation and T-helper subset-associated immunity. Mixed linear models test on LMWH-treated and untreated women showed differences during pregnancy of the Th1-associated chemokines CXCL10 (p = 0.01), CXCL11 (p < 0.001) and the Th17-associated chemokine CCL20 (p = 0.04), while CCL2, CCL17, CCL22, CXCL1, CXCL8, CXCL12, CXCL13 and IL-6 did not differ. Subsequent Student’s t-test showed significantly higher plasma levels of CXCL10 and CXCL11 in treated than untreated women at gw 28 and 34. The consistent increase in the two Th1-associated chemokines suggests a potential proinflammatory and unfavourable effect of LMWH treatment during later stages of pregnancy, when Th1 immunity is known to disrupt immunological tolerance.

Highlights

Low-molecular-weight heparin (LMWH) is widely used to treat recurrent pregnancy loss (RPL) because of its anti-coagulant effects
CXCL11 was the only chemokine that differed between groups (Student’s t-test on log-transformed data p = 0.013), showing significantly higher levels at inclusion, before treatment was started, in women who miscarried compared with the women who continued their pregnancy > gw 22
Intrauterine growth restriction was seen in three cases with treatment and none in the untreated group, while neonatal death occurred in one of the treated women and one intrauterine foetal deaths (IUFD) occurred in each group. In this RCT of in vivo LMWH effects in pregnant women with unexplained RPL (uRPL), the main finding was a significant increase in plasma levels of the Th1-associated chemokines, CXCL10 and CXCL11, and possibly of the Th17-associated chemokine, CCL20, in the second and third trimesters of pregnancy in women treated with LMWH compared to a control group without treatment

Summary

Introduction

Low-molecular-weight heparin (LMWH) is widely used to treat recurrent pregnancy loss (RPL) because of its anti-coagulant effects. The consistent increase in the two Th1-associated chemokines suggests a potential proinflammatory and unfavourable effect of LMWH treatment during later stages of pregnancy, when Th1 immunity is known to disrupt immunological tolerance. For treatment of recurrent pregnancy loss (RPL), low-molecular-weight heparin (LMWH) is used in clinical practice despite the European Society of Human Reproduction and Embryology (ESHRE) guidelines which do not recommend the use of LMWH treatment for women with unexplained RPL (uRPL), because of evidence that treatment does not increase the live birth rate. The maternal immune system needs to be modulated in order to harbour the semi-allogeneic and rapidly growing foetus This modulation is orchestrated by signalling molecules like cytokines and chemokines. In contrast to most cytokines, chemokines are often present in plasma at measurable levels and can be used as markers of different types of immune responses

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