Commonly used preventive therapy for recurrent miscarriage proved ineffective in large trial

Published 01 March 2019

Recombinant human granulocyte-colony stimulating factor (rhG-CSF) administered in the first trimester of pregnancy fails to increase the chance of a live birth for women with unexplained recurrent pregnancy loss.

‘By proving that rhG-CSF does not improve outcomes in unexplained recurrent pregnancy loss, we may have added more disappointment for women diagnosed with recurrent miscarriage and clinicians treating them,’ says Dr Abey Eapen, lead author of the recently published RESPONSE study.(1) However, despite the neutral result, he remains positive, noting that we now have an answer to a very important clinical question, and that ‘short-term disappointment may lead to another exciting discovery’ in the future.

The study was a multicentre, randomised, double-blinded and placebo-controlled trial conducted at 21 sites in the UK. The efficiency of rhG-CSF was investigated in 150 women with a history of unexplained recurrent - defined as three or more - pregnancy loss.

Subcutaneous injections of 130 micrograms rhG-CSF were administered once a day throughout the first trimester of pregnancy in 76 women, and their pregnancy outcomes were compared with those of 74 women given placebo injections. The outcomes of interest included clinical pregnancy at 20 weeks, pregnancy loss, live birth and safety measures such as stillbirth, neonatal birth weight, maternal adverse events and serious adverse events, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation.

There were similar clinical pregnancy rates at 20 weeks in the rhG-CSF group (59%, 45/76) and the placebo group (65%, 48/74), and no difference in the miscarriage rates (37%, 28/76, 34%, 25/74). None of the women suffered a stillbirth. Adverse events occurred in 68% of the rhG-CSF group and 58%in the placebo group, though no safety concerns were raised.

The findings of this trial therefore do not support the positive results from the only previous (single-centre) trial.(2) In that study women who received G-CSF in a dose of 1 mcg/kg/day had a live birth rate of 82.8%, significantly higher than the 48.5% in women given placebo.

rhG-CSF in practice and research
RhG-CSF is a cytokine used routinely for stimulating the proliferation and differentiation of neutrophils in patients suffering from severe chronic neutropenia and chemotherapy induced neutropenia. In the context of reproduction, weak evidence suggests that rhG-CSF might improve endometrial thickness, ovarian follicular function and oocyte quality.

Some clinics are using rhG-CSF alongside other non-evidence based immunomodulatory treatments such as lymphocyte infusion therapy, corticosteroids, intravenous immunoglobulin therapy, intravenous intralipid infusion and anti–TNFα monoclonal antibody therapy as an attempt to modulate a maternal immune response. An immune response to pregnancy has been proposed to explain a large number of otherwise 'unexplained' miscarriages.

‘There remain many unanswered questions about the immunology of early pregnancy,' says Eapen, who nevertheless remains optimistic. 'The team at Tommy's National Centre for Miscarriage Research, based at the University of Birmingham, is learning more about immune mechanisms in early pregnancy,' he says. 'This much needed research may help in defining and setting the standards for immuno-modulatory treatments in general and more importantly in patient stratification.'

1. Eapen A, Joing M, Kwon P, et al. RESPONSE study group. Recombinant human granulocyte-colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial. Hum Reprod 2019.

2. Santjohanser C, Knieper C, Franz C, et al. Granulocyte-colony stimulating factor as treatment option in patients with recurrent miscarriage. Arch Immunol Ther Exp (Warsz) 2013; 61: 159-164.

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