For and against immunosuppression in recurrent implantation failure


Published 03 July 2018

While some groups may benefit, majority opinion at a packed Barcelona debate was strongly against the use of non-targeted immunosuppresion for implantation failure. Laurentiu Craciunas reports.

The hot topic of immonosuppresion for implantation failure was the subject of a debate in Barcelona between two leaders of reproduction research. After an opening clear majority vote AGAINST the use of immunosuppresion in the context of implantation failure, Professor Siobhan Quenby attempted to turn the vote FOR, while Professor Sarah Robertson aimed to strengthen the contra stance.

In the absence of hard evidence to support the use of non-specific suppression, Quenby’s strategy was to explain why the evidence is missing and emphasised the idea that 'absence of evidence is not evidence of absence’. Stronger evidence will emerge once trials identify the correct population of women who may benefit from the treatment. How could this population be identified if there is no accurate test to diagnose immunological defects at the level of the uterus or endometrium? Other steps should precede interventions to improve the outcomes.

Trials so far have used various definitions for implantation failure, from numerous unsuccessful embryo transfers to biochemical pregnancy or even miscarriage. What they are all missing is accounting for the role of the embryo (ploidy and quality) in the implantation failure.

Ogasawara’s paper published in 2000 was cited to support the good prognosis for women suffering up to five recurrent miscarriages, even in the absence of any treatment. It is thus the extreme group of women with more than five miscarriages who should be included in treatment trials if efficiency is expected to be proven. It was thus reassuring to find that there is such a trial of immunosuppresion ongoing in Denmark.

Because uterine natural killer (uNK) cells could not be left out of the discussion, Quenby described the association between high uNK counts and reduced cortisol levels in support of steroid use in this context. Furthermore, hydroxychloroquine, a drug with immunomodulation properties, appears to be more efficient than low molecular heparins in the management of severe cases of antiphospholipid syndrome.

Despite starting from a better initial vote result, Robertson’s strategy was more actively directed against the use of non-targeted immunosuppresion as a ‘brick’ to knock down the immune response in pregnancy. Her presentation focused on the crucial role of the immune system in both early and advanced pregnancy.

In addition to its well known functions in defence and rejection, the immune system has a crucial role in active tolerance, which makes it a ‘friend’ of pregnancy rather than the ‘enemy’. Knocking down the immune system with non-targeted immunosuppresion is a flawed rationale, said Robertson.

Dramatically named uNK cells in fact make important contributions to placental development by controlling the extent of placental invasion and by producing angiogenic factors that facilitate vascular adaptation. Treg cells are key anti-inflammatory regulators over the course of pregnancy and their deficiency is associated with recurrent implantation failure.

Recurrent implantation failure is an immune deficiency or imbalance rather than an excess that requires blanket reduction. Thus, said Robertson, corticoids suppress many immune cells and functions in the immune response and have the potential to harm. Corticoids associate a small but real risk of cleft lip and palate, miscarriage, preterm birth and hypertension. They also have negative impact on weight gain, mood, sugar control and infections.

The conference room was fully packed for this debate, and the voting post presentations was strongly AGAINST non-targeted immunosuppresion for implantation failure. Both debaters agreed on the fact that some women may benefit from such a treatment; however, current science has not yet identified that correct group of women.

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