Immuneresistance /ɪ’mjuːnrɪ’zɪstəns/ substantive

a. Resistance to recommend immunological tests and treatments to infertile patients.

This is a common statement in Spain: Here we say that “cada maestrillo tiene su librillo”. This sentence basically means that each of us we have our own way of doing things based on the experiences we’ve gathered and depending on what we think could be (more) useful in each situation. In reproduction it also happens. We all tend to focus on fields we feel comfortable with when we explain patients why they don’t get pregnant, and we have to admit that it’s rare to find professionals who take all possibilities into account. In this sense BarcelonaIVF team, tend to study more the male factor, but we try not to forget implantation and other potential causes of failure. This is why, bearing in mind the number of patients that have requested our opinion regarding this issue, we’ve eventually decided to write this short article.

Just let’s make one clarification before starting. For us the patients affected by antiphospholipid antibodies are not included in this immunological issues we’re about to discuss. There’s level IA evidence (which means that the association between these antibodies and miscarriages has been repeatedly and clearly demonstrated) that they lead to recurrent miscarriages and fetal losses, and there’s a clear and effective treatment for this problem, heparin, which acts both as an anticoagulation and as an immunomodulator drug. We may discuss about the doses that should be used or whether it’s better to combine it with aspirin or not, but not about its effectiveness.

All other problems are nowadays mainly treated with either high doses of steroids (either prednisone or prednisolone) or IVIg (intravenous immunoglobulins). None of them are free of risks.
Steroids are a class B drug. That means that they have been related to birth defects in animals that could not have been demonstrated in humans. They’ve also been related to an increased risk of high blood pressure, diabetes and intrauterine growth retardation in pregnancy.
IVIg have been related to a number of side effects (including anaphylactic shock) and to a potential risk of transmitting infections (some of them undetectable because involve prions, like Creutzfeld-Jackobs).
The first thing I must say is that IVIg are not legally allowed in Spain for this purpose. This clearly limits the possibility of carrying out our own study to confirm its effectiveness or even to use them in cases in which you have no other options. This is why I write this article taking into account the information I’ve found in several relevant and reliable sources, the HFEA, the Royal Colleague of Obstetricians and Gynecologists (both its Green Guidelines for recurrent miscarriages and its Immunological testing and interventions for reproductive failures) and the Cochrane Library. All three sources provide recent information about the data that have been published.

I won’t repeat what you can already read in those websites, but starting by the conclusion, all four (the three sources consulted plus us, BarcelonaIVF) we agree that there’s no conclusive data (yet) that supports that immunotherapy significantly improves live birth, neither in recurrent miscarriages nor in recurrent unexplained failures. And all three recommend further serious studies to gather data that can eventually allow the fertility community to decide whether it’s worth or not recommending these tests and treatments.

There can be several reasons that can explain this bleak conclusion (I call it bleak because us, as many other colleagues, we want as much as the current immunotherapy defenders that their research leads to finding new useful treatments). Some authors talk about the different effectiveness of the IVIg used in the different articles, others that even in patients treated with IVIg there’s a 30% of miscarriages due to genetic errors that can create an impression of futility, some claim that the lack of significance can be due to the type of patients recruited into the studies or the timing at what the IVIg were given. Or may be it’s just that they’re not effective due to their lack of specificity. In our opinion all these problems could be handled if a serious prospective randomized multicenter study was carried out. Until then we’ll have to work only by “impressions” or basing the decisions on individual cases.
And last but not least, patients have to face the cost of these tests and treatments. It’s not rare that patients may pay up to 3.000€ for the tests and 3.000€ for the treatments. The amount is as high as a full IVF.

To sum up, we have some expensive tests that need expensive and, to some extend, risky treatments. Nowadays there is not enough data to conclude that if any of these tests is positive it could negatively affect implantation or even increase the risk of miscarriage. Moreover, the treatments have not proved to lead to a successful increase of live birth rates when large statistical studies have been carried out.
That said it’s far from our aim to give the impression that BarcelonaIVF is against immunology. We accept that there could be other groups (professionals) with greater experience and good results that have not been published yet. Until we can check their data, we’re willing to collaborate with all the clinics that continue working in this field, helping them to gather more information to disclose the secrets of the immunology.

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