More on the Importance of the Maternal Immune System

Regular readers of these pages may recall that we recently discussed a study that had appeared in the literature, which suggested that women infected with certain parasitic helminthes (the scientific name for worms) were more fertile than either uninfected women or women infected with a different worm. In our comments on this paper we suggested that this study represented further evidence for how important the maternal immune system was for successful female reproduction, and that it seemed high time to pay more attention to the role of the immune system in female infertility.

If a certain helminth can improve female infertility, it, likely, does so by challenging the maternal immune system in ways that enhance the chance of implantation and successful pregnancy.
Despite being “foreign” and, therefore, subject to potential immune attacks and rejection, worms, of course, are parasite, which are “experts” in surviving in humans. The way they achieve survival is, likely, by inducing certain immune responses (pathways), which activate mechanisms within the host’s immune system that actually block such immune attacks, – i.e. induce immunological tolerance toward the helminthes. Induction of such pathways is, however, exactly what the implanting fetus also needs in order to survive because, like the helminth, it, too, is really a “foreign” body for the maternal immune system since it is 50% of paternal origin. Above cited study in South American Indian tribal women, thus, suggested that certain worms, in order to fend off attacks from women’s immune system induce certain immune pathways, which also are helpful to the establishment of pregnancies.

That this is not a farfetched thought was last month (June 19) also discussed by Moises Velasquez-Manoff in the Sunday Magazine of the New York Times in an article that attracted wide attention under the headline, “The Parasite Underground.” In that piece the author reported on the concept that infecting patients with certain helminthes who suffer from intractable autoimmune diseases often obliviates clinical symptoms of the disease. The title of the article referred to the fact that an underground industry has evolved around infecting autoimmune patients, who cannot get relief from traditional medicine, with helminth larvae, which penetrate the skin and end up in the patients’ gastrointestinal tract.

Like in pregnancy, the concept here is again that helminthes induce tolerance-producing pathways in the immune system. Such tolerance is exactly what autoimmune patients need because presence of autoimmunity means that a patient’s immune system has lost its ability to be immunologically tolerant toward self-components of the body.  As a consequence, the patient’s immune system attacks certain tissues in the body, and an autoimmune disease evolves. By inducing and/or enhancing autoimmune pathways, those helminthes not only protect themselves against their host’s immune system but they at the same time also restitute self-tolerance against the body’s own tissues and, thereby alleviate disease symptoms.

But this is not yet the end of the story about tolerance-inducing pathways for today: Just very recently, we discussed in the pages of the VOICE another article, which reported the remarkable observation made by medical colleagues in infectious diseases that administration of Influenza vaccine during pregnancy reduced stillbirths by 50%. In discussing this publication in these pages, we made the point that this observation may suggest that administration of Influenza vaccine during pregnancy may prolong the period of immunological tolerance of the fetal-semi-allograft by the maternal immune system because most stillbirths are likely the consequence of pregnancy complications caused by premature termination of tolerance (preeclampsia/eclampsia, premature labor, etc.).

We further speculated that, like helminthes, Influenza vaccinations also induce immune response pathways that enhance tolerance of the maternal immune system toward the female semi-allograft (the fetus) and, thereby, extend the period of tolerance in patients who, otherwise, would experience premature loss of tolerance and pregnancy complications that stem from such premature termination of tolerance.

Since then we discovered that this was not the only report suggesting that Influenza vaccinations dramatically reduce stillbirths. Indeed, last year a so-called meta-analysis also reported this fact (Bratton et al., CID 2016;60:e11-19).

Assuming that our hypothesis was correct, we also discussed in the VOICE piece the likelihood that Influenza vaccination not only can prevent stillbirths late in pregnancy but also premature labor, which represents the single largest cause of perinatal morbidity and mortality around the world. Low and behold, only weeks later a large observational study was published from South East Asia, which reported exactly that. Indeed, prematurity rates, once again were reduced by approximately half if women were vaccinated in pregnancy, and the effect was maintained after adjustment for covariates (Olsen et al., Clin Infect Dis 2016; May 3, pii: ciw290).

Combined these data increasingly suggest that Influenza vaccination in pregnancy, indeed, extends the period of tolerance for the fetus by the maternal immune system. This, of course, raises an important additional question: If the Influenza vaccine (and, maybe other vaccines or even helminthes) are able to extend the period of tolerance, can they also help in the initial induction of tolerance? With appropriate timing, the likely answer is yes because, like there are patients with premature termination of tolerance, there undoubtedly are also patients with initial difficulties in inducing tolerance for the implanting fetus.

A new clinical trial
Such patients currently are believed to suffer from so-called implantation failure and/or from repeated miscarriages. CHR, therefore, is initiating a new clinical trial, which will be presented to the center’s Institutional Review Board (IRB) for approval in its July meeting. Since CHR has a policy of recommending Influenza vaccinations to all women attempting pregnancy, CHR will prospectively randomize women to receiving this vaccination either before or after tentative implantation of embryos. In women with implantation failure, we hope to be able to establish that vaccination improves implantation rates and, therefore, pregnancy rates in association with IVF. In women with repeat miscarriages, we hope, to establish that vaccination reduces miscarriage risks.

The new trial will, likely, initiated in September with arrival of the annual Influenza vaccine. CHR will provide immunizations free of charge. Patients who are interested in participating in this trial, please call 212-994-4400, and let our staff know that you would like to participate in the “Influenza Trial.”

This is a part of the July 2016 issue of the VOICE. Read the July VOICE in PDF.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.