Article sponsored by Nora Therapeutics, Inc.
One helpful way to look at human fertility is through the analogy of seed and soil. Since the first IVF baby was born in 1978, most of the research and clinical progress in IVF has revolved around embryo quality and embryo selection. In the analogy of seed and soil, these advances have focused almost solely on the quality of the seed (i.e., the embryo). Embryologists are now able to culture embryos to blastocyst stage (day 5) and to select out potential embryos with genetic defects through technologies like pre implantation genetic screening. Resulting live birth rates through IVF have improved significantly, but there is still plenty of room for improvement. What has been largely overlooked is the role of endometrial environment (or the soil). Most would agree that without an optimal environment in which to plant, even the highest quality seed will struggle to take root. The same can be said for human reproduction.
In order for the endometrial environment to be properly prepared for implantation of an embryo, numerous anatomic and physiologic factors must work in concert. To enable implantation, the endometrium, which is the inner lining of the uterus, typically increases in thickness and forms new blood vessels (becomes vascularized). The endometrium begins to change in preparation for implantation (decidualization). In successful pregnancy, the decidua will form the maternal portion of the placenta, the maternal interface with the embryo. While this is taking place, and as an embryo develops in utero, the embryo’s outer cell layer, the trophoblast, invades the decidua and blood vessels between mother and fetus are created. Through this interface the mother will exchange nutrients and oxygen with the developing embryo. Importantly, the decidua will also play an important role in protecting the developing embryo from the maternal immune system.
From the immunologic perspective, pregnancy presents a paradox. An embryo contains genetic material (DNA) in equal proportion from the mother and the father. The paternal portion of the embryo’s genetic material makes the embryo partially foreign with respect to the maternal immune system and thus a target for rejection by the immune system. Why doesn’t the maternal immune system reject the embryo in successful pregnancy? Collectively there is a set of mechanisms referred to as “maternal fetal tolerance.” Maternal fetal tolerance results in temporary changes to the maternal immune system that prevent rejection of the fetus without suppressing the entire immune system, which would render the mother and fetus susceptible to potentially life threatening infection. In a significant subset of women, this does not occur and the result can be repeated IVF implantation failure or recurrent miscarriage, both of which can occur on the basis of inadequate endometrial preparedness.
Little progress has been made in the effort to address impaired endometrial preparedness. Physicians have experimented with a variety of approaches, but an estimated 70% of embryos that are transferred as part of IVF still fail to implant, which is why multiple embryos are often transferred in a single cycle. In other words, if we return to the seed and soil analogy, even with today’s highest quality seeds and most receptive soil, IVF (and for that matter natural conception) is still highly inefficient. However, we are at a point in time where there is important research emerging in the field of maternal fetal tolerance that is moving rapidly from basic science laboratories and into formal clinical trials with FDA oversight. This research may provide for a better understanding of how to improve the soil so that those excellent seeds can germinate and grow.
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