Marilen Benner

GENERAL INTRODUCTION AND SCOPE OF THIS THESIS 11 1 A HISTORIC VIEW OF PREGNANCY AS MYSTERY –THE WOMB AT THE CENTER OF ATTENTION Throughout history, mankind has been in awe of pregnancy. The ability to bear an heir came not only with great power, but also with an enormous responsibility that, for many centuries, has defined a woman’s worth. The lack of power to control reproductive success inspired some of the earliest medical investigations known, at times when female health was otherwise underrepresented in medicine. Already around 2000 B.C., the Egyptian Kahun Gynaecological Papyrus documents the desire to understand the mysterious process of fertility, representing the first evidence of the special role that has been ascribed to the womb throughout ancient times (1, 2). Many of these Egyptian concepts depicting the womb as cause for many (if not all) issues of women’s health were reinforced by the ancient Greeks (3). Theories of the womb ( ὑστέρᾱ - hystera) as origin also for mental (and thus gender specific) illness were prominent until the twentieth century 1 . Moral perceptions hampered the extent to which male medical professionals could examine the female reproductive system. A forward leap in the understanding of uterine health could not be made until the role of physician was not exclusive to men anymore, and the taboos around the menstrual cycle were challenged by feminist movements in the 1960s and early 1970s (4). Current globalized clinical practice now permits us to look beyond mythological and religious associations with female health. Still, there is much left to discover to understand the magic of pregnancy. THE GATEKEEPER FUNCTION OF THE UTERUS Even when all conditions are optimal, human reproduction is relatively inefficient and each cycle the probability of conception is merely 30-40% (5). In an attempt to answer the question “Where have all the conceptions gone?”, Roberts and Lowe (1975) hypothesized that the relatively low incidence of birth defects amongst the population results from a natural selection of fit embryos (6). A large part of pregnancies are lost before women are aware of it, as up to a third of “occult pregnancies” go unnoticed (Figure 1) (5, 7). This window of high fragility continues until mid- gestation (8, 9). Up to 15-20% of pregnancies end in a loss before 28 weeks of gestation (10). About half of these cases are explained by cytogenetic abnormalities of the embryo (11). These miscarriages result not only from the embryo’s failure to interact with the uterine wall, but from an inability on the maternal side to receive the incoming cells (12, 13). The uterine mucosa, termed endometrium , or decidua once it is at its receptive stage towards the end of the menstrual cycle, actively senses quality of the embryo (14). This selection during implantation, a first checkpoint, has to be extremely well-regulated. On the one hand, failure of the decidua to allow implantation 1 It was not until 1980 that “Hysteria” was removed from Diagnostic and Statistical Manual of Mental Disorders (15).