Fetal-Maternal Endocrinology and Parturition

Evolution of Human Pregnancy and Birth

Pregnancy is both a personal event between mother and baby and a sociological and public health concern, as is evidenced by high infant and maternal mortality rates, even in developed countries like the United States. Although scientific advances have allowed us to learn about potential causes of preterm birth and pregnancy complications, it is critical to look back, through an evolutionary lens, to more fully understand the process of pregnancy and birth.

Evolution optimizes reproductive fitness across generations—maximizing transmission of genes to the next generation. Pregnancy and parturition are key events in the reproduction of viviparous species and, as such, would have been subjected to strong selective pressure through evolution. Advances in genetic technologies allow in-depth examination of the influence of evolutionary dynamics on pregnancy—including the impact of genetics and hormones on conception, pregnancy maintenance, and triggers for parturition. Ultimately, genetic makeup reflects natural selection and, as such, evolutionary adaptations may contribute to extant pregnancy complications, because the current genetic makeup of the mother, or even the baby, may not be ideal for current environmental conditions. This mismatch may be the reason for diseases of pregnancy, such as preeclampsia and gestational diabetes—and, in fact, likely influences health throughout the life span.

“Nothing in biology makes sense except in light of evolution,” said geneticist and evolutionary biologist Theodosius Dobzhansky. This concept is certainly reflected in the comparative biology of pregnancy and parturition among viviparous species. The common theme among viviparous species is that the fetal development requires a minimum gestation time and a supply of nutrients for the fetus to achieve functional maturity needed to survive as a neonate. Fetal organ systems (especially the pulmonary, renal, and gastrointestinal) and neuroendocrine axes (especially the hypothalamic-pituitary-adrenal [HPA] and thyroid systems) must be sufficiently developed at birth for the newborn to achieve and maintain homeostasis. Similarly, maternal physiology, which has been modified to provision pregnancy, must be prepared to nurture and protect the newborn. Certain processes are common (e.g., the requirement for progesterone to establish and maintain pregnancy; the promotion of fetal organ maturation by glucocorticoids) to all species, but subtle differences exist that relate to specific selective pressures on pregnancy-related traits that improved reproductive efficiency against the backdrop of general habitus, environmental niche, and overall reproductive strategy.

Viewing conception through an evolutionary lens begs the question: Why doesn’t the mother’s immune system attack the fetus? The “inflammation paradox” hypothesis posits that inflammation may be a necessary process that evolved to aid implantation, rather than attack the fetus. This is just one part of the equilibrium that must be established in a healthy pregnancy between the needs of the mother and the needs of the fetus. This concept has been described as maternal-fetal “cross-talk,” “tug-of-war,” or a “modulation” of gene regulation or cell networks. This often-conflicting cadence between mother and fetus continues throughout pregnancy, highlighting nutritional needs and hormonal fluctuations that must remain balanced for a successful pregnancy to carry to term. Recent studies of individual cells at the maternal-fetal interface have identified regulatory interactions at the cell level between the mother and fetus that prevent immune cell attack of the conceptus. Through an evolutionary framework, preeclampsia, for example, could be the result of shallow trophoblast invasion and inadequate spiral artery remodeling—forcing the fetus to increase maternal blood flow to the placenta by increasing maternal peripheral vascular resistance and providing greater blood flow to the fetal interface.

Another “obstetric dilemma” is conferred by the combined traits of encephalization: the increase in brain mass relative to body mass that is unique to hominid lineages, and obligate bipedalism. Bipedalism evolved between 3 to 5 million years ago, leading to an increase in hominid brain size, estimated at about 1 million years ago. The size of the human brain has remained relatively constant for at least the last 100,000 years. Obligate bipedalism required changes in the pelvic anatomy that decreased the size of the obstetric outlet. This would have limited the extent of intrauterine encephalization and required that parturition occur before the fetal head becomes larger than the pelvic outlet. This trait appears to be unique among human lineages. No other primates face this level of cephalopelvic disproportion, as they have pelvic openings that are larger than the fetal head diameter. Women, however, must pass a large-headed fetus through a relatively small pelvic opening. This means that the fetus cannot grow too large, or it risks death for the baby and the mother. Evolutionary selection of ancestral lineages must have been at work to develop a gestation length optimal for fetal development, especially lung maturity, before parturition. In addition, recent research has found regional and ancestral variability in the shape of birth canal. Strict evolutionary theory might surmise that the birth canal should be similarly shaped. Instead, this new work shows that other evolutionary forces, such as genetic drift, migration patterns, or even climatic adaptation also may have been at work. Study authors Lia Betti and Andrea Manica state that thoroughly understanding this has implications for obstetric practice in multiethnic societies.

Rapid fetal brain growth requires substantial energy, and therefore traits that increase energy transfer from the mother to the fetus would have been favored. This may explain the production of placental lactogen and placenta growth hormone (GH) that promote maternal insulin resistance, providing more glucose for fetal consumption. However, traits that favored fetal brain growth would have conflicted with the problem of birthing a large-headed fetus through a relatively small outlet. This problem may have been solved by altering the parturition timing mechanism to shorten gestation thereby avoiding the obstetric dilemma . Allometric analyses of neonatal brain size to body ratios across primate species, and the fact that human neonates are altricial (referred to as secondary altriciality ), whereas other extant primates are precocial, support the hypothesis that gestation was shortened in modern-day hominids. This is a reasonable hypothesis that explains much of the unique characteristics of human pregnancy and parturition. As natural selection generally operates at the population level and over many generations, traits that increase reproductive efficiency of the population (such as encephalization; fetal neuroendocrine plasticity) and are beneficial over the long term, may impart costs to an individual, such as increased risk for preterm birth or cardiovascular disease over the short term.

Consideration of these traits through an evolutionary lens expands our perspective of pregnancy complications, such as preeclampsia, fetal growth restriction, gestational diabetes, and preterm birth, and normal processes, such as the plasticity of fetal neuroendocrine development in response to environmental cues.

Establishment of Pregnancy

Under normal circumstances, implantation of a viable embryo into a receptive uterine endometrium establishes pregnancy. During the menstrual cycle, the ovarian steroid hormones, estradiol and progesterone, induce structural and functional changes in the endometrium essential for the establishment of pregnancy. During the luteal phase, the endometrium converts to a secretory phenotype in response primarily to progesterone produced by the corpus luteum (CL). The secretory endometrium is spongy and highly vascularized and has a glandular epithelium that secretes factors into the uterus that favors embryo survival. At the same time, epithelial cells in the endometrium produce chemokines, growth factors, and cell adhesion molecules that attract the embryo to specific docking sites for implantation and, in addition, increased vascularization of the endometrial stroma provides an optimal substrate for placentation.

After fertilization, the zygote undergoes an intrinsic program of cell division and differentiation that is not dependent on the hormonal milieu of the fallopian tube or the uterus. At around the fourth day after fertilization, the embryo is a solid cluster of cells encapsulated by the remnant of the oocyte zona pellucida. In the next 24 to 48 hours, as the embryo moves through the fallopian tube toward the uterus, it develops a fluid-filled cavity, the blastocele, and is referred to as a blastocyst . The outer layer of blastocyst cells, known as the trophectoderm , will give rise to the placenta and chorionic membrane. An inner cell mass of the blastocyst will produce the fetus, amnion, and mesenchymal and vascular components of the placenta. The human blastocyst enters the uterus at around the fifth day after fertilization and floats freely in the uterine cavity for 2 to 3 days. By this stage, the zona pellucida degenerates, leaving the nascent blastocyst embryo in an optimal condition to implant into the endometrium.

Embryo implantation into the endometrium has temporal and spatial limits within the receptive uterus. Physical interaction of the blastocyst with the endometrial epithelium occurs at dome-like structures known as pinopodes that express chemokines and cell adhesion molecules that attract the embryo and appear to be the preferred site for embryo adherence and subsequent implantation. Embryo adherence and implantation is most successful between days 21 and 24 of the menstrual cycle (~ 85% success rate), whereas implantation before or after this optimal window has a low (~ 11%) success rate. After day 24 to 25, the endometrial stroma undergoes morphologic and functional changes collectively referred to as decidualization , which is dependent on progesterone and occurs independently of conception and implantation. The decidualized endometrium, composed of large polyhedral cells, containing high levels of glycogen and lipids that secrete a tough pericellular capsule, is hostile to implantation. Therefore successful implantation must occur before the establishment of the decidual barrier. In an infertile cycle, menstruation occurs to eliminate the nonreceptive decidualized endometrium. In the subsequent cycle, the endometrium then renews to a receptive state.

For implantation, trophoblast cells proliferate and secrete proteases that degrade the extracellular matrix between endometrial cells forming a path for the blastocyst to enter the uterine stroma. The invading trophoblast cells are referred to as cytotrophoblasts ( CTBs ) and form columns penetrating to the basal membrane beneath the decidual cells and into the myometrium. Eventually, the entire embryo embeds in the uterine stroma, anchored by CTB columns. Some extravillous CTBs invade into maternal spiral arterioles, displacing endothelial cells and smooth muscle tissue, and dilating the vessels to create a low-resistance arteriolar system. This system directs maternal blood into spaces, known as lacunae , between the invading columns of CTB cells. During this time, some CTBs fuse their plasma membranes to become a syncytiotrophoblast . This becomes the outer layer of the functional placenta. Eventually, the syncytiotrophoblast forms schorionic villi that are bathed in maternal blood within the lacunae.

The embryo is semiallogeneic with respect to the mother, and therefore its invasion into the endometrium represents a major breach of the maternal immune system. For successful pregnancy, the placental syncytiotrophoblast and CTBs at the maternal-fetal interface must avoid attack and destruction by activated maternal immune cells. To this end, the trophoblast cells produce an immunogenic camouflage in the form of human leukocyte antigen (HLA)-G that has reduced polymorphism; therefore maternal immune cells do not recognize it as foreign. CTBs also express multiple factors: Fas ligand that induces apoptosis in immune cells that carry Fas receptor, early pregnancy factor, and the progesterone-induced blocking factor that blocks lytic natural killer (NK) cell activity and several antiinflammatory cytokines (such as transforming growth factor [TGF]-ß, interleukin [IL]-10, IL-4).

For the establishment of pregnancy, menstruation that normally occurs during a nonfertile cycle must be prevented. This happens when the trophoblastic cells of the early embryo secrete chorionic gonadotropin (CG) that prevents CL regression and maintains its secretion of progesterone. In nonfertile cycles, the CL usually regresses at about the second week after ovulation, and the subsequent decline in progesterone leads to menstruation. Thus one of the first endocrine interactions between the conceptus and the mother involves early embryo signaling to promote intrauterine conditions that will allow implantation and the establishment of pregnancy via maintenance of CL progesterone secretion.

Endocrine Placenta: Structure and Function

The placenta fulfills a variety of essential functions during prenatal life. Its global role is to maintain a protected environment that facilitates optimal growth and development of the embryo and fetus. The human, hemochorial placenta includes a chorionic plate and chorionic villi. The chorionic villi consist of stem villi (types 1 to 3) either anchored to the decidua basalis or floating free. Type 3 villi branch out into intermediate and finally terminal villi. The surface of the terminal villi is covered in CTB progenitor cells, derived from the trophectoderm of the early blastocyst, and anchored to a basal lamina. The low oxygen environment of the early placenta protects organogenesis and favors CTB proliferation. However, as development progresses, differentiation of these trophoblast progenitor cells produces different cell phenotypes.

CTBs differentiate into an invasive phenotype, and extravillous trophoblasts (EVTs) invade the uterine wall anchoring some chorionic villi to the decidua basalis entering the maternal blood vessels. These invading CTBs plug maternal arterioles maintaining the state of physiological hypoxia. EVTs continue to move further up maternal spiral arterioles, replacing maternal endothelial cells, remodeling, and increasing the diameter of the arterioles to accommodate the massive increase in blood supply required for fetal growth. Furthermore, several maternal cell types maintain the balance between inflammation and tolerance in the decidua. In particular, innate lymphoid cells, such as NK cells, interact with trophoblasts, stromal cells, and neutrophils to play a key role in the induction and maintenance of pregnancy. Decidual NKs represent 50% to 70% of infiltrating lymphocytes during the first trimester, but numbers diminish throughout gestation. Decidual NK cells are involved in early remodeling of the maternal spiral arteries before trophoblast invasion, as well as secreting chemoattractant factors critical for EVT migration and invasion (such as IL-8, CXCL10, and IL-6). An association exists between impaired trophoblast chemotaxis and improper spiral artery remodeling and abnormal placentation. Abnormal decidual NK (dNK) function also may lead to a loss of control of trophoblast invasion.

During this time, some CTBs fuse their plasma membranes to become a single multinucleated cell known as the syncytiotrophoblast , which becomes the outer layer of the functional placenta. By 10 to 12 weeks of gestation, the CTB plugs are broken down and maternal blood reaches the intervillous spaces (lacunae), resulting in a change in oxygen tension in the placenta and the syncytiotrophoblast comes into direct contact with maternal blood in the lacunae. Remodeling of the placental villi and their associated underlying vasculature, which connects to the umbilical cord, occurs throughout gestation and can be responsive to maternal signals/environmental exposures impacting placental function, fetal growth, and development, and potentially, disease development later in childhood and adulthood (a process known as fetal programming ).

The placental syncytiotrophoblast facilitates oxygen and nutrient transfer from the maternal circulation to the fetus and disposes of fetal waste products. It synthesizes and secretes hormones, growth factors, cytokines, and other bioactive molecules mainly into the maternal compartment. It also metabolizes maternal hormones (such as glucocorticoid and insulin) to prevent fetal exposure, and thus, separates components of the maternal and fetal endocrine systems. Importantly, the hemochorial arrangement allows hormones produced by the syncytiotrophoblast to directly access the maternal circulation. In contrast, the syncytiotrophoblast prevents most maternal hormones from entering the fetal compartment. Most hormones the placenta produces are identical, or close structural and functional homologues, of existing maternal hormones. As such, they interact with cognate receptors on maternal cells. Consequently, placental hormones that are secreted in relatively large amounts to achieve high levels (compared with levels in the nonpregnant women) in the maternal circulation override maternal counterparts and have profound effects on maternal physiology. Placental hormones include members of the prolactin and GH family, steroid hormones, and neuroactive hormones.