To appreciate why it might be advantageous for the fetus to be responsive to maternal state, rather than to entirely buffer the fetus behind an impervious placental/uterine barrier, it is informative to discuss a few zoological examples. Our story did not begin with humans or even mammals and viviparity. We know from observations of egg-laying species that environmental conditions during incubation can be extremely influential. Ambient temperature affects not only the rate of development, but can even change the sex of the developing fetus in some oviparous fish and reptile species (Crews and Bull, 2008). Among birds, the egg-laying female will often vary nutrient and hormone concentrations across her clutch on the basis of the sequential order in which the eggs are laid (Cariello et al, 2006; Royle et al, 2001). Other important lessons about the extent of flexibility in fetal development can be garnered from the marsupial species. They have an extremely short gestation and a joey is born essentially midstream in the fetal state, continuing the rest of its maturation on the nipple within a pouch. These transitional animals include the wallabies and kangaroos with females that can have three offspring simultaneously, each in a different maturational stage. She can maintain one embryo in her reproductive tract in arrested diapause (or signal it to implant), while at the same time controlling the rate of the joey's growth within the pouch by varying the nutrient quality of her milk (Trott et al, 2003). She can further modify the lipid composition and caloric level in one nipple for this immature joey and in her second nipple for the larger infant already mobile and spending most of its time outside the pouch.
Given these examples from reptiles, birds, and marsupials, it is perhaps not too surprising to discover that uterine conditions continued to matter in the eutherian mammals, including ourselves. In fact, as the period of internal development became more extended, there was even greater opportunity for maternal factors and experiential events during pregnancy to shape the course of fetal maturation (Kaiser and Sachser, 2009). In addition, the placenta evolved to become more invasive and to facilitate more intimate support and communication with the fetus (Wildman et al, 2006). Among the species that have a hemochorial placenta, which includes the monkeys, apes, and humans, the barrier between maternal and fetal blood is considerably reduced, allowing for a ready exchange of proteins and even the periodic crossing of cells (in contrast to the greater separation that occurs with the epitheliochorial placenta of farm animals and prosimians).
To appreciate the implications of these types of evolutionary trends for pediatric health, one can look to the progressive changes in how antibody is transferred across the placenta from mother to the infant. Most mammalian species with altricial young provide maternal antibody primarily in breast milk postnatally. However, the higher primates including humans largely transfer immunoglobulin G (IgG) prenatally via the placenta before birth (Coe et al, 1994). This important immune process confers passive protection against bacteria and viruses encountered previously by the mother, enabling the infant to evade disease and to not have to produce substantial amounts of its own antibody for several months after birth. The immunoglobulin found in human milk is predominantly of the IgA class and functions instead to coat the mucosal surfaces of the baby's oral cavity and gut, very distinct from the prenatal bolus of IgG conveying a memory of prior pathogens encountered previously during the mother's life.
Along with the placental transfer of antibody, there is also a transmission of many anti-genic proteins, a second process that becomes important to appreciate when trying to understand why some human babies are born already sensitized to food allergens and plant pollens (Liobichler et al, 2002). The fetal response to these proteins that become embedded in placen-tal tissues or transfer into the fetal compartment helps one to predict which infants will go on to develop atopic dermatitis and asthma. Less frequently there may also be some problematic antibody from the mother transferred as well, which can result in maternal-fetal incompatibilities. One example is the maternal immune reaction against paternal antigens on fetal cells, such as to Rhesus factor. Another hypothesized problem is the transfer of maternal antibody that reacts against the maturing brain tissue in the otherwise healthy fetus, which has been postulated as a putative cause of some types of autism (Braunschweig et al, 2009; Singer et al, 2009).
From the vantage point of evolutionary biology, one can argue further that some degree of maternal regulation over fetal development is for the most part beneficial, providing the mother with control over her investment and reproductive success. Under extreme conditions, including high levels of stress or following viral and bacterial infections, some species respond by embryo resorption, miscarrying, or even sacrificing a more mature fetus via premature delivery. Within the animal kingdom, even this fetal loss seems to serve an adaptive purpose, permitting the female to rear other viable offspring at optimal times when the chances of raising an infant to adulthood would be more successful. In fact, if one closely reads articles on pregnancy in mice and rats, it is not uncommon to see such compromises made within a single litter. After a stressful experimental manipulation or virulent infection, the gravid female often reduces her litter size (Fatemi et al, 2008). A vestige of this type of selection process may carry-over as a legacy to our own species, when one considers that bacterial infections during pregnancy or in the placental tissue (e.g., chorioamnionitis) are still major risk factors for premature delivery (Hiller et al, 1995). In fact, a rise in proinflamma-tory cytokines, especially tumor necrosis factor (TNF), in the third trimester is a major cause of prematurity (Rigo et al, 2004). In the clinical literature, high blood levels of TNF are one of the more sensitive diagnostic biomarkers of obstetrical risk (Menon et al, 2006).
It is important to emphasize that this communication between mother and fetus is bidirectional with an equivalent number of benefits from the fetal perspective. Many physiological changes that occur in a gravid female are actually induced by the placenta and fetus, such as the markedly increased estrogen and progesterone in maternal circulation that sustains the pregnancy. In the case of estrogen, the placenta is the primary source of the elevated hormone levels, not the mother's ovary, and the precursor of the placental estrogen in humans and other primate species is the dehydroepiandrosterone (DHEA) produced by the fetal adrenal (Rainey et al, 2004). Thus, it makes sense that the fetus should be responsive to feedback signals about hormone levels from the maternal compartment. Moreover, the fetus is not just a passive recipient of resources from the mother. Receptor levels on the placenta can be adjusted, as evinced by the placental Fc receptors for IgG, which increase during the final month of pregnancy and actively accelerate the transfer of maternal antibody (Coe et al, 1993). Even more dynamically, when a fetus is confronted with a low level of iron transfer during an anemic pregnancy, the transferrin receptors on the placental surface are upregulated, which serves to enhance the binding of iron in the mother's blood stream (Rao and Georgieff, 2002; see also Fig. 35.4). Finally, another benefit to the fetus of being responsive to environmental and maternal cues is that many of its maturing physiological systems, including the brain and immune system, require some priming to develop appropriately. In a real sense, they should already be thought of as 'learning systems,' even during the fetal period. The information crossing the placenta presages what will be experienced in short order when the neonate encounters the postnatal world. In this way, the infant has already taken important steps in preparing to appropriately pace its growth rate and regulate its energy expenditure in keeping with the likely acquisition of nutrients (Wintour et al, 2003).
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