Genetic Disorders and the Fetus. Группа авторов
(0.1–2 μm) and exosomes (30–100 nm), are released by the placental syncytium into maternal decidua and blood and may play a role in early maternal immune suppression and vascular remodeling.8–11 These microparticles provide a rich source of placental derived material detectable in maternal blood early in pregnancy that has the potential to be used in monitoring the pregnancy.
Failure of implantation and invasion can lead to early miscarriage. The majority of miscarriages occurring in the first trimester of pregnancy are associated with chromosome abnormalities, with trisomy, triploidy, and 45,X accounting for the vast majority of these.12, 13 The reasons for implantation failure in chromosomally abnormal cases are likely complex, involving dysregulation of multiple important genes that then impede trophoblast growth and invasion. Trisomy for chromosomes 1, 11, and 19 are rarely observed even in early miscarriages, and presumably do not survive to clinical detection of pregnancy. Chromosome 19 not only has the highest gene density of any chromosome, but is sometimes referred to as the “placenta chromosome” because of the numerous placenta‐specific genes located on it, including the highly expressed pregnancy‐specific glycoprotein cluster (PSG),14 and the maternally imprinted chromosome 19 miRNA cluster (C19MC), the largest microRNA cluster in humans.15 Failure of implantation among genetically normal conceptuses can be due to a nonreceptive maternal environment resulting from disturbances in maternal hormone levels, immune health, anatomical interference, or a variety of maternal health conditions.16
Angiogenesis
Placental angiogenesis and vasculogenesis serves to increase both uterine (maternal) and umbilical (fetal) blood flow. This process is dependent on a balance between pro‐ and antiangiogenic factors.17 Early in pregnancy, EVTs invade and plug the maternal uterine arteries, helping to maintain a low‐oxygen environment needed for trophoblast proliferation.18 Trophoblast cells (eCTBs) also migrate along the lumina of spiral arterioles, replacing the maternal endothelial lining. This expands the diameter of the maternal vessels and, in combination with gradual disintegration of the spiral artery plugs, results in a dramatic increase in blood flow after 12 weeks gestational age, which is needed to support fetal growth later in pregnancy. In turn, placental vasculature develops, and increases throughout gestation as the needs of the fetus grow.19 FGR can result from poor spiral artery remodeling or reduced vascular development within the placenta. Furthermore, insufficient remodeling of the maternal spiral arteries can result in a prolonged state of hypoxia and increased reoxygenation stress. This leads to increased syncytiotrophoblast apoptosis and necrosis, causing increased debris circulating in the maternal blood that has been associated with maternal PE.20 In addition to FGR and PE, abnormal spiral artery remodeling has been associated with placental abruption, preterm premature rupture of membranes, and intrauterine fetal death.21
Nutrient delivery
Fetal growth is dependent on efficient nutrient delivery to the fetus. This is determined by maternal availability, maternal blood flow to the placenta, the amount of placental surface in contact with maternal blood, and the efficiency of placental transport.22, 23 Transport of substances across the placenta can occur by (i) passive transport (simple or facilitated diffusion); (ii) active transport; and (iii) vesicular transport, by which large molecules are captured by microvesicles. A well‐functioning placenta can be extremely efficient at extracting nutrients for the fetus even when maternal supplies are low. For example, there is a threefold increase in folate concentration in the placenta compared with maternal blood;24 this is accomplished via several folate receptors highly expressed in the human placenta, including folate receptor 1 (FOLR1), proton‐coupled high‐affinity folate transporter (PCFT), and reduced folate carrier (RFC).25 As the fetus grows and requires more nutrients, the placenta alters gene expression to increase nutrient supply to the fetus;26 for example, upregulation of System A transporters can increase delivery of amino acids.3, 27 There is also an increase in iron transport proteins, which absorb iron from maternal blood,28 and of placental CRH, which increases the production of maternal glucose needed to support the growing fetal brain.29 One pathway by which increased cortisol can lead to growth restriction is by interfering with CRH‐driven glucose production.29
Immune function
The placenta employs a number of mechanisms that protect the embryo/fetus from infection. Genes involved in immune regulation are among the most differentially expressed30, 31 and differentially methylated32 in the placenta across different gestational ages. The human placenta is not only the source of hematopoiesis early in pregnancy, but remains a hematopoietic organ throughout gestation.33, 34 The placenta also contains a large number of Hofbauer cells (placental macrophages), which may play roles in placental angiogenesis and prevent pathogens crossing from mother to fetus.35 Exosomes and microvesicles also appear to provide protection against viruses, which may be partially attributable to transmission of members of the chromosome 19 placenta‐specific paternally expressed microRNA cluster (C19MC).36 Understanding how the placenta protects from infection is an important question in the study of preterm birth (PTB). Chorioamnionitis (CA), or intra‐amniotic infection, an inflammation of the chorion and amnion usually caused by bacterial infection, is associated with the majority of extremely (<28 weeks) PTBs and about 16 percent of PTBs at 34 weeks.37, 38 Genetic variants that modify the maternal or fetal immune response have been linked to risk for PTB and/or PTL39, 40 possibly by disrupting cytokine balance (e.g. IL‐6 : IL‐10 ratio).41
Placental insufficiency
Placental insufficiency is the situation whereby the placenta does not deliver an adequate supply of nutrients and oxygen to the growing fetus. It is associated with adverse pregnancy outcomes, including FGR, maternal PE, and PTB. Constitutional chromosomal abnormalities such as triploidy, trisomy 13, or trisomy 18 are commonly associated with placental insufficiency, but would normally be diagnosed through amniocentesis or fetal abnormalities detectable on ultrasound. The most common known genetic cause of FGR in an otherwise normally developed fetus with normal chromosomes at amniocentesis is confined placental mosaicism (CPM) (discussed further in “Developmental considerations in confined placental mosaicism”). Genomic imbalance (i.e. altered ratio of maternal and paternal haploid genomes) is also associated with a variety of adverse pregnancy outcomes. Epigenetic changes can be observed in placentas from complicated pregnancies, though these are more likely consequences than causes of placental pathology.
Fetal growth restriction
FGR, also referred to as intrauterine growth restriction (IUGR), is defined as poor fetal growth due to an underlying pathological cause. Although small for gestational age (SGA) (birthweight <10th percentile) is sometimes used as a surrogate for FGR, the majority of SGA fetuses are healthy.42, 43 FGR represents 10–50 percent of SGA fetuses, with this proportion being dependent upon the population being studied and which growth curves are applied.42, 43 Distinguishing FGR from a constitutionally small baby prenatally is important, as it is specifically the FGR baby that is at risk of adverse perinatal outcomes, including intrauterine death, premature birth, neonatal sepsis, and neurological impairment.44–46 Placental FGR is also a risk factor for adult‐onset diseases such as diabetes, hypertension, and cardiovascular disease.47
To diagnose FGR prenatally, fetuses with abdominal circumference <10th percentile can be further assessed by uterine and umbilical artery Doppler to check for impeded blood flow to the placenta or fetus, amniotic fluid index, and other signs of fetal compromise (see Chapter 17). Altered protein levels in maternal serum have been associated with FGR caused by placental insufficiency, including lower levels of PlGF and increased levels of soluble