villous maturation. DNA methylation profiling of placentas at delivery is useful to distinguish among different etiologies underlying PE169 and may be useful in the future development of new screening approaches.
Many imprinted DMRs are tightly maintained in placenta, and thus DNA methylation testing can be used for diagnosis of chromosomal imbalance in the placenta. For example, the parental origin of triploidy or the level of androgenetic cells in samples from placentas with PMD can be diagnosed from DNA methylation ratios at imprinting control regions.171 However, caution should be used in inferring imprinting defects in the fetus from evaluation of DNA methylation at imprinted DMRs in placenta. Some imprinted genes, such as CDKN1C and IGF2, have placental specific promoters,172, 173 and placental imprinted DMRs may differ from somatic ones for a given imprinted gene. Even for those that are maintained, some imprinting defects may arise post‐zygotically and the degree to which the placenta reflects imprinting status in the fetus has not been well established.
DNA methylation analysis is also typically used to evaluate X‐chromosome inactivation (XCI) skewing. It is important to note that XCI evaluation of the placenta cannot be used to infer skewed XCI in fetal tissues, as XCI occurs separately in these two lineages.174 In addition, the inactive X chromosome is incompletely methylated in the placenta and there are extensive site‐to‐site differences in XCI status due to the clonal manner in which villous trees grow,174, 175 precluding use of a single site to infer XCI status of the placenta as a whole.
Epigenetic studies in the placenta and environment
The placenta exhibits a remarkable degree of developmental plasticity.176 By changing structure/cell composition, blood flow, or gene expression, the placenta may adapt to fetal demands for nutrients.177 Compensatory placental growth has been observed in response to reduced maternal nutrition in the first trimester of pregnancy.178 Placental size relative to the fetus is also affected by maternal smoking,178, 179 psychosocial stress during pregnancy,180, 181 and maternal iron levels early in pregnancy.182 Epigenomic analysis offers great promise in providing a record of the combined effects of a variety of in utero environmental exposures, as the epigenome (DNA methylation and histone modifications) can reflect both altered cell composition and changes to gene expression.182 Nonetheless, interpreting epigenomic studies of placenta faces many challenges. As placental size, shape, and function are associated with postnatal health of the baby into adulthood, there is great interest in overcoming these challenges to enhance our ability to assess the placenta to assist in the assessment of newborn health at birth.
The placenta as a predictor of child health
Increasing attention is being paid to the role of the placenta in predicting postnatal health outcomes (see Chapter 5), in particular related to neurodevelopment.183 For example, placental inflammatory lesions have been reported to be associated with autism spectrum disorder.184, 185 Sex differences in brain volume, cortical thickness, and brain connectivity may arise in fetal development;186 links between genetic risk factors for schizophrenia and abnormal placental function have been suggested.185, 187 It has also been suggested that genes and other factors linked to congenital heart disease may be connected to placental development, either because both share common regulatory pathways or because the dynamics of blood flow from the placenta plays an important role in heart development.188 Although the mechanisms linking prenatal events to childhood health are largely unknown, it seems plausible that examining molecular profiles and pathogenic markers in the placenta at delivery may be useful in predicting future risks for childhood and adult disease.
Further considerations
The placenta can be an important hallmark of fetal wellbeing in pregnancy. However, the placenta shows a remarkable degree of normal variability in size, shape, and gene expression. In particular, there may be areas of the placenta showing pathological features, while other areas appear normal. This makes evaluation of the placenta challenging, as the presence of abnormalities may not necessarily affect outcome if there is sufficient healthy placental tissue. A limitation to the use of placental evaluation is also simply a lack of attention paid to the placenta in research and clinical settings, which has impeded progress in utilizing this important resource. As appreciation for the placenta as an important component of fetal development grows, we are optimistic that we will learn to better extract the wealth of information it contains about the genetic makeup and environmental forces that have played a role in the development of the baby.
References
1 1. Bernischke K, Burton GJ, Baerge RN. Pathology of the human placenta, 6th edn. Berlin: Springer‐Verlag, 2012.
2 2. Barker D, Thornburg K. Placental programming of chronic diseases, cancer and lifespan: a review. Placenta 2013; 34:841.
3 3. Burton G, Fowden A. The placenta and developmental programming: balancing fetal nutrient demands with maternal resource allocation. Placenta 2012; 33:S23.
4 4. Haeussner E, Schmitz C, Von Koch F, et al. Birth weight correlates with size but not shape of the normal human placenta. Placenta 2013; 34:574.
5 5. Alwasel S, Abotalib Z, Aljarallah J, et al. Secular increase in placental weight in Saudi Arabia. Placenta 2011; 32:391.
6 6. Maltepe E, Bakardjiev AI, Fisher SJ. The placenta: transcriptional, epigenetic, and physiological integration during development. J Clin Invest 2010; 120:1016.
7 7. Staun‐Ram E, Shalev E. Human trophoblast function during the implantation process. Reprod Biol Endocrinol 2005; 3:56.
8 8. Luo S, Ishibashi O, Ishikawa G, et al. Human villous trophoblasts express and secrete placenta‐specific microRNAs into maternal circulation via exosomes. Biol Reprod 2009; 81:717.
9 9. Mincheva‐Nilsson L, Baranov V. Placenta‐derived exosomes and syncytiotrophoblast microparticles and their role in human reproduction: immune modulation for pregnancy success. Am J Reprod Immunol 2014; 72:440.
10 10. Salomon C, Torres MJ, Kobayashi M, et al. A gestational profile of placental exosomes in maternal plasma and their effects on endothelial cell migration. PLoS One 2014; 9:e98667.
11 11. Xie L, Mouillet J, Chu T, et al. C19MC microRNAs regulate the migration of human trophoblasts. Endocrinology 2014; 155:4975.
12 12. Hassold T, Abruzzo M, Adkins K, et al. Human aneuploidy: incidence, origin, and etiology. Environ Mol Mutagen 1996; 28:167.
13 13. Hassold T, Chen N, Funkhouser J, et al. A cytogenetic study of 1000 spontaneous abortions. Ann Hum Genet 1980; 44:151.
14 14. Blois SM, Sulkowski G, Tirado‐González I, et al. Pregnancy‐specific glycoprotein 1 (PSG1) activates TGF‐β and prevents dextran sodium sulfate (DSS)‐induced colitis in mice. Mucosal Immunol 2014; 7:348.
15 15. Noguer‐Dance M, Abu‐Amero S, Al‐Khtib M, et al. The primate‐specific microRNA gene cluster (C19MC) is imprinted in the placenta. Hum Mol Genet 2010; 19:3566.
16 16. Coughlan C, Ledger W, Wang Q, et al. Recurrent implantation failure: definition and management. Reprod Biomed Online 2014; 28:14.
17 17. PrabhuDas M, Bonney E, Caron K, et al. Immune mechanisms at the maternal‐fetal interface: perspectives and challenges. Nat Immunol 2015; 16:328.
18 18. Roberts VH, Morgan T, Bednarek P, et al. Early first trimester uteroplacental flow and the progressive disintegration of spiral artery plugs: new insights from contrast‐enhanced ultrasound and tissue histopathology. Hum Reprod 2017; 32:2382.
19 19. Wang Y. Vascular biology of the placenta. San Rafael, CA: Morgan & Claypool Life Sciences, 2010:1–98.
20 20. Kingdom J, Huppertz