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Tracking placental development in health and disease


Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the maldevelopment of a maternal–placental blood supply capable of providing for the growth requirements of the fetus in later pregnancy, without exerting undue stress on maternal body systems. Here, we review normal development of a placental bed with a safe and adequate blood supply and a villous placenta–blood interface from which nutrients and oxygen can be extracted for the growing fetus. We consider disease mechanisms that are intrinsic to the maternal environment, the placenta or the interaction between the two. Systemic signalling from the endocrine placenta targets the maternal endothelium and multiple organs to adjust metabolism for an optimal pregnancy and later lactation. This signalling capacity is skewed when placental damage occurs and can deliver a dangerous pathogenic stimulus. We discuss the placental secretome including glycoproteins, microRNAs and extracellular vesicles as potential biomarkers of disease. Angiomodulatory mediators, currently the only effective biomarkers, are discussed alongside non-invasive imaging approaches to the prediction of disease risk. Identifying the signs of impending pathology early enough to intervene and ameliorate disease in later pregnancy remains a complex and challenging objective.

Key points

  • In the first trimester, uterine secretions support embryonic development; remodelling of the maternal vascular supply to the placental site enables increased volume supply of substrates at low pressure as fetal demand increases.

  • Placental growth and branching of the villous tree yield an increasing surface area for substrate transport, which is coordinated with the elaboration of a fetoplacental vascular network.

  • Fetal growth restriction arises when the supply of nutrients and oxygen to the fetus is insufficient because of maternal vascular malperfusion and/or inefficient extraction of substrates by the placenta.

  • Pre-eclampsia is caused by reaction of the placenta to stress, which triggers the release of factors that induce systemic vascular pathology or suppresses factors that stabilize vascular and immune interfaces.

  • An angiomodulatory imbalance is present in a large proportion of pregnancies with one or more of the clinical features of either pre-eclampsia or fetal growth restriction.

  • Data on many of the potential biomarkers of disease in pregnancy are conflicting, with reports of unchanged, lower or higher levels in the maternal circulation in complicated versus control pregnancies.

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Fig. 1: The placenta and placental bed in the first trimester.
Fig. 2: Steps in normal and failed spiral arterial conversion.
Fig. 3: The near-term placenta and placental bed with spiral arterial pathology.
Fig. 4: Pre-eclampsia and fetal growth restriction — disease aetiology and progression.


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We thank the co-workers in our own groups who have added to our understanding of this field. In summarizing placental development and the evidence for incomplete spiral artery remodelling in disease (especially) we regret being unable to fit in citations to the primary work of many researchers whose contributions were significant.

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J.D.A. made substantial contributions to discussion of content. J.D.A., J.E.M., K.T. and M.W. researched data for the article, wrote the article and carried out review/editing of the manuscript before submission.

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Correspondence to John D. Aplin.

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Nature Reviews Endocrinology thanks B. Huppertz, S. Karumanchi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Covalent epigenetic modifications to the genome that cause genes to be expressed in a parent-of-origin-specific pattern.

Placental villi

Tree-like projections that form the placental exchange surface, and that are the basic functional unit of the placenta, comprising an outer syncytiotrophoblast layer, inner cytotrophoblast layer and a mesenchymal core.


Transformation of endometrial stromal cells that occurs in early pregnancy


The developmental time period between early attachment and gastrulation, or the secondary villous stage in the placenta; it approximates the second week of pregnancy.

Chorionic plate

The disc-shaped, highly vascularized, fetal aspect of the placenta.


The maternal–fetal interface, where maternal blood passes directly over the outer layer of fetal cells in the placenta.

Junctional zone

The tissue layer at the interface between the basal endometrium and the inner myometrium.

Luteal–placental shift

The placenta takes over from the corpus luteum as the major source of oestrogens and progesterone at about 8–9 weeks of pregnancy.

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Aplin, J.D., Myers, J.E., Timms, K. et al. Tracking placental development in health and disease. Nat Rev Endocrinol 16, 479–494 (2020).

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