The placenta: structure, function and disorders

The placenta has been called the most important organ of the body and, paradoxically, the most poorly understood. During its short existence it takes on tasks later carried out by the lungs, liver, gut, kidneys and endocrine glands. Its central job is to supply the fetus, and above all the growing fetal brain, with oxygen and nutrients, while also producing hormones that reshape the mother’s metabolism. The placenta is a fetal organ: it grows from the outer cell layer of the early embryo, described on the page on early embryo development and implantation.

Many ways to build a placenta

Placentas vary greatly between mammal species, and comparative work has long been a strength of reproductive biology. A classic way of sorting them is by how deeply the fetal tissue, the trophoblast, penetrates the mother’s tissues:

• Epitheliochorial placentas, such as that of the sheep, involve little or no invasion: the fetal tissue rests against the intact lining of the uterus.
• Endotheliochorial placentas also limit invasion, stopping short of direct contact with maternal blood.
• Haemochorial placentas, found in humans and the great apes, place maternal blood in direct contact with the trophoblast surface.

These differences have practical consequences. The human placenta lets through dissolved molecules of roughly 1 350 to 5 200 daltons, while the sheep placenta restricts molecules above about 400 daltons. Because placental types vary so much, animal models have been of limited use for understanding human placental development, and newer tools such as three-dimensional trophoblast organoids, stem cell cultures and single-cell RNA sequencing are now being used to study it directly.

Anatomy of the human placenta

At term the human placenta averages about 22 cm across, 2.5 cm thick at the centre and roughly 500 g. Inside, 30 to 40 highly branched villous trees of fetal tissue project into a space filled with maternal blood. Their terminal branches offer an exchange surface of 12 to 14 square metres, and in places the distance separating maternal and fetal blood shrinks to 2 to 3 micrometres. Over the course of pregnancy the placenta develops a network of fetal blood vessels more than 500 km long.

The villi are covered by the syncytiotrophoblast, a single continuous layer containing many nuclei, which grows as underlying progenitor cells, the cytotrophoblast, fuse into it. A striking discovery published in 2000 showed that a protein involved in this fusion, named syncytin, is encoded by the envelope gene of a human endogenous retrovirus, HERV-W: a viral gene that has been captured and put to work in human placental development.

Early pregnancy and the remodelling of maternal arteries

In the first trimester, the embryo is nourished largely by secretions from the uterine glands, in a low-oxygen environment; the maternal blood circulation to the placenta becomes fully established only at the end of the first trimester. Meanwhile a population of invasive extravillous trophoblast cells moves into the uterine wall and remodels the spiral arteries that supply the placenta. Modelling suggests that this remodelling lowers the speed of maternal blood entering the placenta by about tenfold, protecting the delicate villi.

This invasion takes place in the decidua, the transformed uterine lining, which is dominated by a distinctive type of immune cell, the uterine natural killer (uNK) cell. Extravillous trophoblast cells carry an unusual set of tissue-type molecules, including HLA-C, HLA-E and HLA-G, which uNK cells can recognise. Current thinking holds that uNK cells cooperate with trophoblast to ensure correct arterial remodelling. Genetic studies have linked certain combinations of maternal NK cell receptors and paternally inherited fetal HLA-C variants to a higher risk of pre-eclampsia, although the researchers describe these findings as preliminary. The wider immunological questions of pregnancy are discussed on the page on pregnancy, birth and maternal–fetal immunology.

Hormones and the placental barrier

The placenta is also an endocrine organ. The syncytiotrophoblast secretes a family of placental lactogens and a placental form of growth hormone, which, together with progesterone, help the mother first build up energy reserves and later release them to support fetal growth and breastfeeding. The placenta also acts as a selective barrier. Its surface carries enzymes and transporters that handle foreign chemicals, and an enzyme called 11β-HSD2 converts much of the mother’s cortisol into inactive cortisone, limiting the fetus’s exposure to stress hormones. Its hormones also act on the mother’s behaviour: progesterone and placental lactogen both stimulate appetite. Unlike the pituitary hormone, which is released in pulses, placental growth hormone is secreted continuously by the syncytiotrophoblast. Changes in this enzyme have been studied in connection with developmental programming, the idea that conditions before birth affect health later in life.

When placentation goes wrong

Defective formation of the placenta underlies common pregnancy disorders, notably pre-eclampsia and fetal growth restriction. According to the World Health Organization, pre-eclampsia affects 3 to 8% of women who give birth worldwide. It typically begins after 20 weeks of pregnancy and is diagnosed by high blood pressure together with protein in the urine. Hypertensive disorders of pregnancy account for about 16% of maternal deaths worldwide.

Among pregnancy complications, the mechanistic link with deficient remodelling of the spiral arteries is considered strongest for pre-eclampsia. Why the condition is almost unique to humans is still debated: one proposal is that the demands of upright posture on blood flow, combined with the immune interactions involved in arterial remodelling, represent a trade-off for supporting a large fetal brain. Fetal growth restriction, in which the fetus fails to reach its growth potential, is likewise rooted in defective placental formation. Which early events trigger pre-eclampsia in an individual pregnancy, how uNK cells and trophoblast communicate in detail, and how findings from new laboratory models of the human placenta translate to real pregnancies remain open questions.