Fetal circulation and fetal hemoglobin: Considerations for COVID-19

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The anatomic pathway through which blood circulates during fetal life is very different from what happens beginning when the newborn takes her first breath of air. Related to the fetal circulation pathway, the molecule hemoglobin –the protein packed into red blood cells (RBCs) that carries nearly all of the oxygen (O2) and some of the carbon dioxide (CO2) being transported in the blood– differs slightly in the fetus compared with adult hemoglobin. As with many phenomena of pregnancy, we might wonder if these differences hold any significance to COVID-19. The answer is maybe, due to distinct features of hemoglobin and some research that, as of the writing of this post in June, 2020, has yet to be published in a peer reviewed scientific journal, but is nevertheless intriguing.

Since your first question may be what is the deal with fetal circulation, let’s first take a quick look at the standard circulation of blood in adults and children. After supplying body tissues with O2, glucose (blood sugar), and other vital chemicals, and carrying away CO2 and other waste products, blood arrives in the heart’s right atrium (the upper chamber on the right side of the heart). From there, the blood is pumped through a structure called the tricuspid valve into the right ventricle (the lower chamber on the right side of the heart), which sends it through another valve called the pulmonary valve into a large vessel called the pulmonary artery. The pulmonary artery splits into left and right branches, each of which branches into an increasing number of vessels that carry blood through the left and right lungs, respectively. In special capillaries in the lungs’ air sacs, blood releases CO2, which is exhaled, and absorbs O2, then moves into a system of increasingly larger veins that converge into a few (usually four) pulmonary veins that deliver blood to the left atrium (upper chamber in the left side of the heart). When the left atrium contracts, the blood moves through the bicuspid valve, also called the mitral valve, into the left ventricle (the lower chamber on the left side). When the ventricles contract, the blood in the left ventricle moves through the aortic valve into a large vessel called the aorta, from which numerous arteries branch off, supplying body tissues, from which blood returns again to the right atrium, where we began our discussion.

Normally, as blood moves through the heart, there is no mixing between blood on the left and right sides of the heart, because there is a septum dividing the right and left atria and the right and left ventricles. Think of the septum as a wall dividing two rooms, but a wall that has some doors and occasionally also some holes, because the builders went home before finishing the wall. Between the two atria, very commonly, a door called the foramen ovale, that was completely open in fetal life and should have sealed shut in the months after birth was not appropriately shut. In many people, it remains partly opened, or can swing open under certain circumstances. Less often, there is a hole remaining between the atria and still less often a hole between the two ventricles. The reason that we can have these holes and open or swinging doors is that the septum forms gradually throughout pregnancy as the heart develops.

In addition to having the leisure to follow assembly instructions that evolved slowly with our ancestors, from the two-chambered heart of a fish, to the three-chambered heart of an amphibian, and finally to the four-chambered heart that we mammals have in common with reptiles and birds, the gradual development of the heart serves an important physiological function. Since the embryo-fetus has no direct access to the outside air, she must depend on the mother’s lungs, and thus oxygenated blood arrives from the mother’s lungs via the placenta and the umbilical vein. The umbilical vein, in turn, delivers the oxygenated blood into a large vein that carries the blood into the fetal right atrium. Although this fresh blood mixes in the right atrium with blood from other parts of the fetal body that is depleted of O2 and loaded with CO2, it is fresh enough to nourish the fetal body tissues. Since the developing fetal lungs are collapsed with no air to inflate them, pressure in the fetal pulmonary vessels is high. Consequently, when the right ventricle contracts, sending blood into the pulmonary artery, that blood is detoured through a fetal blood vessel called the ductus arteriosus, which leads directly into the fetal aorta. Since blood from the right atrium needs to get into the aorta and bypass the collapsed lungs, it is vital that the ductus arteriosis remains open until birth, but certain common medications, such as ibuprofen can cause the ductus arteries to close during pregnancy, if you take it during the third trimester.

While most of the blood pumped from the right ventricle goes through the ductus arteriosis to the aorta, the right ventricle actually receives only a fraction of the blood from the fetal right atrium during fetal life. The rest of the blood in the right atrium passes through the foramen ovale that leads directly into the left atrium, because its swinging door is open. From the left atrium, the blood is pumped into the fetal aorta, where it mixes with blood arriving from the ductus arteriosus.

To sum up, in the fetus, the foramen ovale and ductus arteriosis work in concert to shunt blood from the right side of the heart to the aorta, and thus to body tissues, without going through the developing, collapsed lungs. This pathway is very different from the post-birth circulation that is probably more familiar to you, but it remains until birth, because the mother breathes for the fetus. O2 comes in through the material lungs, CO2, goes out through the material lungs, and both gases are exchanged back and forth in the placenta, where the maternal blood and the fetal blood never come into physical contact. Rather, each gas diffuses in the needed direction –O2 from the adult hemoglobin within the maternal RBCs to the fetal hemoglobin within the fetal RBCs and CO2 from fetal to maternal blood, carried in a few different ways. For the direction of O2 movement toward the fetus, a couple of things encourage this.

First, due to a beautiful biochemical phenomenon called the Bohr Effect, maternal hemoglobin encountering fetal CO2 in the placenta relaxes its hold on the O2 that it is carrying. At the same time, due to another beautiful biochemical phenomenon called the Haldane effect, fetal hemoglobin encountering O2 in the placenta relaxes its hold on any CO2 that it is carrying. Although hemoglobin only carries a portion of the CO2 in blood, this effect, plus the fact that the maternal blood in the placenta is fresh and thus carrying a lower CO2 load compared with fetal blood, the fetal blood is unloaded of its CO2.

Second, fetal hemoglobin binds O2 more tightly than adult hemoglobin binds it. This happens because of minor differences in one of the two types of protein chains of which hemoglobin is comprised. Each molecule of adult hemoglobin consists of four chains of protein. Two of these chains are called alpha chains and are identical to one another. The other two, called beta chains also are identical to one another but different from the alpha chains. While the embryo-fetus is developing in your womb, its hemoglobin chains are evolving, with some chains acting as forerunners to the adult alpha chains and other chains acting as forerunners to the beta chains. By the end of the fetal period, most of the hemoglobin molecules in a developing human consist of two alpha chains (the same that are present in adult hemoglobin) and two chains called gamma chains, which play the same role in fetal hemoglobin that the beta chains play in adult hemoglobin. The gamma chains are what give fetal hemoglobin its ability to hold grab O2 more strongly than adult hemoglobin grabs it.

The beta chains of hemoglobin are the connection with COVID-19. The reason is that, back in April 2020, researchers published a preprint of a study suggesting that SARS-CoV2 (the virus that causes COVID-19) attacks the hemoglobin beta chain. Being a pre-print, published on a site called MedRxiv (pronounced med archive), the study needs to be reviewed by other scientists and published in an appropriate peer-reviewed journal. Nevertheless, it is interesting as there are issues related to the saturation of hemoglobin with O2 in COVID-19. If it turns out to be true and important to the COVID-19 disease process, in all likelihood, newborns would not be at much risk for this particular effect of the virus, since much of their hemoglobin remains fetal hemoglobin for a long time after birth, when the pathway of blood through the heart and lungs takes its familiar form.

As for how that familiar, post-birth circulation pathway comes to be, a lot of it is stimulated by changes in pressure. When your newborn takes his first breath, suddenly the lungs are inflated, and pressure drops in the pulmonary blood vessels. This enables blood in the pulmonary artery to pass through the lungs, where it is refreshed before entering the pulmonary veins that carry it to the left atrium. Since the ductus arteriosus is narrower than the pulmonary artery, this change results in a sudden increase in the volume of blood entering the left atrium, and from there the left ventricle. Filling of the left ventricle stretches the surrounding muscle, which –through a beautiful biophysical phenomenon called the Frank-Starling mechanism– boosts the force of the contraction the next time the muscle is stimulated to contract. Pressure thus increases in the left ventricle and atrium, while the decreased pressure in the pulmonary vasculature causes pressure on the right side of the heart to decrease as well. Rising pressure on the left side and falling pressure on the right reverses the direction of the pressure difference. As when the wind around an unlatched door changes direction flipping the door the other way, the reversal of pressure between the two sides of the heart flips the foramen ovale closed. Within a few days, the ductus arteriosus closes, and within six months to a year the foramen ovale actually seals itself shut, but sometimes it doesn’t in which case it is capable of swinging back open in pressure change situations that can happen with certain diseases and underwater diving.

David Warmflash
Dr. David Warmflash is a science communicator and physician with a research background in astrobiology and space medicine. He has completed research fellowships at NASA Johnson Space Center, the University of Pennsylvania, and Brandeis University. Since 2002, he has been collaborating with The Planetary Society on experiments helping us to understand the effects of deep space radiation on life forms, and since 2011 has worked nearly full time in medical writing and science journalism. His focus area includes the emergence of new biotechnologies and their impact on biomedicine, public health, and society.

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