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Placenta: How it works, what's normal

The placenta plays a crucial role during pregnancy. Find out what the placenta does, issues that might affect it and how it is delivered.

If you're pregnant, you might wonder what exactly the placenta is, what it does and what might affect it. Here's what you need to know about this important organ.

What does the placenta do?

The placenta is an organ that forms in the womb, also called the uterus, during pregnancy. The placenta is connected to a developing baby by a tubelike structure called the umbilical cord. Through the umbilical cord, the placenta provides oxygen and nutrients to a developing baby. It also removes waste from the baby's blood.

The placenta is attached to the wall of the uterus. Most often, it attaches to the top, side, front or back of the uterus. Rarely, it might attach in the lower area of the uterus. When this happens, the placenta may block the passage that connects the uterus to the vagina, called the cervix. If the placenta is near the opening of the cervix, it's known as a low-lying placenta. If it partly or totally covers the opening of the cervix, it causes a condition called placenta previa.

What affects the health of the placenta?

Various factors can affect the health of the placenta, including:

• Age of the pregnant person. Some conditions that affect the placenta are more common in older people, especially after age 40.
• Water breaking before labor. During pregnancy, the developing baby is surrounded and cushioned by a fluid-filled layer of tissue called the amniotic sac. If the sac leaks or breaks before labor starts, it's known as the water breaking. This raises the risk of problems with the placenta.
• High blood pressure. This condition can cause less blood to reach the placenta.
• Being pregnant with twins or other multiples. Being pregnant with more than one baby might raise the risk of some conditions related to the placenta.
• Blood-clotting conditions. Typically, blood hardens into a clump to help control bleeding from cuts. This process is called clotting. Sometimes, blood clots form inside the body and lead to medical problems. Conditions that cause blood to clot too little or too much raise the risk of some conditions related to the placenta.
• Past surgery on the uterus. C-section, surgery to remove tumors called fibroids and other uterine surgeries raise the risk of some conditions that affect the placenta.
• Previous conditions that affected the placenta. The risk of having medical issues with the placenta might be higher if you had problems with the placenta during a past pregnancy.
• Substance use. Some conditions that can affect the placenta are more common in pregnant people who smoke or use cocaine.
• Injury to the stomach area. A blow to the stomach area makes the placenta more likely to separate from the uterus too soon. Risk factors include trauma from a car accident or a serious fall.

What are the most common conditions and concerns?

Placental abruption

The placenta is a structure that develops in the uterus during pregnancy. Placental abruption occurs when the placenta separates from the inner wall of the uterus before birth. Placental abruption can deprive the baby of oxygen and nutrients and cause heavy bleeding in the pregnant person. In some people, early delivery is needed.

Placenta previa

The placenta is a structure that develops in the uterus during pregnancy. In most pregnancies, the placenta is located at the top or side of the uterus. In placenta previa, the placenta is located low in the uterus. The placenta might partially or completely cover the cervix, as shown here. Placenta previa can cause severe bleeding in a pregnant person before or during delivery. A C-section often is needed.

Conditions that can affect the placenta include:

• Placental abruption. This is when the placenta partly or completely peels away from the inner wall of the uterus before delivery. With placental abruption, the developing baby might not get enough oxygen and nutrients. The pregnant person might have back or stomach pain and bleeding from the vagina. Placental abruption can lead to an emergency in which a baby needs to be delivered early.

Placenta previa. This condition happens when the placenta partly or totally covers the cervix. Placenta previa is more common early in pregnancy. It might get better on its own as the uterus grows.

Placenta previa can cause serious vaginal bleeding during pregnancy or delivery. Treatment depends on various factors. They include the amount of bleeding, whether bleeding stops, how far along the pregnancy is and the placenta's position. If placenta previa continues late into the pregnancy, a healthcare professional likely will recommend a C-section.

Placenta accreta. Most often, the placenta separates from the wall of the uterus after childbirth. With placenta accreta, part or all of the placenta stays firmly attached to the uterus. This condition happens when the blood vessels and other parts of the placenta grow into the uterine wall. This can cause serious blood loss during delivery.

Sometimes, the placenta invades well into the muscles of the uterus or grows through the uterine wall. If this happens, a healthcare professional likely will recommend a C-section followed by surgery to remove the uterus. This is called a C-hysterectomy.

Without treatment, a retained placenta can cause a serious infection or life-threatening blood loss. Treatment may include medicine to help deliver the placenta or a procedure to remove the placenta.

What are symptoms of trouble with the placenta?

Call your healthcare professional if you have any of the following symptoms during pregnancy:

• Bleeding from the vagina, especially if it's heavy.
• Pain in the stomach area, also called the abdomen.
• Tightening and relaxing of the muscles in the uterus, also called uterine contractions.

What can I do to lower my risk of conditions that affect the placenta?

Most medical issues related to the placenta can't be prevented directly. But you can take steps to boost your chances for a healthy pregnancy:

• Go to all of your routine pregnancy checkups.
• Work with your healthcare professional to manage any health conditions, such as high blood pressure.
• Don't smoke or use drugs. If you need help quitting, talk with your health care professional.
• If you're thinking about getting a C-section, ask your healthcare professional about the risks.

If you had a condition that affected the placenta during a past pregnancy and you’re planning another pregnancy, talk with your healthcare professional. Ask about ways to lower the risk of getting that condition again. Also tell your healthcare professional if you've had surgery on your uterus.

How is the placenta delivered?

If you deliver your baby through your vagina, you'll also deliver the placenta that way shortly afterward. This is known as the third stage of labor.

After you give birth, you keep having mild contractions. Your healthcare professional might give you a shot of medicine called oxytocin (Pitocin). This helps you keep having contractions. It also lessens bleeding after you deliver your baby. Your healthcare professional also might massage your lower abdomen. This encourages the uterus to contract and release the placenta through the vagina. You might be asked to push to deliver the placenta.

If you have a C-section, your healthcare professional removes the placenta from your uterus during that procedure.

After it's delivered, your health care professional checks the placenta to make sure it's intact. Any pieces left behind need to be removed from the uterus to prevent bleeding and infection. If you're interested, ask to see the placenta. In some cultures, families bury the placenta in a special place.

If you have questions about the placenta during pregnancy, talk with a member of your healthcare team. Your healthcare professional can help you better understand the placenta's role in pregnancy.

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• Roberts V, et al. Placental development and physiology. https://www.uptodate.com/contents/search. Accessed Oct. 19, 2023.
• Lockwood CJ, et al. Placenta previa: Epidemiology, clinical features, diagnosis, morbidity and mortality. https://www.uptodate.com/contents/search. Accessed Oct. 19, 2023.
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• Lockwood CJ, et al., eds. Placenta previa and accreta, vasa previa, subchorionic hemorrhage, and abruptio placentae. In: Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice. 9th ed. Elsevier; 2023. https://www.clinicalkey.com. Accessed Oct. 19, 2023.
• Wick MJ, ed. Managing mom's health concerns. In: Mayo Clinic Guide to a Healthy Pregnancy. 2nd ed. Mayo Clinic; 2018.
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• Martin RJ, et al., eds. Placental pathology. In: Fanaroff and Martin's Neonatal-Perinatal Medicine: Disease of the Fetus and Infant. 11th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Oct. 19, 2023.
• Weeks A. Retained placenta after vaginal birth. https://www.uptodate.com/contents/search. Accessed Oct. 19, 2023.
• Landon MB, et al., eds. Placenta accreta spectrum. In: Gabbe's Obstetrics: Normal and Problem Pregnancies. 8th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Oct. 19, 2023.
• FAQs: Bleeding during pregnancy. American College of Obstetricians and Gynecologists. https://www.acog.org/womens-health/faqs/bleeding-during-pregnancy. Accessed Oct. 19, 2023.
• What complications can affect the placenta? National Health Service. https://www.nhs.uk/pregnancy/labour-and-birth/what-happens/placenta-complications/. Accessed Oct. 27, 2023.

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The Anatomy of the Placenta

The placenta ensures fetuses get necessary food and oxygen during pregnancy.

Associated Conditions

The placenta develops within the uterus during pregnancy, playing a key role in nourishing and providing oxygen to the fetus, as well as removing waste material. This organ is attached to the wall of the uterus, with the baby’s umbilical cord arising from it. Throughout the course of a pregnancy, the placenta grows and changes shape, with its thickness being a reliable measure of how far along the mother-to-be is in gestation. Furthermore, a number of disorders can impact this organ, including placenta previa, in which some or all of the cervix is covered by the placenta, as well as placenta accreta malformations, which involve different degrees of implantation within the uterine wall.

Structure and Location

The largest fetal organ, the placenta undergoes rapid development over the course of pregnancy. By the time the baby is brought to term, it has a flat, round disc-like shape that is about 22 centimeters (cm) in diameter, with walls that are typically between 2 and 2.5 cm.

The placenta typically sits along the back wall of the uterine wall—about 6 cm from the cervix—occasionally accessing the side walls throughout its course of development. Significantly, the umbilical cord (which brings in nutrients and oxygen and takes out waste material) connects the mid-section of the fetus to the placenta; in turn, the fetus is surrounded by the amniotic or gestational sac.

The placenta undergoes consistent change throughout the course of pregnancy; between week 0 and 13 after conception, the fertilized blastocyst (what the embryo becomes once its cells start differentiating at about five days after the egg is fertilized) embeds itself in the mucous membrane (endometrium) of the uterine wall, allowing for the fetus and placenta to start forming. By the fourth or fifth month of pregnancy, the placenta takes up about half of the uterine surface, though this percentage shrinks as the fetus grows. At birth, the placenta is also ejected from the body.

Crucial to placenta (and, by extension, embryonic) development is the formation of small, finger-like structures called chorionic villi, which are composed of two types of cells—cytotrophoblasts and syncytiotrophoblasts. The former of these interact with arteries and veins in the walls of the uterus to ensure the fetus gets the nutrients and oxygen it needs. Throughout pregnancy, this vasculature grows in size and complexity, allowing for the formation of the following two major components.

• Maternal component: Essentially, this is the portion of the placenta that is formed of the mother’s endometrium or the maternal uterine tissue. It forms what is called the decidua basalis, or maternal placenta.
• Fetal component: Also known as the chorion frondosum or villous chorion, this is the portion of the placenta arising from the blastocyte.

These are held together by outgrowths, called anchoring villi, from the maternal component. The placenta is surrounded by a placental membrane or barrier. While it serves to differentiate blood supply for mother and fetus, many substances can still get through.

Anatomical Variations

Not every placenta forms regularly, and this can have serious implications. Several such malformations, including placenta previa, accreta, increta, and percreta, are considered serious medical conditions that can endanger a mother, the fetus, or both. In addition, there are a number of other commonly identified abnormalities.  

• Bilobed placenta: Also known as “placenta duplex,” this is a case where the placenta is composed of two roughly equal-sized lobes. The umbilical cord may insert into either lobe, run through both, or sit between them. Though this condition doesn’t increase risk of damage to the fetus, it can cause first-trimester bleeding, excessive amniotic fluid within the gestational sac, abruption (premature separation of the placenta from the womb), or retained placenta (when the placenta remains in the body after birth). This condition is seen in 2% to 8% of women. 
• Succenturiate placenta: In these cases, a lobe of placenta forms separately from a main body that is linked via the umbilical cord to the fetus. Essentially, it’s a variation of a bilobed placenta that occurs more commonly in women who are of advanced maternal age or in those who have had in vitro fertilization. Seen about 5% of the time, this condition can also lead to retained placenta as well as placenta previa, among other complications. 
• Circumvallate placenta: This is when the membranes of the placenta tuck back around its edges to form a ring-like (annular) shape. In this case, the outer membrane, known as the chorion causes a hematoma (a collection of blood) at the margin of the placenta, and vessels within its ring stop abruptly. This condition can lead to poor outcomes for the pregnancy due to the risk of vaginal bleeding during the first trimester, potential rupture of the membranes, pre-term delivery, insufficient development of the placenta, as well as abruption. This condition isn’t easily diagnosed during pregnancy.  
• Circummarginate placenta: This is a much less problematic variant of the above, in which the membranes do not curl back.
• Placenta membranacea: In this rare condition, chorionic villi cover the fetal membrane partially or completely, causing the placenta to develop as a thinner structure at the periphery of the membrane that encloses the chorion. This then leads to vaginal bleeding in the second and/or third trimester of pregnancy and may lead to placenta previa or accreta. 
• Ring-shaped placenta: A variation of placenta membranacea, this condition causes the placenta to have either a ring-like or horseshoe-like shape. Occurring in only about 1 in 6,000 pregnancies, this leads to bleeding before or after delivery, as well as reduced growth of the fetus.
• Placenta fenestrata: This condition is characterized by the absence of the central portion of the placenta. Also very rare, the primary concern for doctors is retained placenta at delivery.
• Battledore placenta: Sometimes called “marginal cord insertion,” this is when the umbilical cord runs through the margin of the placenta rather than the center. This occurs in between 7% and 9% of single pregnancies, but is much more common when there are twins, happening between 24% and 33% of the time. This can lead to early (preterm) labor and problems with the fetus, as well as low birth weight.

The placenta plays an absolutely crucial and essential role during the nine months of pregnancy. Via the umbilical cord and the chorionic villi, this organ delivers blood, nutrients, and oxygen to the developing fetus. In addition, it works to remove waste materials and carbon dioxide. As it does so, it creates a differentiation between maternal and fetal blood supply, keeping these separate via its membrane.

Furthermore, the placenta works to protect the fetus from certain diseases and bacterial infections and helps with the development of the baby’s immune system. This organ also secretes hormones—such as human chorionic gonadotropin, human placenta lactogen, and estrogen—necessary to influence the course of pregnancy and fetal growth and metabolism, as well as labor itself.

Aside from the developmental abnormalities listed above, the placenta may also be subject to a number of medical conditions that may be of concern to doctors. Oftentimes, the core of the problem has to do with the position of this organ. Among these are the following.

• Placenta previa : This condition occurs when the placenta forms partially or totally toward the lower end of the uterus, including the cervix, rather than closer to its upper part. In cases of complete previa, the internal os —that is, the opening from the uterus to the vagina —is completely covered by the placenta. Occurring in about 1 in 200 to 250 pregnancies, risk factors for placenta previa include a history of smoking, prior cesarean delivery, abortion, other surgery of the uterus, and older maternal age, among others. Depending on the case, cesarean delivery may be required.   
• Placenta accreta : When the placenta develops too deep within the uterine wall without penetrating the uterine muscle (myometrium), the third trimester of the pregnancy can be impacted. A relatively rare occurrence—this is the case in only 1 in every 2,500 pregnancies—this condition is more likely to occur among smokers and those with older maternal age, as well as those with a history of previous surgeries or cesarean deliveries. This also can happen alongside placenta previa. During delivery, this condition can lead to serious complications, including hemorrhage and shock. While hysterectomy —the removal of a woman’s uterus—has been the traditional treatment approach, other, more conservative options are available.     
• Placenta increta: Representing 15% to 17% of placenta accreta cases, this form of the condition is when development of the placenta is within the uterine wall and it penetrates the myometrium. Childbirth is severely impacted in these cases, since this can lead to severe hemorrhage due to retention of the placenta within the body. As such, cesarean delivery is required alongside hysterectomy or comparable treatment.   
• Placenta percreta: Yet another type of accreta, placenta percreta occurs when this organ develops all the way through the uterine wall. It may even start to grow into surrounding organs, such as the bladder or colon. Occurring in 5% of placenta accreta cases, as with placenta increta, cesarean delivery and hysterectomy is necessary in these cases.
• Placental insufficiency : Arising for a range of reasons, this is when the placenta is unable to provide enough nourishment for the fetus. This can be due to genetic defects, deficiencies of vitamins C and E, chronic infections (such as malaria), high blood pressure, diabetes, anemia, or heart disease, as well as other health issues. Treatment can range from ensuring better diet to taking medications like low-dose aspirin.

Throughout the course of pregnancy, doctors will perform a wide range of tests to ensure the health of the fetus. This can mean everything from blood tests to genetic tests are administered. When it comes to ensuring proper development of the placenta, a number of diagnostic techniques are employed, including the following.

• Ultrasound : A frequently employed approach when it comes to monitoring fetal development as well as the health of the placenta, ultrasound employs high-frequency sound waves to create a real-time video of the uterus and surrounding regions. Especially in the second and third trimesters, this approach can be used for cases of placenta previa, among other disorders. Furthermore, based on ultrasound results, doctors classify placental maturity. This system of placental grading ranges from grade 0 for pregnancy at 18 or less weeks to grade III for when things have progressed beyond week 39. Early onset of grade III, for instance, may be a sign of placental insufficiency.
• Magnetic resonance imaging (MRI): This imaging approach relies on strong magnetic and radio waves to create highly detailed depictions of the fetus and placenta. Though not necessarily the first line of treatment, MRI may be used to diagnose placenta increta and percreta. In addition, this method may be used in cases of placental insufficiency.     

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By Mark Gurarie Gurarie is a freelance writer and editor. He is a writing composition adjunct lecturer at George Washington University.  

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• Review Article
• Published: 29 June 2020

Tracking placental development in health and disease

• John D. Aplin   ORCID: orcid.org/0000-0001-8777-9261 1 ,
• Jenny E. Myers   ORCID: orcid.org/0000-0003-0913-2096 1 ,
• Kate Timms   ORCID: orcid.org/0000-0003-1764-4964 2 &
• Melissa Westwood 1  

Nature Reviews Endocrinology volume  16 ,  pages 479–494 ( 2020 ) Cite this article

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• Endocrine reproductive disorders

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.

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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Acknowledgements

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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John D. Aplin, Jenny E. Myers & Melissa Westwood

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Supplementary information

Supplementary information.

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

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.

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.

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

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). https://doi.org/10.1038/s41574-020-0372-6

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Article Contents

Maternal metabolic adaptations in normal pregnancy, placental hormones in pregnancy, abnormal maternal metabolic adaptations in gestational diabetes, summary and conclusion, acknowledgments, additional information, placental regulation of energy homeostasis during human pregnancy.

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Brooke Armistead, Eugenia Johnson, Robert VanderKamp, Elzbieta Kula-Eversole, Leena Kadam, Sascha Drewlo, Hamid-Reza Kohan-Ghadr, Placental Regulation of Energy Homeostasis During Human Pregnancy, Endocrinology , Volume 161, Issue 7, July 2020, bqaa076, https://doi.org/10.1210/endocr/bqaa076

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Successful pregnancies rely on sufficient energy and nutrient supply, which require the mother to metabolically adapt to support fetal needs. The placenta has a critical role in this process, as this specialized organ produces hormones and peptides that regulate fetal and maternal metabolism. The ability for the mother to metabolically adapt to support the fetus depends on maternal prepregnancy health. Two-thirds of pregnancies in the United States involve obese or overweight women at the time of conception. This poses significant risks for the infant and mother by disrupting metabolic changes that would normally occur during pregnancy. Despite well characterized functions of placental hormones, there is scarce knowledge surrounding placental endocrine regulation of maternal metabolic trends in pathological pregnancies. In this review, we discuss current efforts to close this gap of knowledge and highlight areas where more research is needed. As the intrauterine environment predetermines the health and wellbeing of the offspring in later life, adequate metabolic control is essential for a successful pregnancy outcome. Understanding how placental hormones contribute to aberrant metabolic adaptations in pathological pregnancies may unveil disease mechanisms and provide methods for better identification and treatment. Studies discussed in this review were identified through PubMed searches between the years of 1966 to the present. We investigated studies of normal pregnancy and metabolic disorders in pregnancy that focused on energy requirements during pregnancy, endocrine regulation of glucose metabolism and insulin resistance, cholesterol and lipid metabolism, and placental hormone regulation.

Human pregnancy is an energetically demanding process and requires synchrony between the mother and fetus. Throughout gestation, maternal basal metabolic rate increases ( 1 ), which causes both the resting and total energy expenditure to increase to support fetal development and growth ( 2 ). Both fetal and placental development cause maternal energy intake and expenditure to increase each day by approximately 375 KJ (89 Kcal) in the first trimester, 1200 KJ (286 Kcal) in the second trimester, and 1950 KJ (466 Kcal) in the third trimester ( 3 ). A mother’s prepregnancy nutritional status, height, and weight determine her ability to energetically and metabolically adapt to fetal needs ( 4 ).

Placental hormones and growth factors regulate maternal metabolism to favor increased fat storage during the first and second trimester ( 5 ), representing an “anabolic” state ( 1 ). This anabolic phase is important because fetal energy demands are not met by only increasing energy intake during the third trimester ( 5 ) and, therefore, rely on fat storage that is accumulated early in the pregnancy. In the third trimester, increased lipolysis and the mobilization of fat stores occur ( 1 ), which is observed by increased blood plasma concentrations of fatty acids and glucose ( 6 ). This shift from anabolic to catabolic lipid metabolism allows lipids to be the main source for maternal energy and preserve glucose for the developing fetus ( 7 ).

Glucose metabolism

The maintenance of glucose metabolism is a key factor in a healthy pregnancy ( 7 ). The fetus is unable to undergo gluconeogenesis and it therefore relies on a supply of glucose from maternal blood plasma and the placenta ( 8 ). During the first trimester of pregnancy, maternal glucose homeostasis is regulated by several hormones, such as estrogen, insulin, and cortisol, which function to increase fat storage, decrease energy expenditure, and delay blood glucose clearance ( 9 ).

Fetal glucose demands increase around week 26 of gestation, which requires maternal basal endogenous glucose production to increase via hepatic gluconeogenesis ( 10 ). At the same time, increases in circulating insulin and decreased insulin sensitivity occur. Estrogen assists in the increased glucose production by enhancing cortisol-binding globulin production by the liver to promote gluconeogenesis ( 11 ). Despite a surge in glucose production, plasma glucose concentrations may simultaneously decrease ( 12 ), suggesting that the circulating glucose is supplied to the fetus and placenta ( 13 ). Riskin-Mashiah et al investigated normal fasting plasma glucose levels in a cohort of 7946 healthy, pregnant, hospitalized women ( 12 ). The team demonstrated that fasting glucose levels are critically maintained in order to remain constant throughout pregnancy ( 12 , 14–19 ).

Insulin resistance

Glucose metabolism is also altered by increasing insulin resistance ( 20 , 21 ), elevated plasma lipid concentrations ( 6 ), and pancreatic β-cell expansion due to maternal pancreatic islet hypertrophy ( 22 , 23 ). Estrogen and progesterone regulate insulin resistance at week 6 of pregnancy ( 22 ). Prolactin and human placental lactogen (hPL) levels peak around week 10 ( 9 ), promoting β-cell proliferation and insulin production and secretion to meet higher insulin demands and further increase insulin resistance ( 20 , 21 ). Insulin resistance continues to develop in the second trimester and peaks in the third trimester of pregnancy ( 24 ). Increased circulating progesterone, prolactin, cortisol, and hPL promote insulin resistance in adipocytes and skeletal muscles ( 24 ). High cortisol assists with the insulin resistance needed for delayed glucose clearance ( 25 ). Insulin initiates glucose uptake by binding to its receptor and through phosphorylation of the β-subunit, followed by phosphorylation of the insulin receptor substrate 1 (IRS-1) at a tyrosine residue, which is then primed for initiating signal transduction pathways ( 26 , 27 ). In normal pregnancies, there is decreased insulin phosphorylation of the insulin receptor ( 28 ), and progesterone causes decreased IRS-1 expression, further decreasing the insulin-induced translocation of glucose transporter 4 (GLUT4) to the cell membrane to dampen glucose cellular uptake ( 26 ).

In addition to hormones, the cytokine tumor necrosis factor-α (TNFα) was identified to be a potential mediator for insulin resistance during later stages in pregnancy ( 29 ). Increases in circulating levels of TNFα have been associated with insulin resistance in obesity, sepsis, muscle damage, and even aging ( 30–32 ). It is also produced by the placenta and increased levels have been reported during pregnancy pathologies, such as preeclampsia and gestational diabetes ( 33 , 34 ). In a prospective study, Kirwan et al showed that insulin resistance during late gestation is significantly correlated with changes in circulating TNFα, irrespective of fat mass ( 29 ).

Lipid metabolism

Pregnancy initiates substantial changes in maternal lipid metabolism that are supportive of fetal growth and development. The first and second trimesters are collectively referred to as the “anabolic phase” of pregnancy whereby increased estrogen, progesterone, and insulin concentrations favor lipid deposition and inhibit lipolysis ( 7 ). Changes in hormones like progesterone, growth hormone (GH), prolactin, and others increase maternal appetite to increase extra body fat ( 6 ). On average, pregnant women with a healthy BMI (body mass index; 18.5–24.9) gain 25–35 lbs of body weight throughout the entirety of pregnancy ( 35 ).

During the first 6 weeks of gestation, plasma lipid levels decrease ( 6 ). Increased insulin sensitivity at this time promotes fatty-acid (FA) synthesis and increases lipoprotein lipase, which facilitates the cellular uptake of circulating triacylglycerides (TAGs) ( 6 ). By week 10, higher levels of FAs, TAGs, cholesterol, and phospholipids are observed in the blood and this continues through the third trimester ( 6 ). At 30 weeks of gestation, a metabolic shift to a catabolic state occurs as lipids are used for maternal energy source, while glucose and amino acids are conserved for the fetus ( 7 , 36 ). These changes are driven by insulin resistance, which promote lipid catabolism and decrease lipoprotein lipase levels during the third trimester ( 6 , 36 ). Increased FAs are released and metabolized into TAGs before being absorbed by the syncytial layer of the placenta ( 6 , 37 ).

Cholesterol is a major component of circulating lipids and is continuously recycled and delivered to sites throughout the body, including the placenta ( 6 ). The placenta utilizes cholesterol to synthesize approximately 400–500 mg of steroid hormones daily ( 6 ). Cholesterol is also important for placental oxidation and placental membrane formation ( 6 ). At week 12 of gestation, high density lipoprotein (HDL) cholesterol increases in response to estrogen and remains elevated throughout the pregnancy ( 6 ). TAGs are elevated by approximately 2-fold, and total and low density lipoprotein (LDL) cholesterol are increased by 30% to 50% in the third trimester ( 6 ).

The human placenta has many functions: it regulates temperature, serves as a protective barrier against the maternal microenvironment and infection, helps to establish immunologic tolerance of the fetus, and provides exchange of gases, nutrients, and waste ( 38 , 39 ). Among the many functions of the human placenta, the numerous hormones produced by this organ have significant influences on establishing and maintaining a healthy pregnancy ( 40 ). Altering energy homeostasis in pregnancy can damage the placenta, leading to inadequate function and subsequent pregnancy complications, which is observed in gestational diabetes mellitus (GDM). In the following sections we provide an overview of hormones and growth factors secreted by the placenta that assist in regulating metabolism throughout pregnancy.

Placental growth hormone

The placental growth hormone (PGH) is a growth hormone variant produced by the placenta, which regulates maternal gluconeogenesis and lipolysis to modulate maternal adaptations during pregnancy ( 41 ). Placental growth hormone replaces pituitary GH in the maternal circulation and its concentrations increase in maternal circulation throughout pregnancy until term ( 42 ). Placental growth hormone functions as an insulin antagonist and mediates insulin resistance by directly modulating insulin-like growth factor 1 (IGF-1) ( 36 , 43 ) and also initates increased growth of maternal tissues ( 24 ). Placental growth hormone may act independently or dependently through IGF-1 to increase nutrient supply for the fetus ( 41 ).

Placental growth hormone is predominantly expressed in and secreted from placental syncytiotrophoblasts and, to a lesser extent, in extravillous trophoblasts ( 43 ). Placental growth hormone has a role in the placenta by acting in both a paracrine and autocrine manner to stimulate trophoblast invasion ( 44 ) and placental growth through its receptor, growth hormone receptor (GHR), on syncytiotrophoblasts ( 41 ). A study by Lacroix et al showed that PGH stimulates trophoblast invasiveness through activation of the Janus kinase-2/signal transducer and activator of the transcription factor-5 (JAK-STAT) signaling pathway ( 44 ) to initiate transcription of invasion-promoting genes ( 45 ). In a transgenic mice study, overexpression of PGH induced hyperinsulinemia, or severe insulin resistance ( 46 ). This is thought to result from maternal pancreatic β-cell expansion and a decrease in body fat, similar to conditions observed in the third trimester of human pregnancy ( 46 ).

Despite the many important functions of PGH during normal pregnancy, studies in pregnant women with diabetes have shown no correlation between changes in PGH levels and insulin levels ( 47 ). Additionally, women with deletions in the PGH gene were also reported to have pregnancies that resulted in children with normal birth weights ( 48 ). This could be explained by other hormones acting in overlapping pathways, which compensate for PGH insufficiency, such as GH or hPL ( 41 ).

Human placental lactogens

Human placental lactogens, also called chorionic somatotrophin hormone (CSH), are types of growth hormones that have several roles, including metabolic regulation by increasing maternal glucose levels, decreasing maternal glucose usage, and promoting lipolysis and insulin resistance ( 21 , 36 ). Human placental lactogen is produced by syncytiotrophoblasts and secreted into maternal–fetal circulations after the sixth week of pregnancy ( 24 ). During early gestation, hPL exhibits anabolic activity by promoting glucose uptake and incorporation of glucose into glycogen, glycerol, and FAs ( 48 ).

Human placental lactogen concentrations rise in the third trimester and become an important contributor to insulin resistance ( 9 , 24 ). During the third trimester, hPL augments lipolysis and fat mobilization, increasing free FA levels in maternal circulation ( 24 ). Human placental lactogen increases to 5000–7000 ng/ml at 32 to 35 weeks, then declines at term to approximately 20–50 ng/ml ( 49 ). Aside from its anabolic/catabolic activities, hPL indirectly controls insulin production and secretion by increasing human pancreatic β-cell replication and cell survival rates ( 50 ). Similar to PGH, women with deletions in the CSH gene experience normal pregnancy outcomes, suggesting that alterations in this hormone may not lead to pregnancy complications such as GDM ( 47 , 48 ).

Ghrelin, also known as growth hormone (GH)-releasing peptide, is a gastric-secreted acylated peptide hormone ( 51 ) that controls feeding behaviors by stimulating GH release through GH secretagogue receptors (GHSR) ( 52 ) and stimulating appetite to increase food intake ( 53 ). At the cellular level, ghrelin regulates energy balance and proliferation ( 52 ). Ghrelin also has a role in activating hepatic gluconeogenesis and inititates glucose uptake through phosphorylation of tyrosine molecules on IRS-1 ( 54 ). Ghrelin is also highly expressed in the first trimester of pregnancy by the human placenta—primarily in cytotrophoblasts and also in placental villi stroma ( 55 ). Ghrelin levels increase midpregnancy and decrease thereafter to undetectable levels in full-term human placenta ( 55 ).

The gestational stage dependent expression of ghrelin in the placenta overlaps with energy intake/expenditure requirement of the fetus. Nakahara et al used a rat model of pregnancy to show that ghrelin has a large effect on fetal growth ( 56 ). Their study shows that maternal treatment with ghrelin increased fetal birth weight, despite a restricted diet ( 56 ). This suggests that ghrelin may have physiological functions in homeostatic control of energy balance in pregnancy as well as in modulating fetal growth and development.

The role of ghrelin in the development of GDM still remains unclear. Women with GDM showed no significant differences in plasma levels of ghrelin compared to healthy pregnant women—although ghrelin mRNA was signficantly higher in the placenta of GDM women compared to healthy pregnancies ( 57 ). This suggests ghrelin may have a role in the placenta during GDM pregnancies, which needs to be further investigated. Interestingly, ghrelin knockout mice show normal fertility with no effect on growth or appetite ( 58 ). However, studies with ghrelin-receptor knockout mice revealed increased levels of IGF-1, suggesting that ghrelin-receptor signaling exerts a physiologic role in energy balance ( 58 ). Similar observations are observed in other rodent models and in humans who have deficiencies in grehlin-receptor function ( 59 ).

Leptin is a hormone characterized by its roles in food intake regulation and energy expenditure in white adipose tissue (WAT), where it is secreted in response to increased energy storage ( 60 ). Leptin is also produced in, and modulates, a wide range of cellular functions in numerous tissues and organs, including the hypothalamus ( 61 ), gastric epithelium ( 62 ), and skeletal muscle ( 63 ). Leptin has recently emerged as an important player in reproductive health, from regulating the menstrual cycle and oocyte maturation ( 64 ) to embryo implantation and development ( 65 , 66 ). Leptin expression in the placenta is regulated by exogenous 17beta-estradiol (E2) via crosstalk between estrogen receptor 1 and MAPK-PI3K signal transduction pathways ( 67 , 68 ).

Leptin suppresses the appetite of healthy, nonpregnant (NP) individuals through its receptors (LRb) ( 69 ) on the hypothalamus located in the brain ( 70 ), where it also influences secretion of thyroid hormones, sex hormones, and growth hormones ( 69 ). Leptin binding to LRb causes transphosphorylation of intracellular LRb and activates the Jak kinase family 2 (Jak2) to intiate further signaling pathways ( 69 ). Despite its role in suppressing appetite, circulating levels of leptin gradually increase throughout gestation. Ladyman et al used a rat model of pregnancy to study the effects of leptin on feeding behavior during pregnancy. In their study, they treated NP and pregnant rats with leptin at gestation days 7 and 14 and measured food intake. They showed NP and gestation day-7 pregnant rats had a reduction in food eaten; however, the leptin did not effect feed behavior for gestation day-14 rats. Their results also revealed that leptin-induced STAT3 phosphorylation was reduced in the hypothalamic nuclei of pregnant rats, which could be the mechanism behind pregnancy-induced leptin resistance ( 71 ). Additionally, decreased mRNA of leptin receptor in the hypothalamus ( 70 ) inidicates that these rats experienced resistance to leptin ( 71 ). This finding is in coordinance with another murine study by Bates et al. They show that STAT3 activation occurs through the tyrosine 1138 residue on LRb ( 72 ). They replaced the tyrosine 1138 residue with a serine residue, and this inhibited STAT3 activation, resulting in hyperphagia and obesity ( 72 ).

A similar trend is observed during human pregnancy, where leptin levels and hyperphagia simultaneously increase throughout gestation. The study by Ladyman et al suggests that a similar mechanism occurs in humans that leads to resistance to the anorexigenic effects of leptin during pregnancy ( 71 , 73 ). Leptin resistance during pregnancy is important to maintain increased energy intake to support fetal growth in the second and third trimester ( 70 ). This also contributes to adipose tissue storage in early and midpregnancy by hyperphagia to prepare for lipid mobilization during the catabolic phase of late pregnancy ( 74 ).

Besides its role in metabolism, studies identified autocrine/paracrine activities for leptin in the placenta due to its expression in placental trophoblasts and amnion cells ( 75 , 76 ). These activities include positive regulation of trophoblast differentiation, promotion of placental angiogenesis and nutrient transport, and local immunomodulation at the maternal–fetal interface ( 77 , 78 ). All such regulatory events are essential for fetal development and adequate placental function ( 77 , 78 ).

Irisin is a newly identified myokine that induces energy expenditure by converting WAT to brown adipose tissue ( 79 ). Irisin is also able to regulate glucose and lipid levels and improve insulin sensitivity ( 80 , 81 ). Irisin consists of 112 amino acids and is produced by FNDC5 (fibronectin domain-containing protein 5) cleavage. Physical activity induces expression irisin through the activation of peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), which transcriptionally upregulates FNDC5 ( 82 ). Irisin faciliates glucose uptake in skeletal muscle cells through activation of the AMP-activated protein kinase (AMPK) 2 pathways and translocation of GLUT4 to the plasma membrane ( 82 ). Murine studies have investigated effects of overexpression of irisin and found it decreases fasting insulin levels and improves glucose tolerance during high-fat diets ( 79 ). Irisin also increases expression of uncoupling protein 1, which initiates thermogenesis in adipocytes ( 79 ). It is also hypothesized that irisin can have anti-inflammatory affects through activation of peroxisome proliterator-activated receptor-α (PPARα) ( 82 ).

Garcés et al reported that circulating irisin levels are higher in pregnant compared to NP women; its serum levels increase as gestation progresses, and its levels are significantly lower in preeclampsia ( 83 ). Further studies confirm that irisin is perturbed in other pregnancy complications, such as GDM, spontaneous preterm delivery, and intrauterine growth restriction ( 84–86 ). A study by Chen et al identified that irisin has a role in reducing oxidative stress and improving lipid metabolism in pregnancies complicated by liver dysfunction ( 87 ). Immunohistological evidence shows irisin is localized in cytotrophoblasts in the decidua and in synyctiotrophoblasts ( 82 ). Moreover, Drewlo et al recently showed that irisin may have a role in the placenta by regulating placental trophoblast differentiation in villous and extra villous cell models through activation of AMPK ( 88 ). The detailed physiological role of irisin in human pregnancy remains to be determined, although there are 2 key roles suggested for irisin during normal pregnancy: (1) to contribute to the development of normal gestational insulin resistance, and (2) to regulate body temperature ( 83 ).

Adiponectin

Adiponectin is an antidiabetic adipokine that serves important functions to regulate glucose metabolism and fatty acid oxidation ( 89 ). Adiponectin can promote pancreatic β-cell survival to prevent hepatic production of glucose ( 89 ) through AMPK mechanisms ( 28 ) and increase insulin sensitivity ( 90 ). It is produced in high amounts in lean women compared to overweight or obese NP women ( 91 ).

Adiponectin is produced in and secreted by maternal adipose tissue ( 89 ). Multiple studies described that adiponectin can also be secreted from the human placenta and that it acts in an autocrine/paracrine manner through adiponectin receptors 1 and 2 located on placental trophoblasts ( 91–93 ). However, other studies were unable to detect adiponectin expression in the term placenta ( 94–96 ) and therefore described adiponectin as an “adipose-specific secretory protein” ( 97 ), which is produced by maternal tissues during pregnancy. Depsite this, adiponectin is known to have significant roles in regulating insulin resistance and glucose homeostasis throughout pregnancy ( 98 ); it may function in a paracrine manner to increase adipocyte cell numbers, increase expression of lipid metabolism genes, and regulate local and systemic inflammation ( 97 ). As well, adiponectin decreases glucose production and lipogenesis, and its production is often decreased during unfavorable metabolic situations ( 97 ). Because of this, adiponectin is commonly used as a biomarker to understand metabolic states under certain conditions.

Gestational diabetes mellitus is a type of diabetes mellitus that develops only during pregnancy and usually disappears upon delivery. The American Diabetes Association classifies GDM as “diabetes first diagnosed in the second or third trimester of pregnancy that is not clearly either preexisting type 1 or type 2 diabetes” ( 99 ). It occurs in 15% to 20% of pregnancies and is associated with adverse outcomes, including macrosomia, neonatal hypoglycemia, and an increased rate of cesarean delivery ( 100 ). Gestational diabetes mellitus is generally characterized by maternal hyperglycemia, glucose intolerance, and high insulin resistance ( 101 , 102 ).

In preconception, the median fasting plasma glucose (FPG) for women with normal pregnancies is 81 mg/dL and this slightly decreases to 80 mg/dL, 77 mg/dL, and 76 mg/dL in the first, second, and third trimesters, respectively ( 12 ), as shown in Fig. 1 . Women are screened for GDM through a 1-step or 2-step oral glucose tolerance test (OGTT) at 24 to 28 weeks of gestation, unless they have risk factors for pregestational diabetes or hyperglycemia, in which case they will undergo OGTT at their first visit ( 99 ). The 1-step test involves a 75-gram OGTT that measures FPG, followed by blood glucose levels at 1 hour and 2 hours after glucose consumption ( 99 ). Based on this criteria, women are diagnosed with GDM if their blood glucose levels measure at or above at least 1 of the following: 92 mg/dL FPG, 180 mg/dL at 1 hour, or 153 mg/dL at 2 hours ( 99 ). The 2-step test does not require fasting and is conducted measuring glucose levels 1 hour after a 50-gram OGTT ( 99 ). If the patient measures ≥130, 135, or 140 mg/dL they are required to take a 100-gram OGTT after an 8-hour fast ( 99 ). Gestational diabetes mellitus is then diagnosed if the patient meets at least 2 of the following measurements: 95 mg/dL FPG, 180 mg/dL after 1 hour, 155 mg/dL after 2 hours, or 140 mg/dL after 3 hours ( 99 ).

Fasting plasma glucose levels in normal pregnancy and GDM. In preconception, women who later go on to have normal pregnancies exhibit a mean FPG of 81 mg/dL ( 12 ). Mean FPG levels for women with normal pregnancies slightly decrease to 80 mg/dL, 77 mg/dL, and 76 mg/dL in the first, second, and third trimesters, respectively ( 12 ). A study by Sesmilo et al showed that first trimester FPG may vary, as their cohort of 6845 women had a mean FPG of 83 with a standard deviation of ± 7.3 mg/dL ( 132 ). Of these women, 10.2% developed GDM, which showed that women with a FPG ≥ 88 mg/dL in the first trimester were 1.82 times more likely to be diagnosed with GDM in the second trimester ( 132 ). Gestational diabetes mellitus is diagnosed in the first or second trimester if the patient measures a FPG ≥ 92 mg/dL by the 1-step OGTT ( 99 ). In a study by Seabra et al, they showed that GDM patients had a significantly higher FPG (90 mg/dL) compared to women without pregnancy complications (FPG 77.8 mg/dL, P = 0.016) in the third trimester ( 133 ).

Metabolic disorders in pregnancy, like GDM, often involve aberrant lipid metabolism. Bao et al investigated triglyceride, total cholesterol, LDL cholesterol, and HDL cholesterol levels in women with GDM ( Fig. 2 ) and normal pregnancies ( Fig. 3 ) ( 103 ). High levels of triglycerides and low levels of HDL cholesterol during early pregnancy was shown to increase the risk for developing GDM later on in pregnancy ( 103 ). These data also support the fact that hyperlipidemia is associated with GDM and, in some cases, is a precursor to this condition ( 6 ).

Mean plasma lipid concentrations measured throughout GDM pregnancies. Gestational diabetes mellitus pregnancies often involve abnormal lipid concentrations throughout pregnancy. As well, infants born to mothers with GDM often have increased adipose tissue at birth. Bao et al identified that women with higher triglycerides in early pregnancy have an increased risk of developing GDM in later pregnancy ( 103 ). As well, lower HDL cholesterol in early pregnancy significantly increases the risk for developing GDM in later pregnancy ( 103 ). Changes in LDL cholesterol or total cholesterol throughout pregnancy was not shown to be significantly associated with risk of developing GDM ( 103 ). * P < 0.05 indicates significant differences in HDL, LDL cholesterol, or triglyceride concentration in GDM pregnancies compared to normal pregnancies during that gestation age ( 103 ). Image was adapted from Bao et al. Plasma concentrations of lipids during pregnancy and the risk of gestational diabetes mellitus: a longitudinal study. J Diabetes . 2018;10(6):487–495.

Mean plasma lipid concentrations measured throughout normal pregnancies. Healthy pregnancies typically show HDL cholesterol increases from 60–70 mg/dL in the late first trimester, and these levels decrease to below 60 mg/dL at the end of gestation ( 103 ). Low density lipoprotein cholesterol gradually increases across gestation from around 86–126 mg/dL ( 103 ). Triglycerides increase in the beginning of the second trimester, from around 130 mg/dL, and increase until the end of gestation to approximately 280 mg/dL ( 103 ). Total cholesterol increases from approximately 180 mg/dL at the end of the first trimester to around 230 mg/dL at the end of the third trimester ( 103 ). Image was adapted from Bao et al. Plasma concentrations of lipids during pregnancy and the risk of gestational diabetes mellitus: a longitudinal study. J Diabetes . 2018;10(6):487–495.

Maternal obesity during pregnancy can involve greater lipolysis rates, which may cause lipotoxicity and can lead to maternal endothelial dysfunction ( 37 ). Elevated estrogens and abnormally high insulin resistance may also contribute to high lipid levels during pregnancy ( 6 ). Abnormal lipid metabolism can serve as a precursor to maternal metabolic disease postpartum ( 101 , 104 ) and affect fetal birth weights, as the placenta may accumulate excessive amounts of lipids during obese pregnancies, altering delivery of FAs and TAGs to the fetus ( 37 ).

Gestational diabetes mellitus may also develop due to the dysregulation of pancreatic β-cell function against a background of insufficient insulin action (both insulin sensitivity and secretion defects) and abnormal secretion of pregnancy hormones ( 20 , 23 , 105 ). Leptin, irisin, and adiponectin are among the many placental hormones that are found to be dysregulated in GDM. In this section, we discuss their roles in GDM development.

Leptin involvement during GDM

Leptin and leptin receptor expression are found to be increased in the placenta of women with GDM, and this may result from hyperinsulemia to increase leptin levels ( 106 ). These conditions also promote increases in proinflammatory proteins, which further increase the production of leptin ( 106 ). Besides this, studies have shown that specific single nucleotide polymorphisms in the leptin gene (LEP-2548G/A) predisposes risk for developing GDM ( 106 ). Interestingly, leptin levels measured in early pregnancy have been used as predictive biomarkers for later development of GDM ( 107 ) and in pregnancies complicated by type 1 diabetes ( 108 ). Kautzky-Willer found that pregnant women have higher blood leptin levels than NP women, which peak at around 28 weeks into gestation ( 109 ). In the third trimester, leptin levels start declining and are significantly lowered postpartum in healthy pregnancies ( 109 ). While this trend is similar in women who develop GDM, leptin levels are significantly higher in GDM when compared to normal pregnancies and NP women, as shown in Fig. 4 ( 109 ). It is also reported that leptin levels remain high postpartum in women with GDM, which negatively correlates with placental function and birth weight ( 109 ).

Leptin measurements in the second trimester of pregnancy. Kautzky-Willer et al showed that there is a significant increase in plasma leptin levels in women who have GDM (24.9 ng/mL) compared to normal pregnancies (18.2 ng/mL) ( 109 ). Leptin levels during nonpregnancy are 8.2 ng/mL ( 109 ). *** P < 0.001.

A similar observation was reported by Qiu et al ( 110 ), which investigated a cohort of 823 women and measured plasma leptin in the first trimester of pregnancy. They found that women with higher leptin levels (31.0 ng/ml) had a 4.7% increased risk of developing GDM compared to women with normal or lower leptin levels (≤14.3 ng/ml) ( 110 ). Qiu et al further showed that every 10 ng/ml increase in leptin concentration increased the risk of developing GDM by 20% ( 110 ). A meta-analysis study in 2015 by Bao et al reported similar trends for leptin ( 111 ).

Interestingly, studies by Festa et al and Mosavat et al report significantly lowered leptin levels in women with GDM compared to control ( 112 , 113 ), which is opposite from Qiu et al ( 110 ). Each of these studies compared GDM women with normal pregnant women who have a comparable BMI, maternal age, gestational age, gestational weight gain, and in some cases ethnicity. The opposite results may be attributed to the sampling method, as both Festa et al and Mosavat et al used blood serum to measure leptin levels, while Qiu et al measured leptin from blood plasma. The method and time required for serum and plasma separation from whole blood is shown to have an effect on the levels of certain metabolites such as insulin, peptide C, and other factors such as vascular endothelial growth factor (VEGF) ( 114-116 ). These studies highlight the importance of potential errors introduced in the measurement of clinical samples, and future surveys of blood leptin levels during pregnancy warrant a more critical assessment of specimen collection.

Irisin involvement during GDM

Many reports describe GDM patients as having lower irisin levels compared to healthy, age-matched controls ( 117 , 118 ), as shown in Fig. 5 . A study by Seven et al measured irisin levels in pregnant women with GDM, obese without GDM, and control pregnancies and identified that women with GDM have significantly lower irisin levels, while obese non-GDM women had higher irisin levels (both compared to control pregnancies) ( 119 ). These results point out that irisin likely has different pathogenic effects in GDM and non-GDM obesity during pregnancy ( 119 , 120 ).

Irisin measurements in the first trimester of pregnancy. Erol et al showed that there is a decrease in irisin levels in women who later developed GDM (452 ng/mL) compared to normal pregnancies (752 ng/mL) ( 121 ). *** P < 0.001.

Erol et al also found that GDM patients had significantly lower irisin levels in the first trimester (453 ng/ml in GDM vs. 721 ng/ml in controls) and slightly lower levels during the second trimester (749 ng/ml in GDM vs. 757 ng/ml in controls) ( 121 ). Similarly, Ural et al showed significantly lower irisin levels in blood serum during the second trimester in a cohort of 45 women with GDM and 41 matched controls ( 122 ). However, Ural et al reported values of 1 ug/l (or 1 ng/mL) in comparison to the median value of 749 ng/ml reported by Erol et al. The specificity and sensitivity of ELISA kits used in these studies might contribute to the differences in irisin levels reported by the 2 groups. Both Erol et al and Ural et al report a positive correlation of irisin with fasting insulin levels in these women, which may suggest a role for irisin in glucose and energy metabolism during pregnancy. Moreover, studies have shown that exercise prevents fetal overgrowth ( 123 ), which often occurs during GDM pregnancies. Exercise increases irisin secretion ( 124 ) and insulin sensitivity, decreases plasma glucose concentrations, and increases angiogenic factors in the blood ( 123 ), further showing the importance of irisin during pregnancy.

Current approaches in the field of GDM aim to establish a biomarker panel for diagnosis in the first or second trimester ( 22 ). It is important to indentify women who are at a greater risk for developing GDM in later pregnancy and if their infant is at risk of developing comorbidities as a result ( 22 ). Wang et al suggestes that irisin measurements in the first trimester may serve as a significant risk factor for developing GDM later in the pregnancy ( 125 ). However, a recent study by Jedrychowski et al showed that ELISA-based detection of irisin might not be sufficient and that a more sensitive technology like mass spectrophotometry might be required to correctly assess irisin levels during pregnancy ( 126 ). These results warrant a more thorough investigation into irisin detection and the mechanisms by which irisin contributes to GDM pathology before its development as a biomarker.

Adiponectin involvement in GDM

Adiponectin is known to have major roles regulating energy homeostasis. Multiple reports show decreased levels of adiponectin during GDM pregnancies ( 127–129 ). Adiponectin expression in adipocytes is negatively regulated by proinflammatory factors, like TNFα, which are highly expressed during GDM pregnancies and could explain why adiponectin is decreased in GDM ( 28 ). Using a transgenic knockout mouse model, a recent study revealed that adiponectin-deficient mice developed glucose intolerance and hyperlipidemia in the later stages of pregnancy and their offspring exhibited increased fetal weight ( 130 ). These adiponectin-deficient mice also show increased production of hepatic glucose and triglycerides and decreased β-cell mass compared to the normal pregnant mice, which are characteristic of GDM pregnancies. Interestingly, when these adiponectin knockout mice were then administered adiponectin, it reversed the glucose intolerance and prevented fetal overgrowth. These results show the high impact of adiponectin on maintaining energy homeostasis during pregnancy ( 130 ).

Maternal physiology and overall health prior to pregnancy determine the ability to metabolically adapt to support fetal development. In normal pregnancy, maternal carbohydrate and lipid metabolism and its regulation are altered with advancing gestation. These trends are characterized by a progressive decrease in maternal glucose sensitivity coinciding with increasing lipolysis, indicating a shift from an anabolic state to catabolic state in late pregnancy. Numerous placental hormones—including placental growth hormone, placental lactogens, leptin, ghrelin, irisin, and adiponectin—regulate glucose and lipid metabolism, as well as the insulin sensitivity/resistance that occurs throughout anabolic and catabolic states of pregnancy ( 36 ).

Preconception maternal obesity is a risk factor for placental dysfunction, which drives aberrant metabolic control ( 37 ). Altering the normal trends of maternal energy homeostasis can lead to pregnancy-related metabolic disease, like GDM. This is concerning, as two-thirds of pregnancies in the United States involve overweight or obese women, and conditions like GDM can have lasting effects on maternal–fetal health ( 37 ). Gestational diabetes mellitus leads to insufficient insulin levels and aberrant blood glucose concentrations that impair cognitive, neurological, and endocrine development in the fetus, which negatively impact the offspring in later life. Besides maternal–fetal comorbidities, these pregnancy complications pose a large economic burden accounting for approximately 1.6 billion dollars per year in United States ( 131 ).

It is also important to acknowledge that molecular pathways mediated by placental hormones driving the changes in metabolism during normal pregnancy and GDM are not completely elucidated. This is further complicated by the unavailability of sensitive methods to detect targets like irisin. Understanding the mechanisms that regulate metabolic trends during pregnancy is critical for better identification, treatment, and prevention of metabolic-related pregnancy complications.

The placenta may additionally secrete yet undetected factors that might contribute to this process. Future research should focus on determining accurate levels of known factors and global screening approaches that detect novel factors might be beneficial. It is also crucial to determine the full extent to which aberrant hormone expression may be harmful to the placenta, including the regulation of placental function at the molecular level. Finally, research into means of damping effects of abnormal metabolic trends during metabolic-related pregnancy complications would greatly impact the current means of treatment to alleviate these complications.

We thank Dr. Brian Knight’s team for editoral assistance and Ken Provost from Xavier Studio for the scientific illustrations.

Financial Support:  Funding for this article was received from the Department of Obstetrics, Gynecology and Reproductive Biology in the College of Human Medicine at Michigan State University.

Author Contributions:  All authors contributed to the article design, literature analysis, and drafting of the article. B.A. served as primary editor of this article.

Disclosure Summary:  The authors have nothing to disclose.

Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Deciphering the Epigenetic Landscape: Placental Development and Its Role in Pregnancy Outcomes

• Published: 08 March 2024

Cite this article

• Yujia Chen 1 , 2 ,
• Zhoujie Ye 1 , 2 ,
• Meijia Lin 4 ,
• Liping Zhu 1 , 2 ,
• Liangpu Xu 3 &
• Xinrui Wang   ORCID: orcid.org/0000-0002-7383-9128 1 , 2  

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The placenta stands out as a unique, transitory, and multifaceted organ, essential to the optimal growth and maturation of the fetus. Functioning as a vital nexus between the maternal and fetal circulatory systems, it oversees the critical exchange of nutrients and waste. This exchange is facilitated by placental cells, known as trophoblasts, which adeptly invade and remodel uterine blood vessels. Deviations in placental development underpin a slew of pregnancy complications, notably fetal growth restriction (FGR), preeclampsia (PE), recurrent spontaneous abortions (RSA), and preterm birth. Central to placental function and development is epigenetic regulation. Despite its importance, the intricate mechanisms by which epigenetics influence the placenta are not entirely elucidated. Recently, the scientific community has turned its focus to parsing out the epigenetic alterations during placental development, such as variations in promoter DNA methylation, genomic imprints, and shifts in non-coding RNA expression. By establishing correlations between epigenetic shifts in the placenta and pregnancy complications, researchers are unearthing invaluable insights into the biology and pathophysiology of these conditions. This review seeks to synthesize the latest findings on placental epigenetic regulation, spotlighting its crucial role in shaping fetal growth trajectories and development. Through this lens, we underscore the overarching significance of the placenta in the larger narrative of gestational health.

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Epigenetics Beyond Fetal Growth Restriction: A Comprehensive Overview

The significance of the placental genome and methylome in fetal and maternal health

Epigenetics of pregnancy: looking beyond the DNA code

Data availability.

Data availability is not applicable to this article as no new data were created or analyzed in this study.

Abbreviations

Angiotensin-converting enzyme

Arteriovenous

Cytotrophoblasts

Antioxidant copper-zinc superoxide dismutase

Chromosome 14 miRNA cluster

Chromosome 19 miRNA cluster

Differentially methylated regions

Decidual natural killer

Extracellular matrix

Endocrine gland-derived vascular endothelial growth factor

Exonic circRNA

BAP treated hESC

Extravillous trophoblasts

Enhancer of Zeste Homolog 2

Fetal growth restriction

Gestational diabetes mellitus

Glucose transporter proteins

G protein γ 7

Human chorionic gonadotropin

Histone deacetylases

Human embryonic stem cells

Human leukocyte antigen

Histone methyltransferases

4-Hydroxynonenal

Heme oxygenase-1

Human pluripotent stem cells

Major histocompatibility complex

Matrix metalloproteinases

Nuclear factor erythroid 2-like protein 2

Preeclampsia

Placental Growth Factor

Recurrent spontaneous abortions

Somatic cell nuclear transfer

Soluble endoglin

Soluble fms-like tyrosine kinase-1

Sodium-coupled neutral amino acid transporter 2

Syncytiotrophoblasts

DNA demethylases

Matrix metalloproteinases tissue inhibitors

Transforming growth factor

Tumor necrosis factor receptor-associated factor 6

Tumor necrosis factor-like weak inducer of apoptosis

Uterine natural killer cells

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This study was supported by the Key Project on the Integration of Industry, Education and Research Collaborative Innovation of Fujian Province (No. 2021YZ034011), the Key Project on Science and Technology Program of Fujian Health Commission (No. 2021ZD01002),the Joint Funds for the Innovation of Science and Technology, Fujian Province (No: 2021Y9185),the Province-level special subsidy funds for health in Fujian Province (No: Fujian Finance Index [2019] 827),the Fujian Province health scientific research personnel training project(No: Fujian Finance Index [2021] 55),the Fujian Province health scientific research personnel training project(No: Fujian Finance Index [2021] 500).

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Yujia Chen, Zhoujie Ye, Liping Zhu & Xinrui Wang

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Chen, Y., Ye, Z., Lin, M. et al. Deciphering the Epigenetic Landscape: Placental Development and Its Role in Pregnancy Outcomes. Stem Cell Rev and Rep (2024). https://doi.org/10.1007/s12015-024-10699-2

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Home • Pregnancy • Safety

6 Functions Of Placenta During Pregnancy And Placental Problems

The placenta is responsible for providing the vital oxygen and nutrients the growing fetus needs.

Dr. Subhashis Samajder, a consultant gynecologist-obstetrician with nine years of experience, is currently practicing at Narayana Multispeciality Hospital, Howrah. His area of expertise includes abortion, colposcopy surgery, hysterectomy, h... read full bio

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The placenta is an organ that develops in the uterine wall when a woman is pregnant. The critical functions of the placenta during pregnancy include the growth and development of the fetus (1) . It also aids in maternal-fetal exchange by transporting oxygen and nutrients to the fetus and removing the waste from the fetal blood.

Before we begin any further, let us understand what a placenta is. A placenta is a life-supporting organ for the growing fetus; however, sometimes, its functions may be hindered due to several factors, such as blood clots, abdominal trauma, and blood pressure. These factors may lead to pregnancy complications.

This post informs you about the functions of the placenta, the problems related to it, the symptoms of such complications, and ways to reduce the risk.

Why Is The Placenta Important?

The placenta is your unborn baby’s life support system and plays a key role in its development. It connects the mother to the fetus through the umbilical cord during gestation period and carries out the functions your fetus cannot perform by itself  (2) .

Functions Of The Placenta During Pregnancy

The placenta serves the functions of organs such as the lungs, kidneys, and liver until your fetus develops them. Some of the main functions that the placenta performs include (1) (3) :

• Respiratory, excretory, nutritive, endocrine i X System of glands that secrete hormones directly into the bloodstream , barrier function, immunological function.
• Supplying oxygen and output of co2 is done via simple diffusion (respiratory) and nutrients to the fetus via the umbilical cord (nutritive).
• Clearing out waste products, such as urea, creatinine, uric acid from the fetus (excretory).
• Metabolizing and releasing food substances and required products into the maternal and fetal blood circulations.
• Protecting the fetus from xenobiotics (compounds including food additives, drugs, and environmental pollutants).

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• Producing steroid and peptide hormones that help in the growth and development of the baby (endocrine).
• Protecting the fetus from infections (bacterial) and maternal diseases.
• Fetal membrane protects the transfer of noxious i X Extremely harmful substances less than 500 dalton except antibody and antigen (barrier).
• Produces different enzymes such as diamine oxidase and oxytocinase (enzymatic).

Factors That Affect The Placental Function

Various factors can affect the placental function during pregnancy and make the mother prone to certain risks. They may include:

• Mother’s age: Mothers who conceive after the age of 35 are likely to experience placental problems (4) .
• Twin or multiple pregnancies: Mothers carrying more than one baby are likely to develop a weak placenta. It may raise the risk of early placental detachment (5) .
• Premature rupture of membranes: Your baby is usually cushioned and protected by the amniotic sac (membrane filled with amniotic fluid).  If it breaks or leaks before labor, you may be at risk of placental infections (chorioamnionitis) and placental abruption (premature placental separation from the uterus) (6) .
• Blood-clotting disorders: Blood clotting as a result of genetic susceptibility, obesity, increased maternal age, medical illnesses, prolonged immobility, etc., are likely to form inside the placenta too. It may, sometimes, cut off the blood supply, and pose danger to the baby (7) .
• Abdominal trauma: A fall or any type of blow that causes abdominal trauma increases the risk of placenta abruption (8) .
• Prior placental problems: If you have experienced any placental problems in your previous pregnancy, you might develop it again (9) .
• Prior uterine surgery: Any previous surgery, such as cesarean section or uterine fibroids i X Non-malignant, fibrous tumors that are commonly found on the wall of the uterus removal surgery, may increase your risk of placental conditions (10) .
• Blood pressure: High blood pressure or hypertension levels might affect your placental function (11) .
• Substance abuse: If you smoke or take drugs, you may be at risk of placental conditions (12) .

Problems Related To The Placenta

Some of the possible problems related to the placenta include:

• Placental abruption: It is a condition in which the placenta separates from the uterine wall before delivery. It could deprive the fetus of oxygen and nutrients and may result in premature birth , stillbirth, and growth problems; it can cause severe bleeding (13) . One-third of the cases of abruption are associated with any form of hypertension.
• Placenta previa: It occurs when the placenta lies low in the lower uterine segment of uterus and covers the opening of the cervix partially or totally. It may, therefore, block the baby’s exit from the womb, resulting in preterm labor, placental tear, and antepartum i X The period leading up to the birth of a baby and intrapartum i X The period from the onset of labor to the delivery of the placenta hemorrhage (14) (15) .
• Placenta accreta: This rare complication occurs when the placenta grows into the uterine wall and is unable to be detached properly during delivery. It could lead to vaginal bleeding during and after delivery (16) .
• Retained placenta: A part of the placenta or membranes remain intact in the womb after childbirth. It may occur when the placenta gets stuck behind a uterine muscle. It could be a life-threatening condition and requires manual removal of placenta (MROP) after a few hours of delivery (17) .
• Placental insufficiency: The placenta may not be able to transfer nutrients to the fetus. It may lead to fetal growth restriction (FGR), stillbirth, and low birth weight (18) .
• Anterior placenta: The placenta develops on the front of the uterus with the fetus behind it. It could make it difficult for you to feel the fetal kicks and for sonographers to find the heartbeat. It may lead to placental abruption, intrauterine growth restriction, and fetal death (19) .

Placenta previa may resolve as pregnancy progresses. Liz Miller, a mother from the United States, says, “We had thought for a long time that he might be early- due to the possibility of a c-section because of complications with my placenta. I had what is called placenta previa- where the placenta sits on top of the cervix, getting in the way of a natural birth. However, my placenta began to move out of the way and by 36 weeks, I was cleared to try a vaginal birth. I was ready to go ( i ).”

What Are The Signs And Symptoms Of Placental Problems?

The signs and symptoms that may indicate placental problems include:

• Vaginal bleeding
• Abdominal pain
• Constant uterine contractions
• Decreased fetal movement

You should see your doctor if you begin to experience these symptoms suddenly and often.

Can You Reduce The Risk Of Placental Problems?

You might not be able to prevent several of the placental problems. But you may take a few measures for a healthy pregnancy.

• Go for regular prenatal checkups. According to the CDC National Center for Health Statistics , about 2.1% of mothers received no prenatal care, and 12.5% received insufficient care, potentially leading to undetected placental problems during pregnancy. Therefore, prioritizing proper and timely prenatal care is crucial for supporting a healthy pregnancy.
• Manage health conditions such as blood pressure and gestational diabetes i X A condition characterized by elevated blood sugar levels due to hormonal and physical changes in pregnancy .
• Quit smoking and use of illegal drugs.
• Inform your doctor if you had any placental problem in your previous pregnancy or had any surgery of the uterus.

How Is The Placenta Delivered?

Usually there are mild contractions (sometimes there may not) that could help the placenta to separate from the uterine wall and move through the birth canal.

In a vaginal delivery, the third stage of labor begins with childbirth and ends with placental delivery. Your practitioner may inject Pitocin (oxytocin) into your body to induce uterine contraction and speed up placenta expulsion (20) .

In a C-section, your practitioner physically removes the placenta before closing the incision. The remaining fragments are removed to prevent infection and bleeding (21) .

Does A Doctor Check For Placental Abnormalities Even Without Symptoms?

During the regular ultrasound scans, the healthcare practitioner checks for all possible placental abnormalities. Placental conditions are likely to be associated with vaginal bleeding, and it is important to seek medical attention.

Frequently Asked Questions

1. When does the placenta fully form?

The placenta fully forms by weeks 18 to 20 and continues to grow throughout the pregnancy. It is likely to weigh around one pound at the time of delivery (22) .

2. Is the placenta part of the baby or the mother?

The placenta is a fetomaternal organ comprising two parts—the fetal placenta that develops from the same blastocyst, which forms the fetus (villous chorion), and the maternal placenta that develops from the tissue of the maternal uterus (decidua basalis).

3. Which placenta position is best for normal delivery?

The placental position may not be a cause of concern in several cases. The anterior placenta position—the placenta in front of the stomach—could make it difficult to hear the fetal heart sounds.

4. What is the correlation between the placenta and preterm labor?

Chronic inflammation of the placenta and problems with placental vasculature (blood flow to placenta from maternal and fetal systems) have been associated with preterm birth in scientific studies (24) .

5. What prenatal testing is available to evaluate the placenta?

Placental abnormalities are usually screened using ultrasound scans. Such scans may be performed transabdominally or transvaginally (25) .

6. How does the placenta protect the baby from infections?

The placenta forms a physical barrier between the maternal and fetal circulations that allows only selective substances to pass through and prevents the transfer of pathogens. However, some pathogens may still be transferred from the mother to the fetus and cause fetal infection (26) .

7. Can stress cause placenta problems?

Dr. Laila Kaikavoosi , a UK-based hormone specialist, says, “The placenta can experience a negative impact from stress during pregnancy. The increased transfer of maternal cortisol to the fetus through the placenta, caused by stress or worry is only one explanation. The placenta can typically neutralize cortisol, but this defense system may fail under great stress. In addition, stress can influence the health and function of the placenta by causing disorders like pre-eclampsia, gestational diabetes, pre-diabetes, and maternal microbiota abnormalities.”

The placenta supports a baby’s life inside the womb. It offers the baby nourishment and performs all the necessary functions that a baby can’t do itself. Hence, ensuring proper placental functioning is essential for the viability of the pregnancy. Going for prenatal checkups regularly and quitting smoking, alcohol, and illegal drugs are a few ways to prevent some of the placental problems. Keep your doctor informed about any placental or uterine problems so they can guide you better.

Infographic: What Are The Risks Of Pills Made From Your Own Placenta?

Illustration: Momjunction Design Team

Key Pointers

• The placenta connects the mother to the fetus and provides essential oxygen and nutrients to the fetus.
• It protects the fetus from potential toxins, including food additives, drugs, and pollutants.
• Factors such as the mother’s age, substance abuse, and high blood pressure can affect the functioning of the placenta.
• The placenta produces growth-regulating hormones that aid fetal development.
• Symptoms of placental problems include back and abdominal pain, vaginal bleeding, and decreased fetal movement.
• Regular prenatal care and monitoring can help identify potential placental problems to ensure proper maternal and fetal health.

Personal Experience: Source

MomJunction articles include first-hand experiences to provide you with better insights through real-life narratives. Here are the sources of personal accounts referenced in this article.

i. My birth story; https://apparentinprogress.blogspot.com/2020/11/my-birth-story.html

1. Gude NM, et al.; Growth and function of the normal human placenta ; Thrombosis Research (2004). 2. Wang Y and Zhao S; Chapter 2 – Placental Blood Circulation; Vascular Biology of the Placenta ; Morgan & Claypool Life Sciences; (2010). 3. Graham J. Burton and Abigail L. Fowden; The placenta: a multifaceted, transient organ ; Philosophical Transactions of the Royal Society B: Biological Sciences (2015). 4. Advanced Maternal Age ; Texas Children’s Hospital – Pavilion for Women 5. Complications of Multiple Pregnancy ; University of Rochester Medical Center 6. Premature Rupture of Membranes (PROM)/Preterm Premature Rupture of Membranes (PPROM) ; The Children’s Hospital of Philadelphia 7. Blood Clotting & Pregnancy ; American Society of Hematology 8. Lavin JP and Polsky SS; Abdominal trauma during pregnancy ; Clinics in Perinatology (1983). 9. Kimberly M. Rathbun and Jason P. Hildebrand; Placenta Abnormalities ; Treasure Island (FL): StatPearls Publishing (2020). 10. Tayyaba Majeed, et al.; Frequency of placenta previa in previously scarred and non scarred uterus ; Pakistan Journal of Medical Sciences (2015). 11. Khattak SN, et al.; Association of maternal hypertension with placental abruption ; Journal of Ayub Medical College Abbottabad (2012). 12. Punam Sachdeva, B.G. Patel, and B.K. Patel; Drug Use in Pregnancy; a Point to Ponder ; Indian Journal of Pharmaceutical Sciences (2009). 13. Placental abruption ; Better Health Channel; State Government of Victoria, Australia 14. Placenta previa ; U.S. Department of Health and Human Services National Institutes of Health Abdulrahman Abdulelah Almnabri et al.; Management of Placenta Previa During Pregnancy ; The Egyptian Journal of Hospital Medicine (2017) 15. Placenta Accreta ; USF Health Obstetrics and Gynecology 16. Andrew D Weeks; The Retained Placenta ; African Health Sciences (2001). 17. Usha Krishna and Sarita Bhalerao; Placental Insufficiency and Fetal Growth Restriction ; J Obstet Gynaecol India (2011). 18. Shumaila Zia; Placental location and pregnancy outcome ; Journal of the Turkish-German Gynecological Association (2013). 19. Labour and Delivery Care Module: 6. Active Management of the Third Stage of Labour ; The Open University 20. Cesarean Delivery; Stanford Children’s Health 21. Stages of Development of the Fetus ; The Merck Manual 22. Placenta and Extraembryonic Membranes; Anatomy ; University of Michigan Medical School 23. Placenta ; Cleveland Clinic 24. Sunitha C Suresh et al.; A comprehensive analysis of the association between placental pathology and recurrent preterm birth ; American Journal of Obstetrics and Gynecology (2022) 25. Kimberly M. Rathbun and Jason P. Hildebrand; Placenta Abnormalities ; National Library of Medicine (2022) 26. Regina Hoo et al.; Innate Immune Mechanisms to Protect Against Infection at the Human Decidual-Placental Interface ; Frontiers in Immunology

• Fact-checker

Subhashis Samajder MS, DNB

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REVIEW article

The role of placental hormones in mediating maternal adaptations to support pregnancy and lactation.

• Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom

During pregnancy, the mother must adapt her body systems to support nutrient and oxygen supply for growth of the baby in utero and during the subsequent lactation. These include changes in the cardiovascular, pulmonary, immune and metabolic systems of the mother. Failure to appropriately adjust maternal physiology to the pregnant state may result in pregnancy complications, including gestational diabetes and abnormal birth weight, which can further lead to a range of medically significant complications for the mother and baby. The placenta, which forms the functional interface separating the maternal and fetal circulations, is important for mediating adaptations in maternal physiology. It secretes a plethora of hormones into the maternal circulation which modulate her physiology and transfers the oxygen and nutrients available to the fetus for growth. Among these placental hormones, the prolactin-growth hormone family, steroids and neuropeptides play critical roles in driving maternal physiological adaptations during pregnancy. This review examines the changes that occur in maternal physiology in response to pregnancy and the significance of placental hormone production in mediating such changes.

Introduction

Pregnancy is a dynamic and precisely coordinated process involving systemic and local changes in the mother that support the supply of nutrients and oxygen to the baby for growth in utero and in the subsequent lactation. Inappropriate adaptation of maternal physiology may lead to complications of pregnancy, such as gestational diabetes, preeclampsia, fetal growth restriction, fetal overgrowth and pre-term birth; which can have immediate consequences for fetal and maternal health. Furthermore, these pregnancy complications can also lead to long-term health consequences for the mother and infant. Altered fetal growth is associated with an increased risk of the offspring developing obesity, type-2 diabetes and cardiovascular disease in adulthood ( Hales and Barker, 2001 ; Barker, 2004 ; Fowden et al., 2006 ). Moreover, women who develop gestational diabetes or preeclampsia are more likely to develop type-2 diabetes or cardiovascular disease in later life ( Kim et al., 2002 ; Petry et al., 2007 ). Maternal adaptations to pregnancy are largely mediated by the placenta; the functional interface between the mother and fetus that secretes hormones and growth factors into the mother with physiological effects. This review aims to provide an overview of the physiological changes that occur in the mother in response to pregnancy and to discuss the role of key placental hormones in mediating such adaptations. In particular, this review focuses on the importance of the prolactin-growth hormone family (e.g., prolactin, placental lactogen and growth hormone), steroids (estrogens and progesterone) and neuropeptides (serotonin, melatonin and oxytocin) in adaptations of maternal physiology during pregnancy. Where possible, this review draws upon findings in women and animal models, including rodents and sheep. However, differences exist between species in the specific hormones produced by the placenta, the access of these hormones to the maternal circulation, and the relative proportion of conceptus mass to maternal size (hence constraint on the mother to provide resources for fetal growth; Haig, 2008 ; Carter, 2012 ; Fowden and Moore, 2012 ). Where such differences between species exist, these have been highlighted and discussed as necessary in the relevant sections. Nevertheless, although some effects described may not be applicable to all species, the different animal models of pregnancy still provide novel insight into the fundamental mechanisms of maternal adaptation during gestation.

Adaptations in Maternal Physiology During Pregnancy and Lactation

Most tissues and organs in the mother respond to the pregnant state. Changes include alterations in size, morphology, function and responsiveness of tissues and organs to hormonal and metabolic cues. These changes arise in the cardiovascular, pulmonary, immune, and metabolic systems of the mother (Figure 1 ). Some of these changes are seen from very early in pregnancy, prior to the establishment of a fully functional placenta, highlighting that non-placental factors may also be important ( Paller et al., 1989 ; Drynda et al., 2015 ). The specific nature of changes in maternal physiology depends on the stage of the pregnancy and appears to track with alterations in the metabolic requirements of the mother versus the developing fetus.

Figure 1 . Schematic diagram highlighting the main physiological modifications in the maternal physiology in response to pregnancy. Many of the changes described in the figure for women during pregnancy also occur in other species, including mice. Respiratory system ( Macrae and Palavradji, 1967 ; Weinberger et al., 1980 ; Contreras et al., 1991 ; Hegewald and Crapo, 2011 ; Frise et al., 2013 ; Lomauro and Aliverti, 2015 ; Soma-Pillay et al., 2016 ); cardiovascular system ( Adamova et al., 2009 ; Li et al., 2012 ; Pieper, 2015 ; Soma-Pillay et al., 2016 ); hematological system ( Shakhmatova et al., 2000 ; Chang and Streitman, 2012 ; Rodger et al., 2015 ; Soma-Pillay et al., 2016 ); spleen ( Maroni and De Sousa, 1973 ; Sasaki et al., 1981 ; Norton et al., 2009 ); renal system ( Davison and Dunlop, 1980 ; Atherton et al., 1982 ; Krutzén et al., 1992 ; Elsheikh et al., 2001 ; Cheung and Lafayette, 2013 ; Lumbers and Pringle, 2014 ; Pieper, 2015 ; Soma-Pillay et al., 2016 ); pancreas ( Ziegler et al., 1985 ; Ernst et al., 2011 ; Ohara-Imaizumi et al., 2013 ; Baeyens et al., 2016 ); adipose tissue ( Catalano et al., 2006 ; Hauguel-De Mouzon et al., 2006 ; Lain and Catalano, 2007 ; Nien et al., 2007 ; Hadden and Mclaughlin, 2009 ; Valsamakis et al., 2010 ; Musial et al., 2016 ); skeletal muscle ( Alperin et al., 2015 , 2016 ; Musial et al., 2016 ); bone ( Shahtaheri et al., 1999 ; Ulrich et al., 2003 ; Hellmeyer et al., 2006 ; Salles, 2016 ); digestive tract ( Everson, 1992 ; Fudge and Kovacs, 2010 ; Pieper, 2015 ); liver ( Munnell and Taylor, 1947 ; Van Bodegraven et al., 1998 ; Lain and Catalano, 2007 ; Bacq, 2013 ); mammary tissue ( Elling and Powell, 1997 ; Neville et al., 2002 ; Sternlicht, 2006 ; Pang and Hartmann, 2007 ); immune system ( Clarke and Kendall, 1994 ; Kendall and Clarke, 2000 ; Veenstra Van Nieuwenhoven et al., 2002 ; Norton et al., 2009 ; Mor and Cardenas, 2010 ; Saito et al., 2010 ; Racicot et al., 2014 ; Groen et al., 2015 ; Zöllner et al., 2017 ; Edey et al., 2018 ); nervous system ( Shingo et al., 2003 ; Gregg, 2009 ; Roos et al., 2011 ; Hoekzema et al., 2017 ).

Alterations in the maternal cardiovascular system begin very early in gestation ( Chapman et al., 1998 ) and ultimately lead to systemic vasodilation and increased blood perfusion of maternal organs, including the gravid uterus. Systemic vascular resistance is reduced by 25–30% and accompanied by a 40% increase in cardiac output during human pregnancy; while in mice, blood pressure decreases by 15% and cardiac output is increased by 48% ( Bader et al., 1955 ; Kulandavelu et al., 2006 ; Soma-Pillay et al., 2016 ). Renal blood flow and glomerular filtration rates are also increased ( Davison and Dunlop, 1980 ; Soma-Pillay et al., 2016 ). The renin-angiotensin-aldosterone system (RAAS) which is a major determinant for sodium balance during gestation, is progressively upregulated toward term with associated plasma volume expansion ( Elsheikh et al., 2001 ; Tkachenko et al., 2014 ). This rise in blood volume, which is required to cope with the oxygen requirements of the maternal organs and the conceptus growth, plateaus by the late gestation, resulting in an increase in total blood volume by approximately 30% at the end of pregnancy ( Chang and Streitman, 2012 ). There is also an increase in the numbers of red blood cells in the mother during pregnancy, due to proliferation of erythroid progenitors in the spleen ( Bustamante et al., 2008 ). Pulmonary function is also altered and encompasses changes in ventilation rates and blood gases. For instance, lung tidal volume and minute ventilation increases by 30–50% ( Hegewald and Crapo, 2011 ). As a result of increased oxygen consumption during hyperventilation, there is greater carbon dioxide production, which leads to chronic respiratory alkalosis that is compensated by an increased renal excretion of bicarbonate ( Weinberger et al., 1980 ). Overall, these adaptations ensure the well-being of the mother, while also providing an adequate blood flow to the placenta for fetal nutrition, oxygenation and maturation.

There are also alterations in maternal metabolic and endocrine state during gestation. In early pregnancy, the maternal pancreatic β-cell mass expands due to both hyperplasia and hypertrophy of islets, which for example in rats, results in a >50% increase ( Ackermann and Gannon, 2007 ; Rieck and Kaestner, 2010 ). The threshold for glucose-stimulated insulin production is also lowered and maternal circulating insulin concentration is greater compared to the non-pregnant state. In early pregnancy, when fetal demands are relatively low, whole body maternal insulin sensitivity is unchanged or increased and there is accumulation of energy reserves in the mother. In particular, early pregnancy is associated with adipocyte hypertrophy, increased lipogenesis and lipid storage and relates to improved insulin sensitivity of white adipose tissue in the mother ( Hadden and Mclaughlin, 2009 ; Mcilvride et al., 2017 ). Interestingly, in pregnant mice, brown adipose stores of the dam also switch to a white adipose tissue-like phenotype in early gestation ( Mcilvride et al., 2017 ). Additionally, glycogen accumulates in the liver, which also increases in size from early gestation ( Bustamante et al., 2010 ). In contrast, late pregnancy is associated with diminished maternal tissue insulin sensitivity and a concomitant increase in lipolysis and hepatic gluconeogenesis ( Freemark et al., 2002 ; Lain and Catalano, 2007 ; Musial et al., 2016 ). Despite the pregnancy-related rise in leptin and insulin concentrations, maternal appetite increases in pregnancy ( Villar et al., 1992 ; Douglas et al., 2007 ; Hadden and Mclaughlin, 2009 ; Díaz et al., 2014 ). Together, these metabolic and endocrine alterations increase lipid and glucose availability for the rapidly growing fetus in late gestation. Intriguingly in rodents, whole body responsiveness to insulin starts to improve near term, which may be important for conserving nutrients for maternal use, as parturition and lactation approach ( Musial et al., 2016 ). There are also notable changes in maternal bone metabolism during pregnancy. In particular, intestinal calcium absorption is enhanced in the mother during pregnancy via upregulation of 1,25-dihydroxyvitamin D levels, improved renal conservation and increased calcium mobilization from the maternal skeleton ( Hellmeyer et al., 2006 ). These processes support the supply of calcium for the formation, growth and mineralization of the fetal skeleton ( King, 2000 ; Kalkwarf and Specker, 2002 ).

The immune system of the mother during pregnancy is tightly regulated to prevent an unwanted immune response against the paternal antigens present in the developing conceptus ( Racicot et al., 2014 ; Groen et al., 2015 ; Zöllner et al., 2017 ). As gestation progresses, there is suppression of the pro-inflammatory Th1 type of immunity and a shift toward a more anti-inflammatory, Th2 immune state in the mother ( Saito et al., 2010 ), which supports fetal growth and maternal well-being ( Mor and Cardenas, 2010 ). In particular, the total abundance of circulating leukocytes, monocytes, granulocytes and T lymphocytes increase in the mother in response to pregnancy ( Groen et al., 2015 ). However, expression of major histocompatibility complex class II by circulating monocytes is reduced in the mother, which would decrease antigen presentation and stimulation of T cells during pregnancy and prevent the maternal immune system from mounting an unwanted response against fetal antigens ( Groen et al., 2015 ). The total number of circulating natural killer cells and secretion of pro-inflammatory cytokines (IFN-gamma) is also reduced in the pregnant state ( Veenstra Van Nieuwenhoven et al., 2002 ). However, close to parturition, the maternal immune system shifts to a pro-inflammatory state, particularly locally within the uterus, to promote labor ( Mor and Cardenas, 2010 ; Edey et al., 2018 ). There are also specific changes in the numbers of different leukocyte populations in the maternal thymus and spleen during pregnancy ( Clarke and Kendall, 1994 ; Kendall and Clarke, 2000 ; Norton et al., 2009 ). The spleen, which also has functions in hematopoiesis, enlarges due to an expansion of the splenic red pulp during pregnancy ( Maroni and De Sousa, 1973 ; Norton et al., 2009 ). Neurological changes must also occur during pregnancy to increase maternal nursing behavior and enable the mother to properly care for her newborn infant ( Bridges et al., 1997 ; Bridges, 2015 ; Kim, 2016 ; Kim et al., 2016 ). For instance, there is increased activation of the prefrontal cortex and neurogenesis of the forebrain olfactory bulb ( Shingo et al., 2003 ), which are important in regulating behavior. In addition, formation of lobulo-alveolar units in the mammary gland commences during pregnancy, in preparation for lactational support of the neonate.

Placental Hormones that Mediate Maternal Adaptations to Pregnancy, Parturition and Lactation

The placenta is a highly active endocrine organ during gestation; secreting a variety of hormones with physiological effects in the mother. Placental hormones include members of the prolactin and growth hormone family, steroid hormones and neuroactive hormones. The function of these hormones in driving physiological changes during pregnancy has been assessed in two main ways. First, the expression and activity of the hormones have been manipulated in vivo by either exogenously administering or genetically manipulating the expression of hormones and hormone receptors to study the physiological consequences for the animal. Secondly, hormones have been manipulated similarly in cultured cells and tissue explants to inform on the cellular and molecular mechanisms by which they modulate function. The effects of hormones in non-pregnant animals have been included as they provide information on the baseline of physiological changes that occur in the absence of hormone expression/activity, which is especially important in the case of some placental-derived hormones, where analyses in the pregnant state have not been conducted.

Prolactin (PRL)-Growth Hormone (GH) Family

The PRL-GH family is one of the main families of hormones secreted by the placenta during gestation. Members of this family consist of prolactin (PRL) ( Handwerger et al., 1992 ), placental lactogens (PLs) ( Wiemers et al., 2003 ), PRL-like hormones ( Wiemers et al., 2003 ), proliferins (PLF) ( Lee et al., 1988 ), proliferin-related proteins (PRP) ( Jackson et al., 1994 ) and growth hormone (GH). Between mammalian species, there are differences in the number and type of family members expressed by the placenta [reviewed elsewhere ( Linzer and Fisher, 1999 ; Soares, 2004 ; Soares et al., 2007 )]. For instance, in the mouse and rat, the placenta expresses all these members except for PRL and GH whereas the human placenta only expresses GH and PL genes. In mice and rats, expression of the individual PRL-GH family members vary spatially and temporally in the placenta ( Dai et al., 2002 ; Simmons et al., 2008 ; Urbanek et al., 2015 ). The anterior pituitary also produces PRL and GH; however this is diminished by mid-pregnancy, when placental hormone production predominates ( Bridges, 2015 ). In several species including rodents and humans, PRL is additionally produced by the decidua during pregnancy. The family members share structural similarity to one another and may bind, with varying affinity to PRL and GH receptors (PRLR and GHR, respectively), which are widely expressed by tissues in the body ( Haig, 2008 ; Trott et al., 2008 ; Ben-Jonathan and Hugo, 2015 ). As the PRL-GH members also exert similar functions, these have been presented in a grouped fashion in the text and tables (Tables 1 , 2 ). However, where possible, the roles of individual family members of the PRL-GH in physiological changes have been described.

Table 1 . Effects of the prolactin-growth hormone family in vivo .

Table 2 . Effects of the prolactin-growth hormone family in vitro .

Studies performed both in vivo and in vitro support a role for the PRL-GH family in mediating maternal metabolic adaptations to pregnancy (Tables 1 , 2 ). PRL, PRL-like proteins and PL, principally via the PRL receptor, induce β-cell mass expansion by both increasing β-cell proliferation and reducing apoptosis of islets in vivo and in vitro (Table 2 ; PRL/PL/GH; Brelje et al., 1993 ; Huang et al., 2009 ). PRL and PL also increase insulin secretion during pregnancy, particularly in response to glucose, by enhancing the expression of glucose sensors (glucokinase, hexokinase and glucose transporter-2) and activating the serotonin biosynthesis pathway in pancreatic islets (Table 2 ; PRL/PL/GH; Nielsen, 1982 ; Brelje et al., 1989 , 1993 ; Weinhaus et al., 1996 ; Sorenson and Brelje, 1997 ; Arumugam et al., 2014 ). Moreover, PL protects β-cells against streptozotocin-induced cell death in mice ( Fujinaka et al., 2004 ). GH may also be important for modulating pancreatic insulin production ( Billestrup and Nielsen, 1991 ; Brelje et al., 1993 ). However, GH from the placenta appears to be primarily important in the acquisition of insulin resistance and shifting metabolic fuel use from glucose to lipid in the mother during pregnancy (Table 1 ; PRL/PL/GH; Horber and Haymond, 1990 ; Goodman et al., 1991 ; Galosy and Talamantes, 1995 ; Barbour et al., 2002 ; Dominici et al., 2005 ; Boparai et al., 2010 ; Liao et al., 2016b ; Sairenji et al., 2017 ). Placental GH reduces insulin receptor expression and signaling, as well as, diminishes the abundance of the insulin-sensitive glucose-transporter, GLUT-4, in the skeletal muscle ( Barbour et al., 2004 ; Kirwan et al., 2004 ). Insulin receptor abundance and signaling in the liver is also reduced in response to increased GH abundance in transgenic mice ( Dominici et al., 1999 ). In white adipose tissue, GH also disrupts the insulin signaling pathway, and inhibits insulin action on glucose uptake and lipid accumulation ( Del Rincon et al., 2007 ). In part, the effects of GH may be mediated through insulin-like growth factor-1 (IGF1), which is primarily secreted from the liver in response to GH and exerts lipolytic effects during pregnancy ( Randle, 1998 ; Sferruzzi-Perri et al., 2006 ; Del Rincon et al., 2007 ). Insulin-like growth factor-2 (IGF2), which is not directly regulated by GH, but is secreted by the placenta is also important for modulating the sensitivity of β cells to glucose (Tables 1 , 2 ; IGF2; Casellas et al., 2015 ; Modi et al., 2015 ) and maternal insulin and glucose concentrations during pregnancy ( Petry et al., 2010 ; Sferruzzi-Perri et al., 2011 ). Polymorphisms/mutations in the PRL-GH family of genes and receptors have been reported in human pregnancies associated with gestational diabetes and fetal growth restriction ( Rygaard et al., 1998 ; Le et al., 2013 ). Moreover, loss of PRLR signaling in β-cells causes gestational diabetes mellitus (GDM) in mice ( Banerjee et al., 2016 ). Taken together, the production of PRL-GH family of hormones by the placenta appears to be important in regulating both insulin production and sensitivity of the mother in response to pregnancy.

The PRL-GH family is also implicated in the regulation of appetite and body weight. For instance, exogenous PRL increases food intake through inhibiting the action of leptin in non-pregnant rats (Table 1 ; PRL/PL/GH; Sorenson et al., 1987 ; Farmer et al., 1991 , 1992 ; Ladyman et al., 2010 ). In contrast, GH appears to decrease food intake in rodents through reducing ghrelin production and hypothalamic expression of appetite-stimulating neuropeptides, AgRP and NPY (Table 1 ; PRL/PL/GH; Farmer et al., 1991 , 1992 ). In non-pregnant animals, GH is important for controlling body weight and composition (such as adiposity; Farmer et al., 1991 , 1992 ; Zhou et al., 1997 ). However, in pregnancy, exogenous GH or GH releasing hormone (GHRH) does not appear to affect maternal weight gain in mice, although increases it in pigs (Table 1 ; PRL/PL/GH; Brown et al., 2012 ). The effect of PRL on weight gain and body adiposity is even less clear; with both no effect and an increase reported for non-pregnant and pregnant rodents.

The PRL-GH family also plays an important role in lactation and maternal behavior. In mice, a deficiency in PRLR or inhibition of PRL secretion in vivo compromises mammary gland development, differentiation and milk production; the latter of which is associated with loss of STAT5 signaling and fewer leaky tight junctions (Table 1 ; PRL/PL/GH; Weinhaus et al., 1996 ; Zhou et al., 1997 ). In contrast, exogenous GHRH in sheep and cows increases mammary gland milk production ( Hart et al., 1985 ; Enright et al., 1988 ). There is also evidence that PRL induces maternal behaviors, such as nurturing, nursing and pup retrieval in non-pregnant rodents (Table 1 ; PRL/PL/GH; Bridges and Millard, 1988 ). Taken together, members of the PRL-GH family appear to promote changes in maternal glucose metabolism, behavior and mammary gland function which are expected to be important for supporting the growth of offspring during pregnancy and lactation.

Steroid Hormones

The placenta is a primary source of steroid hormones during pregnancy. Placental steroid hormones include estrogens and progesterone ( Costa, 2016 ; Edey et al., 2018 ). In species like rodents, the corpus luteum continues to contribute to the circulating pool of steroid hormones during pregnancy, whereas in other species such as humans and ruminants, the placenta serves as the main source ( Costa, 2016 ). Physiological effects of progesterone are mediated predominately by nuclear receptors (PR-A, PR-B) although membrane bound-type receptors (mPR) enable non-genomic actions. Steroid hormones are implicated in pregnancy complications such as gestational diabetes and preeclampsia. High progesterone and estrogen concentrations have been reported for women with gestational diabetes ( Branisteanu and Mathieu, 2003 ; Qi et al., 2017 ). Moreover, placental estrogen and progesterone levels are reduced in preeclamptic patients compared with healthy pregnant women ( Açikgöz et al., 2013 ).

Studies performed in vivo , suggest placental steroid hormones may be important in driving the changes in insulin sensitivity and glucose metabolism of the mother during pregnancy (Table 3 ). Hyperinsulinemic-euglycemic clamp studies in women and rodents highlight a role for progesterone in reducing maternal insulin sensitivity during pregnancy. Progesterone administration decreases the ability of insulin to inhibit glucose production by the liver, and diminishes insulin-stimulated glucose uptake by skeletal muscle and to a lesser extent in the adipose tissue of non-pregnant animals (Table 3 ; Progesterone; Leturque et al., 1984 ; Ryan et al., 1985 ; Kim, 2009 ). In contrast, exogenous estrogen increases whole body insulin sensitivity in non-pregnant state (Table 3 ; Estrogen; Ahmed-Sorour and Bailey, 1980 ). Similarly, genetic deficiency of ERα or aromatase (Cyp19), which is involved in estrogen production, reduces hepatic and whole body insulin sensitivity and impairs glucose tolerance in non-pregnant mice ( Takeda et al., 2003 ; Bryzgalova et al., 2006 ). Loss of the estrogen receptor or estrogen production is also associated with increased body weight, adiposity and hepatic lipogenesis (Table 3 ; Estrogen; Takeda et al., 2003 ; Bryzgalova et al., 2006 ). Progesterone and estrogen also exert opposite effects on food intake in vivo (Table 3 ). In particular, estrogen depresses food intake in part via induction of leptin production by adipose tissue, whereas progesterone increases food intake by enhancing NPY and reducing CART expression by the hypothalamus (Table 3 ; Fungfuang et al., 2013 ; Stelmanska and Sucajtys-Szulc, 2014 ). Estrogen and progesterone however seem to have similar effects on the pancreas; they both appear to induce islet hypertrophy and/or increase pancreatic insulin levels and glucose-stimulated secretion in vivo (Table 3 ; Costrini and Kalkhoff, 1971 ; Bailey and Ahmed-Sorour, 1980 ). Nevertheless, there is some evidence that progesterone may inhibit the PRL-induced proliferation and insulin secretion of β cells in vitro (Table 4 ; Progesterone; Sorenson et al., 1993 ). Furthermore, in rodent models of type 1 and 2 diabetes mellitus, estrogen supplementation protects pancreatic β-cells from oxidative stress, lipotoxicity and apoptosis (Table 3 ; Estrogen; Tiano and Mauvais-Jarvis, 2012 ). Therefore, both estrogen and progesterone play roles in regulating insulin and glucose homeostasis, lipid handling and appetite regulation, which may be important in promoting metabolic changes in the mother during pregnancy.

Table 3 . In vivo effects of steroid hormones in vivo .

Table 4 . Effects of steroid hormones in vitro .

Work conducted both in vitro and in vivo indicate that estrogen and progesterone may also facilitate some of the cardiovascular changes that accompany pregnancy (Tables 3 , 4 ). Estrogen attenuates the vasoconstrictor responses of blood vessels, impairs vascular smooth muscle cell proliferation and calcium influx, and increases vasodilatory nitric oxide synthase activity in vitro (Table 4 ; Estrogen; Takahashi et al., 2003 ). It also increases uterine artery angiogenesis and amplifies the vasodilatory impact of vascular endothelial growth factor on isolated rat uterine vessels ( Storment et al., 2000 ; Jobe et al., 2010 ). In non-pregnant mice, deficiency of the ERβ gene leads to defects in vascular smooth muscle function, hypertension and signs of heart failure (Table 4 ; Estrogen; Zhu et al., 2002 ; Fliegner et al., 2010 ). Conversely, estrogen supplementation appears to protect the heart and vasculature from pressure overload or vessel injury ( Zhang et al., 1999 ; Zhu et al., 2002 ; Fliegner et al., 2010 ). Progesterone also exerts cardiovascular effects. It stimulates nitric oxide synthesis by human umbilical vein endothelial cells in vitro and by rat abdominal aorta and mesenteric arteries in vivo (Tables 3 , 4 ; Progesterone; Chataigneau et al., 2004 ; Simoncini et al., 2004 ). It also decreases blood pressure, when infused into ovariectomised ewes and protects against vascular injury in non-pregnant mice ( Pecins-Thompson and Keller-Wood, 1997 ; Zhang et al., 1999 ). In culture, progesterone induces hypertrophy and inhibits apoptosis of rodent cardiomyocytes ( Morrissy et al., 2010 ; Chung et al., 2012 ). Thus, via its impacts on cardiomyocytes, progesterone may mediate the pregnancy-induced growth of the mother's heart in vivo . In late pregnancy, the murine heart shifts to use fatty acids, rather than glucose and lactate, as a metabolic fuel. In part, this metabolic shift is proposed to be mediated by progesterone during pregnancy, which inhibits pyruvate dehydrogenase activity in ventricular myocytes ( Liu et al., 2017 ). Thus, placental-derived progesterone and estrogen may mediate part of the changes in the maternal cardiovascular system during pregnancy.

In many mammalian species, progesterone levels decline just before parturition and this is associated with the initiation of labor. Indeed, in rodents, inhibition of progesterone synthesis or administration of a progesterone antagonist results in premature delivery of the neonate (Table 3 ; Progesterone; Fang et al., 1997 ; Kota et al., 2013 ). In humans, circulating progesterone levels continue to be high until birth. Commencement of labor is therefore proposed to be related to a functional withdrawal of progesterone activity in the myometrium of women ( Brown A. G. et al., 2004 ; Norwitz and Caughey, 2011 ). In experimental animals, progesterone reduces the production of prostaglandins and decreases the expression of contraction-associated genes including oxytocin and prostaglandin receptors, gap junction proteins and ion channels in the myometrium (Table 3 ; Progesterone; Fang et al., 1997 ; Soloff et al., 2011 ; Edey et al., 2018 ). Together, these progesterone-mediated actions decrease contractility of uterine smooth muscle cells and maintain uterine quiescence until term. In contrast to progesterone, estrogen levels rise prior to term and estrogen promotes the expression of contraction-associated genes and contraction of the myometrium (Table 4 ; Estrogen; Nathanielsz et al., 1998 ; Di et al., 2001 ; Chandran et al., 2014 ). Therefore, in many species, the high ratio of estrogen to progesterone in the maternal circulation is thought to contribute the onset of labor. Parturition is associated with an influx of inflammatory cells and release of pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α, in the myometrium, cervix and fetal membranes ( Golightly et al., 2011 ). In mice, progesterone reduces the expression of pro-inflammatory cytokines, including IL-1β and IL-6 by the uterus and trophoblast and may modulate the abundance of myometrial monocytes (Table 3 ; Estrogen; Edey et al., 2018 ). Progesterone also decreases the ability of LPS to induce pro-inflammatory cytokine secretion by human myometrium and placental explants ( Youssef et al., 2009 ; Garcia-Ruíz et al., 2015 ). It also diminishes the ability of estrogen to induce the infiltration of macrophages and neutrophils into the uterus, and decreases LPS-induced leukocyte adhesion to human umbilical vein cells ( Simoncini et al., 2004 ). Thus, it is perhaps not surprising that progesterone receptor null mice demonstrate chronic uterine inflammation, particularly in response to estrogen treatment (Table 3 ; Estrogen; Lydon et al., 1995 ). There is also evidence that placental steroids participate in cervical softening, by regulating the expression of matrix remodeling enzymes as well as leukocyte infiltration and function ( Chinnathambi et al., 2014 ; Gopalakrishnan et al., 2016 ; Berkane et al., 2017 ). In addition to regulating the events leading to parturition, recent data suggest that during the course of pregnancy, both estrogen and progesterone contribute to the maternal tolerance of the fetus by modulating proliferation and cytokine expression of CD4 and CD8 T cells and enhancing the suppressive function of T-regulatory cells ( Mao et al., 2010 ; Robinson and Klein, 2012 ; Lissauer et al., 2015 ).

Additionally, both estrogen and progesterone are key stimulators of mammary gland development. For instance, progesterone stimulates proliferation of mammary stem cells and mammary epithelium (Tables 3 , 4 ; Progesterone; Joshi et al., 2010 ; Lee et al., 2013 ). In mice, deficiency of the progesterone receptor restricts mammary gland development, whereas exogenous progesterone induces ductal side branching and lobuloalveolar differentiation and development (Table 3 ; Progesterone; Plaut et al., 1999 ; Joshi et al., 2010 ). In addition, both estrogen and progesterone may have indirect effects on mammary gland development by regulating prolactin secretion from the pituitary gland ( Rezaei et al., 2016 ).

Maternal behavior during and after birth are regulated by the steroid hormones. Estrogen stimulates maternal nurturing behavior in numerous species, including rats, mice, sheep and primates ( Bridges, 2015 ). In particular, maternal care is induced by estrogen treatment, whereas the converse happens when ERα expression is suppressed; deficiency of ERα increases the latency to pup retrieval and reduces the length of time dams spend nursing and licking their pups (Table 3 ; Estrogen; Ribeiro et al., 2012 ). Findings from animal models suggest that progesterone plays a role in regulating anxiety and depression-related behavior. For instance, exogenous progesterone stimulates anti-anxiety and anti-depressive actions in mouse dams (Table 3 ; Progesterone; Koonce and Frye, 2013 ). In contrast, progesterone withdrawal increases these types of behaviors ( Gulinello et al., 2002 ). Thus, placental-derived steroids may modulate several aspects of maternal physiology which are beneficial to both pregnancy and post-partum support of the offspring.

Neuroactive Hormones

One major target of placental hormones is the maternal brain and related neuroendocrine organs such as the hypothalamus and pituitary glands. These neuroendocrine effects enable the mother to respond and adapt accordingly to her environment, so as to mitigate the adverse effects of stress and maintain homeostasis ( Voltolini and Petraglia, 2014 ). Neuroactive hormones also prepare and enable the future mother to adequately care for her young ( Lévy, 2016 ). In addition to their impact on the maternal neuroendocrine system, these hormones have additional functions in vivo and in vitro functions as well, which are detailed in Tables 5 , 6 , respectively.

Table 5 . Effects of neuropeptides in vivo .

Table 6 . Effects of neuropeptides in vitro .

Melatonin and Serotonin

Melatonin and its precursor, serotonin, are tryptophan-derived hormones with well-known neuroendocrine impacts. In humans, circulating concentrations of melatonin and serotonin increase as pregnancy advances ( Lin et al., 1996 ; Nakamura et al., 2001 ). In the non-pregnant state, melatonin and serotonin are primarily produced by the pineal gland and the brain, respectively. However, the enzymes involved in melatonin and serotonin biosynthesis are also expressed by the human placenta throughout gestation ( Iwasaki et al., 2005 ; Soliman et al., 2015 ; Laurent et al., 2017 ). The mouse placenta similarly expresses the enzymes needed for serotonin synthesis ( Wu et al., 2016 ), although work is required to assess if melatonin synthesizing enzymes are also expressed. The rat placenta does not produce melatonin de novo due to the lack of synthesizing enzymes ( Tamura et al., 2008 ). However, the same study demonstrated that conditioned medium from cultured term rat placentas stimulated melatonin release by the maternal pineal gland ( Tamura et al., 2008 ). These findings suggest that placental-derived factors may indirectly regulate melatonin levels by the mother during pregnancy. Placental expression of melatonin, serotonin and their respective enzymes, also remains to be investigated in other species such as rabbits and sheep, which are commonly used in pregnancy-related studies. Mouse models that result in deficiencies or reduced bioactivity of these hormones demonstrate altered sleep patterns, melancholic behavior, hyperactivity and aggression in the non-pregnant state (Table 5 ; Serotonin and Melatonin; Weil et al., 2006 ; Alenina et al., 2009 ; Kane et al., 2012 ; Adamah-Biassi et al., 2014 ; O'neal-Moffitt et al., 2014 ; Comai et al., 2015 ). Serotonin is thus a major regulator of maternal mood and behavior ( Angoa-Pérez and Kuhn, 2015 ). For instance, genetically-induced serotonin deficiency leads to increased maternal aggression, lower pup retrieval and greater pup cannibalization, which reduces postnatal survival of offspring in mice ( Angoa-Pérez et al., 2014 ). There is some evidence that serotonin and melatonin may also impact maternal feeding behavior. For example, increased serotonin signaling reduces food intake in pregnant cows ( Laporta et al., 2015 ; Weaver et al., 2016 , 2017 ; Hernández-Castellano et al., 2017 ). Similarly, exogenous melatonin lowers food intake in pregnant rats ( Nir and Hirschmann, 1980 ; Jahnke et al., 1999 ; Singh et al., 2013 ). These negative effects on maternal food intake suggest that peak serotonin and melatonin concentrations in late pregnancy may serve to control the maternal appetite and prevent excessive weight gain.

Another key function of melatonin and serotonin is glucose homeostasis and the regulation of steroid synthesis (Table 5 ; Serotonin and Melatonin). In mice, loss of melatonin or serotonin signaling leads to glucose intolerance and insulin resistance, with consequences for blood glucose and insulin concentrations in both the non-pregnant and pregnant state ( Contreras-Alcantara et al., 2010 ; Kim et al., 2010 ; Owino et al., 2016 ). However, these neuroactive hormones appear to have differential effects on the pancreas (Table 6 ; Serotonin and Melatonin). Serotonin promotes pancreatic β-cell proliferation in vitro ( Kim et al., 2010 ), and is thus important for pancreatic β-cell mass expansion during pregnancy in mice ( Goyvaerts et al., 2016 ). In contrast, melatonin reduces insulin release by rodent pancreatic islets in vitro ( Mühlbauer et al., 2012 ). Non-pregnant mice with deficient serotonin signaling have impaired lipid handling and excessive lipid accumulation in association with reduced adipose aromatase expression and circulating estrogen ( Zha et al., 2017 ). Similarly, treating placental-derived trophoblast cells with norfluoxetine, a selective serotonin-reuptake inhibitor, inhibits aromatase activity and estrogen secretion in vitro ( Hudon Thibeault et al., 2017 ). Supplementation of melatonin in non-pregnant humans reduces circulating triglycerides and cholesterol levels, but effects of lipid handling in pregnancy are unknown ( Mohammadi-Sartang et al., 2017 ). Melatonin also modulates steroid production. For instance, melatonin treatment in pregnant cows reduces circulating estrogen and progesterone ( Brockus et al., 2016 ), while lack of melatonin signaling raises blood corticosterone in mice ( Comai et al., 2015 ).

Given melatonin's additional effects on regulating the circadian rhythm ( Mühlbauer et al., 2009 ), there is some weak evidence for its role in the timing of parturition ( Yellon and Longo, 1988 ; González-Candia et al., 2016 ). Melatonin can either enhance or reduce uterine myometrial contractility depending on the species (Table 6 ; Melatonin; Ayar et al., 2001 ; Sharkey et al., 2009 , 2010 ). Both melatonin and serotonin are also important for lactation, specifically for mammary gland development and milk nutrient content ( Okatani et al., 2001 ; Xiang et al., 2012 ; Laporta et al., 2014a , b ). For instance, mammary gland proliferation and calcium transport is impaired in pregnant mice with genetically-induced serotonin deficiency ( Laporta et al., 2014a , b ). Conversely, supplementation of a serotonin precursor increases mammary calcium transporter expression and milk calcium content in lactating mice and cows ( Laporta et al., 2013a , b , 2015 ; Weaver et al., 2016 , 2017 ; Hernández-Castellano et al., 2017 ). In contrast to serotonin, increased melatonin signaling is associated with reduced ductal growth and branching, as well as impaired terminal end bud formation in the non-pregnant state ( Xiang et al., 2012 ). Thus, during lactation, these mice with increased melatonin signaling have impaired mammary gland lobulo-alveolar development and reduced milk protein content, which reduces the weight of suckling pups ( Xiang et al., 2012 ). Indeed, a recent study showed antenatal melatonin supplementation further exacerbated the growth restriction of offspring and raised circulating maternal cortisol in a sheep model of fetal growth restriction ( González-Candia et al., 2016 ). Nevertheless, melatonin supplementation during pregnancy confers significant beneficial neuroprotective effects on the fetus and enhances maternal antioxidant capacity ( Miller et al., 2014 ; González-Candia et al., 2016 ; Castillo-Melendez et al., 2017 ). Therefore, while melatonin supplementation shows promise for use in the clinic, particularly for enhancing the neurodevelopmental outcomes of offspring in growth compromised pregnancies, the potential adverse outcomes for both mother and child must also be considered and should be assessed in further studies.

Another key neuroendocrine factor is oxytocin. Oxytocin is widely known for its role in triggering maternal nursing behavior ( Bosch and Neumann, 2012 ). This is mediated by oxytocin's actions on the maternal brain, as well as, the mammary glands. Indeed, a greater rise in circulating oxytocin concentrations from early to late pregnancy in pregnant women, is associated with a stronger bond between a mother and her infant ( Levine et al., 2007 ). Concurrently, placental expression of oxytocin also peaks at term in humans ( Kim S. C. et al., 2017 ). The rat placenta also produces oxytocin ( Lefebvre et al., 1992 ), while placental expression in other species remains unclear. Reduced oxytocin signaling decreases maternal nurturing behavior such as pup retrieval in rats ( Van Leengoed et al., 1987 ). It also decreases the willingness of female voles to care for, groom and lick unrelated pups ( Keebaugh et al., 2015 ). Low oxytocin signaling can additionally impair social bonding in voles and mice ( Ferguson et al., 2000 ; Takayanagi et al., 2005 ; Lee et al., 2008 ; Keebaugh et al., 2015 ), while high levels builds trust and cooperation in a group setting to facilitate group survival in humans ( Declerck et al., 2010 ; De Dreu et al., 2010 ). Moreover, a lack of oxytocin disrupts mammary gland proliferation and lobuloalveolar development, which impairs milk release from the mammary tissues in mice ( Nishimori et al., 1996 ; Wagner et al., 1997 ). Therefore, high oxytocin levels enable the mother to bond better and protect her newborn, when it is most vulnerable.

Oxytocin is also important in the process of parturition (Table 6 ; Oxytocin); it stimulates the contraction of smooth muscle cells in the myometrium ( Ayar et al., 2001 ; Arrowsmith and Wray, 2014 ), by inducing calcium influx and stimulating prostaglandin release ( Wilson et al., 1988 ; Voltolini and Petraglia, 2014 ; Kim S. H. et al., 2017 ). Cardiovascular effects of oxytocin include its ability to significantly lower blood pressure in non-pregnant rats ( Petersson et al., 1996 ). There is also some evidence that oxytocin induces anti-inflammatory and antioxidant effects in the heart under hypoxic conditions in non-pregnant rats ( Gutkowska and Jankowski, 2012 ). Nevertheless, the specific cardiovascular effects of oxytocin in pregnancy remain to be explored.

Studies performed in non-pregnant rodents show that oxytocin also affects metabolic function in vivo (Table 5 ; Oxytocin). In particular, loss of oxytocin reduces glucose and insulin tolerance and increases adiposity ( Camerino, 2009 ), whereas exogenous oxytocin has the reverse effect ( Deblon et al., 2011 ). Studies are however, required to determine whether the rise in oxytocin in late pregnancy ( Levine et al., 2007 ) may serve to improve insulin sensitivity in the mother in preparation for the metabolic requirements of delivery and lactation. There is some evidence that oxytocin may additionally play a role in controlling energy expenditure and thermoregulation during pregnancy. Even with a similar diet and activity level to control mice, oxytocin-deficient mice become obese due to reduced energy expenditure from poor thermoregulation in the non-pregnant state ( Chaves et al., 2013 ). Furthermore, exogenous oxytocin in non-pregnant mice causes a rise in body temperature ( Mason et al., 1986 ; Tamma et al., 2009 ). Nevertheless, whether oxytocin may play a role in controlling heat dissipation due to the increased maternal energy expenditure during pregnancy requires exploration. Exogenous oxytocin also reduces food intake in non-pregnant rats ( Arletti et al., 1989 , 1990 ). However, the role of oxytocin in appetite regulation during pregnancy remains to be explored. There is also evidence for oxytocin's possible involvement in maternal bone metabolism and calcium homeostasis during pregnancy and lactation. For instance, oxytocin stimulates both bone resorption and bone formation by osteoclasts and osteoblasts respectively in vitro ( Tamma et al., 2009 ). Moreover, oxytocin administration in rats reduces circulating calcium with an overall skew toward bone formation ( Elabd et al., 2007 ). These findings may suggest that the peak in circulating oxytocin toward term promote the restoration of depleted maternal skeletal calcium stores.

Other Neuroactive Hormones

In addition to the aforementioned melatonin, serotonin and oxytocin, the human placenta also produces neuroactive hormones such as kisspeptin and thyrotropin-releasing hormone (TRH), which may function in adapting maternal physiology to support pregnancy ( Bajoria and Babawale, 1998 ; De Pedro et al., 2015 ). In humans, circulating kisspeptin rises throughout pregnancy to concentrations 10,000-fold that of the non-pregnant state, with the placenta speculated as a major source ( Horikoshi et al., 2003 ). In the non-pregnant state, kisspeptin can both stimulate and impede glucose stimulated insulin secretion in mice ( Bowe et al., 2009 ; Song et al., 2014 ). The nature of the effect may partly relate to differences in the actions of kisspeptin isoforms on pancreatic islets ( Bowe et al., 2012 ). Kisspeptin may also have effects on the maternal cardiovascular system, given its reported vasoconstrictive effects on vascular smooth muscle cells and fibrotic effects on the heart in non-pregnant rats ( Mead et al., 2007 ; Zhang et al., 2017 ). Studies in humans highlight the importance of regulating kisspeptin production during gestation; increased placental kisspeptin is associated with pre-eclampsia ( Whitehead et al., 2013 ; Matjila et al., 2016 ) and reduced circulating kisspeptin is observed in women with hypertension and diabetes during pregnancy ( Cetković et al., 2012 ; Matjila et al., 2016 ). Like the human, the murine placenta produces kisspeptin. Although a kisspeptin-deficient mouse has been established, previous work has been focused on feto-placental outcomes, with no examination of maternal physiology ( Herreboudt et al., 2015 ). Studies are required to determine the consequences of abnormal placental kisspeptin on the maternal physiology during pregnancy.

In the non-pregnant state, hypothalamic TRH stimulates release of thyroid-stimulating hormone and PRL from the pituitary ( Hershman et al., 1973 ; Vale et al., 1973 ; Askew and Ramsden, 1984 ). However, during pregnancy, the placenta serves as an additional source of TRH ( Bajoria and Babawale, 1998 ). Excess TRH in pregnancy raises blood concentrations of thyroid-stimulating hormone and PRL in humans, rhesus monkeys, sheep and rats ( Thomas et al., 1975 ; Azukizawa et al., 1976 ; Roti et al., 1981 ; Moya et al., 1986 ; Lu et al., 1998 ). Conversely, a lack of TRH reduces blood PRL in mice ( Rabeler et al., 2004 ; Yamada et al., 2006 ). Thyroid hormones are necessary for optimal brain development as well as thyroid function ( Miranda and Sousa, 2018 ). Impaired TRH signaling is associated with anxiety-like and depressive-like behavior in non-pregnant mice ( Zeng et al., 2007 ; Sun et al., 2009 ) and there is some evidence which suggests a link between thyroid dysfunction and poor maternal mood during pregnancy in humans ( Basraon and Costantine, 2011 ). However, whether any direct causal relationship between placental hormones, like TRH and perinatal depression remains unclear. Additionally, TRH is implicated in glucose homeostasis and appetite regulation. For example, mice with TRH deficiency are hyperglycaemic, due to an impaired insulin response to glucose ( Yamada et al., 1997 ). Reduced TRH signaling also impedes leptin production and ghrelin acylation, which results in less energy conservation during fasting and a lower body mass in the non-pregnant state ( Groba et al., 2013 ; Mayerl et al., 2015 ). Investigations are warranted to identify whether TRH may contribute to the regulation of glucose handling and appetite in the mother during pregnancy.

Additional Hormones

The placenta also produces numerous other hormones with pleiotropic effects. Several key ones, which have been implicated in pregnancy failure or disorders of pregnancy such as hypertension, hyperglycemia and hypercalcemia, are discussed here. The hormones presented here are by no means exhaustive and were selected primarily on their major associations with abnormal maternal physiology during pregnancy. The gonadotropin, chorionic gonadotropin (CG); transforming growth factor β (TGF β) family member, activin; angiogenic factor, relaxin; bone metabolism-associated parathyroid hormone-related protein (PTHrP) and energy homeostasis regulator, leptin are reviewed (Tables 7 , 8 ).

Table 7 . Effects of additional hormones in vivo .

Table 8 . Effects of additional hormones in vitro .

Chorionic Gonadotropin (CG)

CG, is secreted by the human (hCG) and equine (eCG) placenta, although hCG has been more extensively studied. hCG is a large glycoprotein composed of α and β subunits, of which the α subunit identical to luteinizing hormone (LH), follicle stimulating hormone (FSH) and thyroid stimulating hormone (TSH). As a result, hCG can interact with LH, FSH and TSH receptors. In women, hCG is secreted from the trophoblast from very early in gestation and is thought to be the first placental hormone to act on the mother ( Ogueh et al., 2011 ). Indeed, maternal circulating hCG concentrations peak in the first trimester and then decline toward term ( Ogueh et al., 2011 ). In early pregnancy, hCG maintains corpus luteum allowing the continued secretion of ovarian progesterone and estrogens until the steroidogenic activity of the fetal-placental unit can compensate for maternal ovarian function ( Fournier et al., 2015 ). In particular, hCG increases the abundance of low-density lipoprotein receptor and thus uptake of cholesterol for steroidogenesis. It also enhances the expression and/or activity of steroidogenic enzymes including 3β-hydroxysteroid and aromatase. There is also some evidence which suggests hCG may inhibit factors that promote luteal demise, such as the prostaglandins. The high levels of hCG in early pregnancy are also sufficient to bind to the TSH receptor and may act to increase maternal thyroid hormone production, which as mentioned previously, may exert effects in the mother and fetus.

CG may also play important autocrine and paracrine roles at the maternal-fetal interface. Administration of hCG antisera prevents implantation in marmoset in vivo ( Hearn et al., 1988 ). Recent proteomic analysis of estrogen and hCG treated human endometrial epithelial cells demonstrates that hCG targets pathways involved in metabolism, basement membrane and cell connectivity, proliferation and differentiation, cellular adhesion, extracellular-matrix organization, developmental growth, growth factor regulation and cell signaling ( Greening et al., 2016 ). Such pathways are likely to be important for placental development, as attenuating hCG signaling disrupts trophoblast differentiation in vitro ( Shi et al., 1993 ). In contrast, supplementing human trophoblast cells with hCG increases their differentiation, migration, invasion and adhesion to uterine epithelial cells, and decreases their leptin secretion in vitro (Table 8 ; hCG; Shi et al., 1993 ; Prast et al., 2008 ; Lee C. L. et al., 2013 ; Chen et al., 2015 ). hCG also promotes angiogenic vascular endothelial growth factor secretion by both trophoblast and endometrial epithelial cells ( Islami et al., 2003a ; Berndt et al., 2006 ) and enhances endothelial tube formation and migration ( Zygmunt et al., 2002 ). Furthermore, hCG is key in suppressing the maternal immune system from mounting a response against paternal antigens carried by the allogenic conceptus. Administration of hCG in a mouse model of spontaneous abortion significantly reduces the number of fetal resorptions due to improved immune tolerance of the fetus ( Schumacher et al., 2013 ). In vitro , hCG enhances proliferation of immunosuppressive uterine natural killer cells ( Kane et al., 2009 ), and the production of immunosuppressing IL-10 by B cells ( Fettke et al., 2016 ). hCG can also modulate the immune system even in a non-pregnant state, as shown by its efficacy in preventing the development of autoimmune diabetes in a mouse model ( Khil et al., 2007 ). In pregnancy, hCG additionally inhibits the contractile function of smooth muscle cells in the uterus to help sustain myometrial quiescence ( Ambrus and Rao, 1994 ; Eta et al., 1994 ), so as to prevent premature expulsion of the fetus. Glycosylation of hCG affects its biological activity and half-life ( Fournier et al., 2015 ). Given its involvement with multiple systems, it is perhaps unsurprising that abnormal concentrations of hCG and hCG glycoforms have been linked with pregnancy complications such as fetal growth restriction and preeclampsia ( Chen et al., 2012 ). However, whether the abnormal concentrations of hCG are cause or consequence of the disorders remains to be determined.

Activins are members of the TGFβ family and were first discovered for their role in stimulating FSH production and determining estrus cyclicity and fertility in mice ( Ahn et al., 2004 ; Sandoval-Guzmán et al., 2012 ). Activin signaling promotes the decidualization, as well as, apoptosis of endometrial stroma cells (Table 8 ; Activins; Tessier et al., 2003 ; Clementi et al., 2013 ; Yong et al., 2017 ); processes that accommodate implantation and conceptus development ( Peng et al., 2015 ). Additionally, activin A enhances steroid production, invasion and apoptosis of human trophoblast in vitro ( Ni et al., 2000 ; Yu et al., 2012 ; Li et al., 2015 ). However, activins may also be of importance in modulating the physiology of the mother during pregnancy (Table 7 ; Activins). In normal human pregnancy, activin A concentrations gradually rise during gestation and peak at term ( Fowler et al., 1998 ). The placenta is thought to be the main source of activin A in the maternal circulation during pregnancy, given the rapid clearance after delivery of the placenta ( Muttukrishna et al., 1997 ; Fowler et al., 1998 ). A similar rise of activin in the maternal circulation is observed in pregnant ewes ( Jenkin et al., 2001 ), while the circulating profiles in other species remain undetermined. Nevertheless, in mice, impaired activin signaling leads to poor pregnancy outcomes such as fewer viable pups ( Clementi et al., 2013 ; Peng et al., 2015 ). However, there is evidence that an increase in activin may also be pathological and detrimental to pregnancy outcome. For instance in pregnant mice, infusion of activin A or plasmid overexpression of activin A results in the development of a preeclamptic phenotype; dams display hypertension and proteinuria, in addition to growth restriction and greater in utero deaths ( Kim et al., 2008 ; Lim et al., 2015 ). The maternal hypertension observed likely results from pathological concentrations of activin A inducing vascular endothelial dysfunction ( Yong et al., 2015 ). In the non-pregnant state, activins are also important for renal glomeruli development ( Maeshima et al., 2000 ), as well as, for bone, fat and muscle metabolism ( Yogosawa et al., 2013 ; Ding et al., 2017 ; Goh et al., 2017 ). The possible contributions of activin to these latter functions in pregnancy are currently unclear. Therefore, the impact of activin signaling on these other body systems during pregnancy remains to be determined.

Relaxin is a potent vasodilator ( Danielson et al., 1999 ), and regulates hemodynamics in both the non-pregnant and pregnant state (Table 7 ; Relaxin; Conrad et al., 2004 ). In pregnant women, circulating relaxin concentration peaks in the first trimester, declines in the second trimester and is maintained until delivery in the third trimester ( Quagliarello et al., 1979 ; Seki et al., 1985 ). In contrast, circulating relaxin peaks toward term in mice, rats, guinea pigs and hamsters ( O'byrne and Steinetz, 1976 ; O'byrne et al., 1976 ; Renegar and Owens, 2002 ). In pregnant mice, relaxin deficiency leads to proteinuria, suggesting a particular role of relaxin in modulating renal function during pregnancy ( O'sullivan et al., 2017 ). In addition, relaxin-deficient mice remain sensitive to vasoconstrictors such as angiotensin and endothelin, and are hypertensive during pregnancy ( Marshall et al., 2016a ; Mirabito Colafella et al., 2017 ). During pregnancy, relaxin-deficient mice also display stiffer uterine vessels and fetal growth is retarded ( Gooi et al., 2013 ). Relaxin also enhances capillarisation and glucose uptake of skeletal muscles in non-pregnant mice ( Bonner et al., 2013 ). Taken together, these data highlight the importance of relaxin in mediating changes in maternal vascular function that serve to promote blood flow to the gravid uterus during pregnancy.

Relaxin may play additional roles within the uterus that are important for implantation, placentation and pregnancy maintenance (Tables 7 , 8 ; Relaxin). In vitro , relaxin increases decidual cell insulin-like growth factor binding protein-1 expression, a marker of decidualization ( Mazella et al., 2004 ). It also enhances survival and proliferation of cultured human trophoblast cells ( Lodhi et al., 2013 ; Astuti et al., 2015 ). During early mouse pregnancy, relaxin modulates the uterine expression of genes involved in angiogenesis, steroid hormone action and remodeling ( Marshall et al., 2016b ). Indeed in pregnant marmosets, exogenous relaxin improves uterine and placental growth ( Einspanier et al., 2009 ). Relaxin infusion also alters the endometrial lymphocyte number in vivo ( Goldsmith et al., 2004 ), which suggests a possible role of relaxin in achieving immune tolerance of the allogenic conceptus. Relaxin impedes spontaneous contractility of myometrium in humans, rats and pigs ( Maclennan and Grant, 1991 ; Longo et al., 2003 ), and is thus thought to play a role in regulating the onset of parturition ( Vannuccini et al., 2016 ). In mice with a deficiency in relaxin signaling, obstructed deliveries occur at a higher rate due to poor maturation of the cervix ( Zhao et al., 1999 ; Kamat et al., 2004 ; Krajnc-Franken et al., 2004 ; Kaftanovskaya et al., 2015 ). Conversely in hamsters, the rise in circulating relaxin toward term coincides with cervical ripening in preparation for delivery ( O'byrne et al., 1976 ). Insufficient relaxin signaling also impedes mammary development through excessive duct dilation and reduces the nursing of offspring in mice ( Zhao et al., 1999 ; Kamat et al., 2004 ; Krajnc-Franken et al., 2004 ). Conversely, overexpression leads to hypertrophy of the nipples in non-pregnant mice ( Feng et al., 2006 ). Hence, relaxin is important in driving changes at the maternal-fetal interface that establish pregnancy, adapts the cardiovascular system of the mother to support the pregnancy and prepares the mother for lactation post-partum.

Parathyroid Hormone-Related Protein (PTHrP)

During pregnancy, the placenta serves as an additional source of PTHrP ( Bowden et al., 1994 ; Emly et al., 1994 ), a key hormone involved in bone metabolism (Table 7 ; PTHrP). PTHrP concentrations in the maternal blood rise throughout gestation in humans ( Gallacher et al., 1994 ; Ardawi et al., 1997 ; Hirota et al., 1997 ) and correlate with the rise in maternal circulating calcium during pregnancy ( Bertelloni et al., 1994 ). However, excessively high circulating PTHrP can lead to hypercalcaemia during pregnancy ( Winter and Appelman-Dijkstra, 2017 ). PTHrP increases maternal bone resorption, thereby enabling calcium transfer from mother to fetus for bone development ( Salles, 2016 ). Thus, it is perhaps not surprising that complete knockout of PTHrP in mice is lethal at birth in association with abnormal bone development ( Karaplis et al., 1994 ). Carrying one defective PTHrP copy is enough to also impede bone development and reduce snout length in mice ( Amizuka et al., 1996 ). Mammary-specific PTHrP deletion increases maternal bone mass and protects against lactation-associated bone loss by reducing bone turnover in mice ( Williams et al., 1998 ; Vanhouten et al., 2003 ). However, deleting bone-specific PTHrP increases skeletal fragility, both in the non-pregnant and pregnant state ( Kirby et al., 2011 ). PTHrP infusion of lactating goats increases mammary gland uptake calcium, phosphorous and magnesium for transfer in milk to the neonate ( Barlet et al., 1992 ). These findings imply that a fine balance of PTHrP production by gestational and maternal tissues must be achieved for appropriate regulation of maternal bone metabolism and offspring calcium requirements during pregnancy and lactation.

Placental-derived PTHrP may also exert additional effects on the placenta and the mother which are beneficial for offspring development and growth. PTHrP stimulates the proliferation, differentiation, outgrowth and calcium uptake of trophoblast in vitro (Table 8 ; PTHrP; Hershberger and Tuan, 1998 ; El-Hashash and Kimber, 2006 ). In vivo , blocking PTHrP signaling during mouse pregnancy leads to excessive uterine growth and decidualization in association with a decrease in decidual cell apoptosis ( Williams et al., 1998 ; Vanhouten et al., 2003 ). Moreover, over-expression of PTHrP impairs mammary gland branching morphogenesis ( Wysolmerski et al., 1995 ; Dunbar et al., 2001 ). These studies highlight a possible important regulatory role of PTHrP in the control of decidualization and mammary gland development in vivo . In non-pregnant mice, PTHrP enhances pancreatic β-cells proliferation and insulin secretion whilst it inhibits islet cell apoptosis ( Vasavada et al., 1996 ; Porter et al., 1998 ; Cebrian et al., 2002 ; Fujinaka et al., 2004 ). It also increases renal plasma flow and glomerular filtration rate, and exerts proliferative effects on renal glomerular and tubule cells in rodents ( Izquierdo et al., 2006 ; Romero et al., 2010 ). Additionally, in vitro studies show PTHrP can induce relaxation of uterine arteries ( Meziani et al., 2005 ). However, the significance of PTHrP on glucose-insulin dynamics and renal and vascular function of the mother during pregnancy remains to be investigated.

Leptin is an abundant circulating hormone involved in regulating appetite. In the non-pregnant state, the adipose tissue is the exclusive source of circulating leptin. During pregnancy in humans, baboons and mice, concentrations of leptin rapidly rise throughout gestation, peaking toward term ( Highman et al., 1998 ; Henson et al., 1999 ; Malik et al., 2005 ). The rise in leptin positively correlates with increases in maternal body fat ( Highman et al., 1998 ). In humans, blood leptin rapidly falls to non-pregnant concentrations within 24 h of delivery, indicating that the placenta contributes to the main rise of leptin in pregnancy ( Masuzaki et al., 1997 ). In particular, leptin is produced by the human placental trophoblast cells ( Masuzaki et al., 1997 ). A similar post-pregnancy decline and placental trophoblast expression is seen in baboons ( Henson et al., 1999 ). However, this is not the case for mice, as the murine placenta does not produce leptin ( Malik et al., 2005 ). Nevertheless, leptin studies in mice still provide useful knowledge about pregnancy-related effects of leptin (Table 7 ; Leptin). For instance, leptin in pregnancy helps prepare the mother for lactation, as a deficiency results in impaired mammary gland development, which is detrimental for lactation post-delivery ( Mounzih et al., 1998 ; Malik et al., 2001 ). Another significant effect of leptin in pregnancy observed through mouse studies is leptin resistance, whereby the dam increases her food intake in mid-pregnancy to meet increased energy demands despite an increase in circulating leptin, which in the non-pregnant state would lead to satiety ( Mounzih et al., 1998 ). In contrast, excessive leptin significantly decreases maternal food intake and restricts feto-placental growth ( Yamashita et al., 2001 ). Leptin exposure of rat and human islets and cultured insulinoma cells significantly decreases insulin production in vitro , demonstrating that leptin may be directly involved in glucose metabolism (Table 8 ; Leptin; Kulkarni et al., 1997 ). Indeed dysfunctional leptin signaling in pregnancy leads to the spontaneous development of a gestational diabetic phenotype in db/+ mice, who are heterozygous for the leptin receptor (Table 7 ; Leptin; Yamashita et al., 2001 ). Further in vitro studies on placental explants or trophoblast cultures highlight a potential for leptin to be involved in immune modulation and placental hormone production, given its stimulatory effects on HLA-G and hCG expression (Table 8 ; Leptin; Chardonnens et al., 1999 ; Islami et al., 2003a , b ; Barrientos et al., 2015 ). Additional effects of leptin on the placenta are thoroughly reviewed elsewhere ( Schanton et al., 2018 ). Therefore, placental leptin can have systemic effects on the mother in pregnancy.

Pregnancy represents a unique physiological paradigm; there are dynamic and reversible changes in the function of many organ systems in the mother that are designed to support offspring development. In part, these changes are signaled via the placental secretion of hormones, which in turn, alter in abundance, interact with one another and exert wide effects on maternal tissues during pregnancy. For instance, steroid hormones modulate most systems of the mother throughout pregnancy. However, they also alter the production of other hormones, such as prolactin and placental lactogens, which in turn, may contribute to the physiological changes in the mother (Figure 2 ). However, further work is required to better define how placental hormones elicit their actions in the mother, as well as, identify the extent to which they interplay with hormones produced by maternal tissues. As the endocrine and metabolic state of the mother is also influenced by her environment, maternal conditions such as poor nutrition and obesity may modulate placental hormone production and pregnancy adaptations. Indeed, previous work has shown that an obesogenic diet during pregnancy alters the expression of PRL/PL genes in the placenta in association with mal-adaptations of maternal metabolism in mice ( Musial et al., 2017 ). Further studies are nonetheless needed to assess the interaction of the maternal environment with placental endocrine function. Placental hormones are also released into the fetal circulation, where they may have direct impacts on fetal growth and development ( Freemark, 2010 ). Investigations exploring the importance of placental endocrine function on fetal growth, independent of the mother, will require future examination. Collectively, further studies on the nature and role of placental endocrine function in maternal adaptations and fetal growth will undoubtedly provide novel insights into understanding of the potential causes of obstetrical syndromes such as gestational diabetes and preeclampsia that are marked by maternal physiological maladaptation.

Figure 2 . Summary of expression profiles, interactions and maternal physiological effects of placental-derived hormones. PRL, prolactin; PL, placental lactogen; PLF, proliferins; PRP, proliferin-related proteins; GH, growth hormone; GHRH, growth hormone releasing hormone; IGF1/2, insulin-like growth factor-1/2; E2, estrogen; P4, progesterone; MEL, melatonin; SER, serotonin; KISS, kisspeptin; OXY, Oxytocin; TRH, thyrotropin-releasing hormone; RELAX, relaxin; ACTIV, activin; CG, chorionic gonadotropin; LEP, leptin; PTHrP, parathyroid hormone-related protein.

Author Contributions

TN and HY substantially contributed to the conception of the work, drafting and revision of the manuscript, preparation of the tables and approved of the final version. JL-T substantially contributed to the conception of the work, drafting and revision of the manuscript, preparation of the figures and approved of the final version. AS-P substantially contributed to the conception of the work, critical revision of the manuscript for intellectual content and approved of the final version.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

TN was supported by the Marie Skłodowska-Curie Individual Fellowship from the European Union; HY was supported by an A*STAR International Fellowship from the Agency for Science, Technology and Research; JL-T was supported by the Newton International Fellowship from the Royal Society; AS-P was supported by the Dorothy Hodgkin Research Fellowship from the Royal Society.

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Keywords: pregnancy, placenta, hormones, maternal adaptations, metabolism, fetal growth, endocrine, cardiovascular

Citation: Napso T, Yong HEJ, Lopez-Tello J and Sferruzzi-Perri AN (2018) The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation. Front. Physiol . 9:1091. doi: 10.3389/fphys.2018.01091

Received: 20 April 2018; Accepted: 23 July 2018; Published: 17 August 2018.

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Copyright © 2018 Napso, Yong, Lopez-Tello and Sferruzzi-Perri. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Amanda N. Sferruzzi-Perri, [email protected]

† These authors have contributed equally to this work

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What is placenta? Mention its role during pregnancy?

The embryo gets nutrition from the mother’s blood with the help of a special tissue which looks like a disc-shaped sac called placenta. the placenta is embedded in the uterine wall. it contains villi on the embryo’s side of the tissue and on the mother’s side are blood spaces, which surround the villi. this provides a large surface area for glucose and oxygen to pass from the mother to the embryo. the developing embryo will also generate metabolic waste which can be removed by transferring them into the mother’s blood through the placenta..

Question 54 What is placenta? Mention its role during pregnancy?

What is placenta? State its two role during pregnancy.