The fetal membranes are the four

extraembryonic membrane The extraembryonic membranes are four membranes which assist in the development of an animal's embryo. Such membranes occur in a range of animals from humans to insects. They originate from the zygote, but are not considered part of the embryo. The ...

s, associated with the developing

embryo An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sp ...

, and

fetus A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...

in humans and other mammals. They are the

amnion The amnion (: amnions or amnia) is a membrane that closely covers human and various other embryos when they first form. It fills with amniotic fluid, which causes the amnion to expand and become the amniotic sac that provides a protective envir ...

chorion The chorion is the outermost fetal membrane around the embryo in mammals, birds and reptiles (amniotes). It is also present around the embryo of other animals, like insects and molluscs. Structure In humans and other therian mammals, the cho ...

allantois The allantois ( ; : allantoides or allantoises) is one of the extraembryonic membranes arising from the yolk sac. It is a hollow sac-like structure filled with clear fluid that forms part of the developing conceptus in an amniote that helps the ...

, and

yolk sac The yolk sac is a membranous wikt:sac, sac attached to an embryo, formed by cells of the hypoblast layer of the bilaminar embryonic disc. This is alternatively called the umbilical vesicle by the Terminologia Embryologica (TE), though ''yolk sac' ...

. The amnion and the chorion are the chorioamniotic membranes that make up the

amniotic sac The amniotic sac, also called the bag of waters or the membranes, is the sac in which the embryo and later fetus develops in amniotes. It is a thin but tough transparent pair of biological membrane, membranes that hold a developing embryo (and l ...

which surrounds and protects the embryo. The fetal membranes are four of six accessory organs developed by the

conceptus A conceptus (from Latin Latin ( or ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken by the Latins (Italic tribe), Latins in Latium (now known as Lazio), ...

that are not part of the embryo itself, the other two are the

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

, and the

umbilical cord In Placentalia, placental mammals, the umbilical cord (also called the navel string, birth cord or ''funiculus umbilicalis'') is a conduit between the developing embryo or fetus and the placenta. During prenatal development, the umbilical cord i ...

Structure

The fetal

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...

s surround the developing embryo and form the fetal-maternal interface. The fetal membranes are derived from the trophoblast layer (outer layer of cells) of the implanting

blastocyst The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the ''embryoblast'' which subsequently forms the embryo, and an outer layer of trophoblast cells called the ...

. The trophoblast layer differentiates into amnion and the chorion, which then comprise the fetal membranes. The amnion is the innermost layer and, therefore, contacts the

amniotic fluid The amniotic fluid is the protective liquid contained by the amniotic sac of a gravid amniote. This fluid serves as a cushion for the growing fetus, but also serves to facilitate the exchange of nutrients, water, and biochemical products betwee ...

, the

and the

. The internal pressure of the amniotic fluid causes the amnion to be passively attached to the chorion. The chorion functions to separate the amnion from the maternal decidua and

uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...

. The placenta develops from the chorion of the embryo and the uterine tissue of the mother.

Development of the fetal membranes

Initially, the amnion is separated from the chorion by chorionic fluid. The fusion of the amnion and chorion is completed in the human at the 12th week of development.

Microanatomy

From inside to outside, the fetal membranes consist of amnion and chorion. In addition, parts of

decidua The decidua is the modified mucosal lining of the uterus (that is, modified endometrium) that forms every month, in preparation for pregnancy. It is shed off each month when there is no fertilized egg to support. The decidua is under the influe ...

are often attached to the outside of the chorion.

Amnion

The amnion is

avascular Blood vessels are the tubular structures of a circulatory system that transport blood throughout many animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the tissues of a body. They also take waste and ...

, meaning it does not contain its own blood vessels. Therefore, it must obtain necessary nutrients and oxygen from nearby chorionic and amniotic fluid, and fetal surface vessels. The amnion is characterised by cuboidal and columnar epithelial layers. The columnar cells are located in the vicinity of the

, whereas the cuboidal cells are found in the periphery. During early pregnancy, the amnionic epithelium is sparsely covered in

microvilli Microvilli (: microvillus) are microscopic cellular membrane protrusions that increase the surface area for diffusion and minimize any increase in volume, and are involved in a wide variety of functions, including absorption, secretion, cellula ...

, which increase in number throughout pregnancy. The function of this microvillous surface is associated with a densely-packed glycocalix with anionic binding sites; these are thought to be involved with intra-amnionic lipid synthesis. This amnionic epithelium is connected to a

basement membrane The basement membrane, also known as base membrane, is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tis ...

, which is then attached by filaments to a

connective tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...

layer.

Chorion

The chorionic membrane is a fibrous tissue layer containing the fetal blood vessels.

Chorionic villi Chorionic villi are Wiktionary:villus, villi that sprout from the chorion to provide maximal contact area with maternal blood. They are an essential element in pregnancy from a histology, histomorphologic perspective, and are, by definition, a pr ...

form on the outer surface of the chorion, which maximise surface area for contact with maternal blood. The chorionic villi are involved in fetal-maternal exchange.

Yolk sac

The yolk sac is a membranous sac attached to an

, formed by cells of the

hypoblast In amniote embryology, the hypoblast is one of two distinct layers arising from the inner cell mass in the mammalian blastocyst, or from the blastodisc in reptiles and birds. The hypoblast gives rise to the yolk sac. The hypoblast is a layer of ...

layer of the

bilaminar embryonic disc The bilaminar embryonic disc, bilaminar blastoderm or embryonic disc is the distinct two-layered structure of cells formed in an embryo. In the development of the human embryo this takes place by day eight. It is formed when the inner cell mass, a ...

. This is alternatively called the ''umbilical vesicle''. In humans, the yolk sac is important in early embryonic blood supply.

Allantois

The

human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

allantois is a caudal out-pouching of the yolk sac, which becomes surrounded by the

mesodermal The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical Embr ...

connecting stalk The connecting stalk, or body stalk, is an embryonic structure that is formed by the third week of development and connects the embryo to its shell of trophoblasts. The connecting stalk is derived from the extraembryonic mesoderm. Initially it li ...

or body-stalk. The vasculature of the body-stalk develops into

umbilical arteries The umbilical artery is a paired artery (with one for each half of the body) that is found in the abdominal and pelvic regions. In the fetus, it extends into the umbilical cord. Structure Development The umbilical arteries supply systemic arte ...

that carry deoxygenated blood to the

. It is externally continuous with the

proctodeum A proctodeum is the back ectodermal part of an alimentary canal. It is created during embryogenesis by a folding of the outer body wall. It will form the lower part of the anal canal, below the pectinate line The pectinate line (dentate line) i ...

and internally continuous with the

cloaca A cloaca ( ), : cloacae ( or ), or vent, is the rear orifice that serves as the only opening for the digestive (rectum), reproductive, and urinary tracts (if present) of many vertebrate animals. All amphibians, reptiles, birds, cartilagin ...

. The embryonic allantois becomes the fetal

urachus The urachus forms from the distal end of the allantois in the embryo, and develops into a closed cord between the base of the bladder, and the navel. It drains the bladder of the fetus that joins and runs within the umbilical cord. The fibrous r ...

, which connects the fetal bladder (developed from cloaca) to the yolk sac. The urachus removes nitrogenous waste from the fetal bladder. After birth the urachus is closed, and becomes the

median umbilical ligament In human anatomy, the median umbilical ligament is an unpaired midline ligamentous structure upon the lower inner surface of the anterior abdominal wall. It is covered by the median umbilical fold. The median umbilical ligament represents the re ...

Function

The fetal membrane surrounds the fetus during the gestational period and ensures maintenance of pregnancy to delivery, protection of the fetus as well as being critical in maintaining the conditions necessary for fetal health.

Barrier function

The fetal membranes separate maternal tissue from fetal tissue at a basic mechanical level. The fetal membrane is composed of a thick cellular chorion covering a thin amnion composed of dense collagen fibrils. The amnion is in contact with the amniotic fluid and ensures structural integrity of the sac due to its mechanical strength. The underlying chorion is fused to the decidua at the maternal-fetal interface. This interaction is vital in controlling the local immune systems which in turn is vital for maintaining a semi-allogeneic fetus. At the end of gestation, a 'weak zone' develops in the fetal membrane overlying the cervix due to collage remodelling. This eventually leads to rupture of the fetal membrane and the onset of labour.

Signalling of fetal maturation and parturition

As pregnancy advances to term, the fetal membranes undergo weakening. The amnion is vital in the synthesis of

prostaglandin Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...

s which reach the myometrium and create and initiate parturition. The chorion expresses chemicals that balance synthesis and metabolism of these prostaglandins to ensure that the myometrium is not activated pre-term.

Prostaglandin E2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnanc ...

is thought to be synthesized by cells in the amnion and is essential in dilation of the cervix at the initiation of parturition.

Glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...

s have been implicated in fetal maturation, regulation of immune response and many other pregnancy associated changes. As well as its function in parturition, Prostaglandin E2 is vital for fetal lung maturation. Additionally, there is an abundance of 11β-hydroxysteroid dehydrogenase 1 expressed in the foetal membranes. This enzyme converts biologically inactive

cortisone Cortisone is a pregnene (21-carbon) steroid hormone. It is a naturally-occurring corticosteroid metabolite that is also used as a pharmaceutical prodrug. Cortisol is converted by the action of the enzyme corticosteroid 11-beta-dehydrogenase ...

into active

cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...

, another chemical vital for fetal maturation and labour initiation.

Pathophysiology

Preterm birth Preterm birth, also known as premature birth, is the Childbirth, birth of a baby at fewer than 37 weeks Gestational age (obstetrics), gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 ...

s (births taking place before 37 weeks) can be the result of a number of causes such as, in utero infection, inflammation, vascular disease and uterine overdistension. The risk of spontaneous preterm birth is increased by a previous preterm birth, black race, periodontal diseases and low maternal

body-mass index Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms (kg) an ...

. Key indicators of preterm birth are short cervical length and a raised cervical-vaginal fetal

fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as col ...

concentration. Pathophysiology of the fetal membranes, such as microfractures, senescence of cells in the fetal membrane and inflammation can lead to an increased chance of preterm premature rupture of the fetal membranes (pPROM).

Microfractures of the fetal membranes

Throughout gestation the fetal membranes undergo remodeling to allow for the increase in size of the uterus. The remodeling of the fetal membranes occurs at both the level of the cells and the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...

(ECM). Structural abnormalities such as areas of where

collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

has degraded, known as microfractures, have been observed in the amniotic membrane layer. Microfractures are characterised by: * Alterations to or shedding of the epithelial cells of the amnion layer *

Basement membrane The basement membrane, also known as base membrane, is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tis ...

damage or degradation * Cells in the ECM migrating * The presence of tunnels from the basement membrane to the spongy layer of the amnion. Microfractures of the fetal membranes are seen in pregnancies where pPROM has occurred. It has been suggested that the presence of more fetal membrane microfractures may mean the fetal membranes may be predisposed for preterm rupture.

Inflammation and senescence of the fetal membranes

Inflammation of the fetal membranes is called chorioamnionitis. Balanced inflammation is an important factor in maintaining fetal membranes by regulating the remodeling. However, if the inflammatory response increases above this level it can have dangerous and potentially fatal effects for the mother and child. These elevated levels of inflammatory molecules in the fetal membrane is called ‘sterile inflammation’. Sterile inflammation can be caused by both microbial infection and non-infectious factors, such as senescence of fetal membranes. Senescence is associated with the aging of actively cycling and dividing cells. As the fetal membrane cells proliferate during remodelling, the

telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes (see #Sequences, Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In ...

s (short length or

non-coding DNA Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, microRNA, piRNA, ribosomal RNA, and reg ...

on the end of chromosomes that protect essential coding DNA from degradation during replication) shorten as chromosomes can not be copied end-to-end fully. Once the telomeres have reached a critical length the cell can no longer divide and can hence cause telomere-dependent replicative senescence. This should occur naturally at term (37 weeks), as it is an important factor to increase the inflammatory environment in the uterus to initiate parturition. However, fetal membrane senescence can be accelerated by

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

and hence, stimulate sterile inflammation to occur prior to term; consequently, causing preterm birth.

References

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