Fetal membranes

Initially, the amnion is separated from the chorion by chorionic fluid.[4] The fusion of the amnion and chorion is completed at the 12th week of development.[6]

The amnion is avascular, 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.[7] The amnion is characterised by cuboidal and columnar epithelial layers.[7] The columnar cells are located in the vicinity of the placenta, whereas the cuboidal cells are found in the periphery.[7] During early pregnancy, the amnionic epithelium is sparsely covered in microvilli, which increase in number throughout pregnancy.[4] 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.[4] This amnionic epithelium is connected to a basement membrane, which is then attached by filaments to a connective tissue layer.[8]

The chorionic membrane is a fibrous tissue layer containing the fetal blood vessels.[4] Chorionic villi form on the outer surface of the chorion, which maximise surface area for contact with maternal blood.[4] The chorionic villi are involved in fetal-maternal exchange.[9]

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 foetal membrane overlying the cervix due to collage remodelling. This eventually leads to rupture of the fetal membrane and the onset of labour.

As pregnancy advances to term, the fetal membranes undergo weakening.[10] The amnion is vital in the synthesis of prostaglandins 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 is thought to be synthesized by cells in the amnion and is essential in dilation of the cervix at the initiation of parturition.[11] Glucocorticoids have been implicated in fetal maturation, regulation of immune response and many other pregnancy associated changes.[11] 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 into active cortisol, another chemical vital for fetal maturation and labour initiation.

Throughout gestation the fetal membranes undergo remodelling to allow for the increase in size of the uterus. The remodelling of the fetal membranes occurs at both the level of the cells and the extracellular matrix (ECM).[11] Structural abnormalities such as areas of where collagen has degraded, known as microfractures, have been observed in the amniotic membrane layer.[14][15]

Microfractures are characterised by:

• Alterations to or shedding of the epithelial cells of the amnion layer [11]
• Basement membrane damage or degradation [11]
• Cells in the ECM migrating [11]
• The presence of tunnels from the basement membrane to the spongy layer of the amnion.[11]

Microfractures of the fetal membranes are seen in pregnancies where pPROM has occurred.[11] It has been suggested that the presence of more fetal membrane microfractures may mean the fetal membranes may be predisposed for preterm rupture.[11]

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’.[11] 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.[14] As the fetal membrane cells proliferate during remodelling, the telomeres (short length or non-coding DNA 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.[16] 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 and hence, stimulate sterile inflammation to occur prior to term; consequently, causing preterm birth.[14]