March 14, 2024

Parturition: Understanding the Molecular Basis of Human Labor and Delivery

Introduction

The physiology of human birth is awesome. Human birth, like births of all mammalian species, is a miracle that literally happens every minute all over the world. This blog is a description of physiological birth. A discussion of birth complications is for another time.  At a molecular level, birth is an extremely complicated and controlled process that involves the activation of numerous biochemical pathways over an extended period of time. In each individual situation it is almost impossible to determine exactly when this birth process starts. There is no one diagnostic test that can be given to determine the point in time of labor initiation. This time is determined in retrospect as the process advances. During labor uterine contractions become coordinated and close together to work to expel the fetus. The uterine cervix must open and dilate so that the fetus can enter the birth canal and then be born. For eons humans have understood this.  But how exactly at a basic science level does this happen?  Many chemical pathways are initiated and hormones and other factors involved are activated and expressed in a sequential manner Each biochemical molecule with one or more specific roles is activated and expressed prior to the next in the pathway in a stepwise fashion. Many pathways have feedback loops, meaning that as new factors are expressed during the progression of the pathway cascade, they are able to push the pathway forward in a positive way or exert an inhibitory affect on the factors already expressed to cause a negative affect on the pathway.  In the labor process the pathways are often redundant, meaning that if that particular pathway is not functioning, other pathways are capable of working together without that particular one to enable birth. All this complexity and redundancy is helpful in order to ensure the “fail-safe” aspect of human birth. Human babies will be born no matter what the circumstances.  Babies are born during wars, famines, hurricanes and other natural disasters. Having stated this it is also very important to note that the best situation is when all the pathways of the system are working properly. Birth is the most critical process for the survival of humans on earth. The intent of all who care for pregnant individuals is to work ensure that the birth process is optimal in all circumstances.

The whole birth process is designed to overcome two challenges. The first challenge has to do with getting a fairly large baby out of the uterus and through the birth canal. Because humans walk on two legs or are bipedal, by necessity the pelvis cannot be wider or bigger than it is or we could not walk upright. This means that the passage through the pelvic birth canal is a tight fit for the baby.  Evolution provided a situation, a solution for this challenge. The human baby’s head contains a not fully developed brain is not too large at birth so the infant can pass through the pelvic bones. Thus, human babies are born at a developmentally early stage to ensure that birth will occur at a time when the infant can get out of the birth canal. Compared to other mammals, the human newborn cannot walk, or communicate very well and has no functional control over many body functions such as urination and defecation. That all comes later in childhood as the brain grows and develops. The second challenge is how the uterus- a organ made up of three layers of smooth muscle cells changes from quiescent muscle cells to cells that contract to expel the baby. During pregnancy the smooth muscle cells must remain quiet and not contract to keep the fetus in the uterus. Thus, in pregnant individual there is a “switch” from a quiescent phenotype, (cells that express factors that keep them non-contractile) to a contractile phenotype (cells that are able to contract in concert with other uterine smooth muscle cells) at the very last part of pregnancy. Conversely, the very firm uterine cervix of early pregnancy, which is composed of extracellular matrix proteins, primarily type 1 and type 3 collagen and a number of glycosaminoglycans becomes the soft and pliable cervix of later pregnancy that will dilate or open with the increasing force of the uterine muscle contractions. The role of the cervix during pregnancy is to stay closed to allow the fetus to remain in the uterus until the time is ripe for birth. It also acts a barrier to prevent infection of the fetus and fetal membranes. These changes from a firm cervix to a soft one occur over time in the last part of pregnancy.

Uterine Preparation for Labor

During the first part of pregnancy the uterine smooth muscle cells proliferate, grow and hypertrophy. There are three layers of smooth muscle cells in the uterus which are longitudinal, oblique and circular which make up the myometrium. The extracellular matrix of the uterus expands in order to accommodate the growing fetus. Later in pregnancy the myometrial cells begin to secrete many types of molecules that are vital to the preparation for and initiation of labor. In human pregnancy the hormone, progesterone and the progesterone receptors that bind progesterone are two important chemicals that are present in the uterine myometrium that maintain the uterine myometrium in a quiet state throughout pregnancy. There are two progesterone receptors, PRA and PRB. They have different functions and their expression levels change as pregnancy advances which contributes to the changes from a quiet myometrium to a contractile myometrium. Progesterone and its receptors provide inhibition of the expression of contractile genes and a dampening of the expression of two transcription factors called NF-kB and Ap-1 which are regulators of many factors prominent in tissue remodeling and inflammatory responses. Do not get confused by the word inflammation. This does not mean infection but an influx of cells such as leukocytes, neutrophils and macrophages that are involved in tissue remodeling that occurs as part of the switch from quiet cells to contractile cells. These cells become activated and is an important part of process of the switch from a quiet muscle cell to a cell that will respond go contractile genes. During most of pregnancy another transcription factor, called ZEB1 is up-regulated which also inhibits contractile genes. Since progesterone in humans is known to remain in human myometrium as well a in circulation during late pregnancy and in labor something else needs to occur to facilitate the switch. As pregnancy advances near term the progesterone receptors start to change their function.   There is evidence that as the uterus stretches, the inflammatory or tissue remodeling activity is stimulated by chemokine production. Signals from the fetus contribute to this production as well and begin to cause a decline in the uterine progesterone function as well.  Estrogen and estrogen receptors are also increased by mother and fetus and begin to start a decline in the function of progesterone receptors. This increase further enhances the inflammatory tissue remodeling response which then triggers a shift to a contractile phenotype of the myometrial smooth muscle cells.  An important change occurring during this process is that the myometrial smooth muscle cells form links between themselves, called gap junctions that form due to the expression of connexin 43, a gap junction protein. Thus, the myometrium develops to the point where the contractions of each cell are synchronized allowing for uterine muscle contractions of each individual cell to work together. Oxytocin and oxytocin receptors are upregulated and prostaglandins are secreted. All of these actions contribute to the change in the behavior of the smooth muscle cells and their secretion and activity. They are interwoven as they all contribute to labor initiation and its ultimate success. These are very complex activation and inhibition pathways and are confusing to most individuals. What one needs to remember is that these pathways all work together to gradually change the quiescent myometrium needed to maintain the fetus in the uterus until it is mature enough to be born to a myometrium that will contract as a syncytium of connected cells that will produce a way to have the baby move out of the uterus into the world. 

The placenta and fetal membranes are also involved in the process of labor. At some point they rupture releasing amniotic fluid. This might be at the onset of labor, but it usually occurs spontaneously in the active phase of labor. The fetal membranes also contribute to the labor cascade, sending signaling molecules to the mother from the fetus.

The uterine cervix must also undergo changes and become softer and thinner to allow it to easily dilate or open. Throughout pregnancy it has undergone changes to make it softer. The is an increase in proteoglycans, especially hyaluronic acid and a gradual loosening of the triple helical conformation of type 1 and type 3 collagen. The physiological challenge is that the cervical tissue must be able to resist opening during pregnancy as it softens. There is an increase in water content as pregnancy advances.  There is biomechanical evidence that as this softening occurs the cervix increases in volume and this change allows it to maintain pregnancy and resist uterine contractions that might occur.  In fact, in humans a shortening of the uterine cervix in pregnancy is a risk factor for preterm birth.

Labor

By definition human labor is the process of childbirth where increasingly strong and synchronized uterine muscle contractions dilate the uterine cervix and allow the baby to be pushed out of the uterus into the world. Oxytocin, a small peptide is synthesized in the hypothalamus and also in the uterus at the fetal membrane/decidua interface. Near term oxytocin receptors are increased in the uterine myometrium. Oxytocin is released in pulses throughout labor. Through a complex system of actions mediated by oxytocin and its receptor, calcium flows into the smooth muscle cells to cause the onset of uterine contractions. These synchronized contractions enable the expulsion of the baby and become stronger as labor progresses.  Not only does oxytocin cause uterine contractions, it also activates in inflammatory or tissue remodeling cascades in the fetal membranes and the uterine cervix. Oxytocin is also important in establishing lactation following birth and is though to promote maternal behavior. It is also secreted in males. One of its functions is to promote social activity by increasing social recognition and reducing fear. Prostaglandins are substances that are important in the whole complex interwoven pathways necessary for human birth. Both oxytocin and prostaglandins are used by clinicians to augment the labor process if necessary.  Clinicians divide labor into three stages traditionally. In the 1950s research into the stages of labor established the idea of stages. They also assessed that labor progressed more rapidly as measured by the dilation of the cervix as labor progressed.  The published their findings showing the cervical dilation when plotted on a graph displayed a sigmoid curve. They also published data about the length of these stages. There have been a number of research studies published subsequently that show different types of curves and suggest that normal stages may be longer that originally conceived. Stage One is from the start of regular synchronized contractions to full dilation of the cervix at 10 centimeters. This stage is divided into a latent phase and an active phase.  Active phase starts when the contractions are strong and close together and able to dilate the cervix from about 4 to 6 centimeters to full dilation. As the uterine smooth muscle cells contract and then relax, they do not return to exactly the same length as previously. The lower part of the uterine become thin and the upper part of the uterus, the fundus becomes thicker. This causes the uterine cavity housing the infant to get smaller so that that the baby stays in the place where he/she has been pushed. This physiological event also allows the fetal head to be maintained against the cervix keeping it dilated. Stage Two starts when the cervix is fully dilated or open until the baby is born. This second stage in when the baby passed through the mother’s bony pelvis. The biomechanical challenge is to allow the largest part of the baby’s head through the narrowest part of the mother’s pelvis. The maternal pelvic joints are influenced by relaxin, a hormone released in pregnancy which allows the pelvis some extra room, the baby’s skull bones are not yet fused together and so they can overlap somewhat. The contractions of the uterus and spontaneous pushing by the mother push the baby through this passage. The biomechanical mechanisms that occur to allow the soon to be born baby, are due to the resistance of the its head (in the majority of births the infant is born head first) against the maternal pelvic bones and soft tissue when pushed by the muscle contractions. First the baby’s head comes into the pelvis, called engagement, then starts to descend through the birth canal. In moving through the birth canal, the baby’s head and shoulders must go through the movement of flexion of the chin on the chest, then rotation to the side, then extension as the birth begins and finally another rotation after the baby’s head is born and then birth of the body (expulsion).  The mother’s position is important also in this process. When standing or squatting rather than staying in a supine lying down position, it is possible to increase the room for the baby to move through the pelvis. Stage Three ends with the delivery of the placenta. Here is where the oblique uterine muscle layer functions.  As the uterine muscles contracts this layer is vital in constricting the small blood vessels in the placental bed and the overall uterus and keeps the mother from hemorraghing. Overall human labor for a first pregnancy lasts about 12 to sometimes 24 hours all together while labor for subsequent births is shorter, lasting on average about 8 hours. A very important part of labor and birth is the establishment of the infant-parent bond. Mother and child as well as father child bond is enhanced by skin to skin contact of baby to the patent. This contact also has thermoregulatory effects as well in that the baby is kept warm. Breastfeeding immediately postpartum is very beneficial and provides early nourishment in the from of colostrum, and early breast secretion that provides in baby with immunoglobulins (IgA), high amounts of protein and vitamins A, B12 and K. Early breastfeeding aids the mother as increased oxytocin is secreted aiding in the contraction of the uterus to prevent excessive bleeding and helps start the uterus on its path to obtain a normal size following the end of the postpartum periods.

Birth occurs by an incredible and complex cascade of molecules and pathways.  It can be slowed by the chemical pathway associated with discomfort and fear.  It is aided by a calm and supportive environment for the mother. This cannot be emphasized enough. If the laboring mother is stressed to becomes fearful, labor will slow down or stop due to the actions of the hormones released in the flight or fight pathway.  The most awesome fact, however, is that the physiology of birth while very complex is designed for the safe birth for the mother and a healthy baby.

Further reading:

Colon-Caraballo M, Lee N, Nallasamy S, Myers K, Hudson D, Iozzo RV, Mahendroo M. Novel regulatory roles of small leucine-rich proteoglycans in remodeling of the uterine cervix in pregnancy. Matrix Biol. 2022 Jan;105:53-71. doi: 10.1016/j.matbio.2021.11.004. Epub 2021 Dec 1. PMID: 34863915; PMCID: PMC9446484.

Iversen JK, Kahrs BH, Eggebø TM. There are 4, not 7, cardinal movements in labor. Am J Obstet Gynecol MFM. 2021 Nov;3(6):100436. doi: 10.1016/j.ajogmf.2021.100436. Epub 2021 Jun 30. PMID: 34214716.

Khader N, Shchuka VM, Shynlova O, Mitchell JA. Transcriptional control of parturition: insights from gene regulation studies in the myometrium. Mol Hum Reprod. 2021 May 8;27(5):gaab024. doi: 10.1093/molehr/gaab024. PMID: 33823545; PMCID: PMC8126590.

Liu N, Yang H, Han L, Ma M. Oxytocin in Women's Health and Disease. Front Endocrinol (Lausanne). 2022 Feb 15;13:786271. doi: 10.3389/fendo.2022.786271. PMID: 35242106; PMCID: PMC8886718.

Menon R. Initiation of human parturition: signaling from senescent fetal tissues via extracellular vesicle mediated paracrine mechanism. Obstet Gynecol Sci. 2019 Jul;62(4):199-211. doi: 10.5468/ogs.2019.62.4.199. Epub 2019 Jun 28. PMID: 31338337; PMCID: PMC6629986.

Neal JL, Lowe NK, Ahijevych KL, Patrick TE, Cabbage LA, Corwin EJ. "Active labor" duration and dilation rates among low-risk, nulliparous women with spontaneous labor onset: a systematic review. J Midwifery Womens Health. 2010 Jul-Aug;55(4):308-18. doi: 10.1016/j.jmwh.2009.08.004. PMID: 20630357

Renthal NE, Williams KC, Montalbano AP, Chen CC, Gao L, Mendelson CR. Molecular Regulation of Parturition: A Myometrial Perspective. Cold Spring Harb Perspect Med. 2015 Sep 3;5(11):a023069. doi: 10.1101/cshperspect.a023069. PMID: 26337112; PMCID: PMC4632865.

Shynlova O, Nadeem L, Lye S. Progesterone control of myometrial contractility. J Steroid Biochem Mol Biol. 2023 Nov;234:106397. doi: 10.1016/j.jsbmb.2023.106397. Epub 2023 Sep 6. PMID: 37683774.

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