CAUSES AND ONSET OF NORMAL LABOUR

CAUSES AND ONSET OF NORMAL LABOUR

MODERATOR – DR ROHINI RAOPRESENTED BY – DR SWATI SUGANDHA

OVERVIEW◦DEFINITION◦NORMAL LABOUR◦ONSET OF NORMAL LABOUR◦ STAGES OF LABOUR◦ PARTURITION◦ PHASES OF PARTURITION◦ PHYSIOLOGY OF PHASE 1◦ PHYSIOLOGY OF PHASE 2◦ CAUSES OF NORMAL LABOUR◦MECHANISM OF NORMAL LABOUR

◦WHO defines normal labour as ◦  “spontaneous in onset, low-risk at the start of labour and remaining so throughout labour and delivery. The infant is born spontaneously in the vertex position between 37 and 42 completed weeks of pregnancy. After birth, mother and infant are in good condition”1

1World Health Organization, Maternal and Newborn Health/Safe Motherhood Unit. Care in normal birth: a practical guide.

NORMAL LABOR (EUTOCIA):◦ Labor is called normal if it fulfils the following criteria.

Spontaneous onsetSpontaneous expulsion, of a single, mature foetus,    presented by vertex,     through the birth canal,   within a reasonable time (not less than 3 hours or more than 18 hours),  without complications to the mother, or the foetus.

Onset of labourPRELABOUR (Premonitory stage)- this may begin 2-3 weeks before the onset of true labour in primigravida and a few days before in multipara, & consist of the following :

1. Lightening- Few weeks prior to the onset of labor specially in primigravidae, the presenting part sinks into the true pelvis. It is

due to active pulling up of the lower pole of the uterus around the presenting part. It signifies incorporation of the lower uterine segment into the wall of the uterus.

This diminishes the fundal height and hence minimizes the pressure on the diaphragm. The mother experiences a sense of relief from the mechanical cardiorespiratory embarrassment. There may be

frequency of micturition or constipation due to mechanical factor—pressure by the engaged presenting part. It is a welcome sign as it rules out cephalo-pelvic disproportion and other conditions preventing the head from

entering the pelvic inlet.2. Cervical changes: Few days prior to the onset of labor, the cervix

becomes ripe. A ripe cervix is soft, less than 1.5 cm in length, admits a finger easily and is dilatable.

3. Appearance of false pain(i) Dull in nature (ii) Confined to lower abdomen and groin (iii) Not associated with hardening of the uterus (iv)They have no other features of true labor pains (v)Usually relieved by enema or sedative.

ONSET OF LABOUR 1. Characterized byThe showTrue labour painsDilatation and effacement of cervixFormation of bag of forewaters

SHOW◦With the onset of labor, there is profuse cervical secretion. Simultaneously, there is

slight oozing of blood from rupture of capillary vessels of the cervix and from the raw decidual surface caused by separation of the membranes due to stretching of the lower uterine segment.

◦ Expulsion of cervical mucus plug mixed with blood is called “show”.◦ It is a sign of the impending onset of active labor.

TRUE LABOUR PAINSCHARACTERIZED BY :◦ (i) Uterine contractions at regular intervals ◦ (ii) Frequency of contractions increase gradually ◦ (iii) Intensity and duration of contractions increase progressively ◦ (iv) Associated with “show” ◦ (v) Progressive effacement and dilatation of the cervix ◦ (vi) Descent of the presenting part ◦ (vii)Formation of the “bag of forewaters” ◦ (viii) Not relieved by enema or sedatives.

TRUE Vs. FALSE LABOUR PAINS

UTERINE CONTRACTIONS IN LABOURCharacteristics of normal uterine contractions: ◦Pace maker: situated in the region of tubal ostia from where wave

of contraction spread downwards. Sometimes there is emergence of multiple pace maker foci leading

to less efficient contractions and hence causing primary dysfunction labour

◦Fundal dominance with gradual diminishing contractions towards the lower segment.

◦Polarity of uterus : when upper segment contracts, retracts and pushes the fetus down the lower uterine segment and cervix dilates in response.

Lack of fundal dominance and the reverse polarity leads to spastic lower uterine segment. Here pacemaker does not work in rhythm.

◦Good synchronization of contraction waves from both sides of uterus. ◦Regular pattern of contractions◦Good relaxation in between the contractions◦Intra amniotic pressure during relaxation is 8mm & rising beyond 20mm during contraction.

INTENSITY: describes degree of uterine systole. It increases with progress of labour & Maximum during 2nd stage of

labour.◦ Intrauterine pressure is raised to 40–50 mm Hg during first stage and about 100–

120 mm Hg in second stage of labor during contractions. In spite of diminished pain in third stage, the intrauterine pressure is probably the same as that in the second stage. The diminished pain is due to lack of stretching effect.

DURATION: initially last for 10-15 seconds gradually increases up to 40-45 sec. during the second stage.

FREQUENCY: in the early stage of labour, contractions come at the interval of 10-15min and increases to maximum in 2nd stage of labour.

Clinically contractions are said to be good when they come after interval of 3-5minutes and at the height of contractions uterine wall can not be indented by fingers.

TONUS : It is the intra-uterine pressure in between the contractions. During Quiscent stage- 2-3mm Hg During first stage of labour 8-10mmHg.It is inversely proportional to contraction.Factors governing tonus are:◦ Contractility of uterine muscles◦ Intra-abdominal pressure◦ Over-distension of uterus as in twins and hydramnios.

If the intensity diminishes, duration is shortened and period between the increases it leads to hypotonic uterine dysfunction. Here intrauterine pressure during the contractions remains below 25mm of Hg.

If there is increased frequency and duration without adequate relaxation in between it leads to incoordinate uterine action.

LABOUR PAINS◦Pain during contractions is distributed along the cutaneous nerve distribution of T10 to L1.

◦Pain of cervical dilatation is radiated to back through sacral plexus.

Causes of pain:◦Myometrial hypoxia during contractions◦Streching of peritonium over the fundus◦Streching of cervix during dilatation◦Compression of nerve ganglia

Interval between contractions 10 minutes at the onset of the first stage → diminishes gradually → 1 minute or less in the second stage Periods of relaxation between contractions - essential to welfare of the fetus - unremitting contraction of uterus

compromises uteroplacental blood flow, cause fetal hypoxia Duration of contraction in active phase Duration 30-90 seconds (average 60 sec) Pressure 20-60 mmHg (average 40 mmHg )

DILATATION & EFFACEMENT OF CERVIX

◦ Prior to the onset of labor, in the prelabor phase (Phase-1) there may be a certain amount of dilatation of cervix, specially in multiparae and in some primigravidae.

◦Predisposing factors which favor smooth dilatation are—◦ (a) softening of the cervix ◦ (b) fibro-musculo-glandular hypertrophy ◦ (c) increased vascularity ◦ (d) accumulation of fluid in between collagen fibers and ◦ (e) breaking down of collagen fibrils by enzymes collagenase and elastase ◦ (f) change in the various glycosaminoglycans (e.g. increase in hyaluronic acid, decrease in

dermatan sulfate) in the matrix of the cervix. ◦ These are under the action of hormones—estrogen, progesterone and relaxin. ◦ As the result of the action of uterine contractions, two fundamental changes take place

in the already ripened cervix “effacement & dilatation”.

CERVICAL EFFACEMENT◦Taking up of the cervix◦Effacement is the process by which the muscular fibers of the cervix are pulled upward and merges with the fibers of the lower uterine segment. ◦The cervix becomes thin during first stage of labor or even before that in primigravidae. In primigravidae, effacement precedes dilatation of the cervix, whereas in multiparae, both occur simultaneously. ◦Expulsion of mucus plug is caused by effacement.

FORMATION OF BAG OF MEMBRANES◦ The process of cervical effacement and dilatation causes the

formation of the forebag of amniotic fluid which is the leading portion of amniotic sac and fluid located in front of the presenting part.

The membranes (amnion and chorion) are attached loosely to the decidualining the uterine cavity except over the internal os. In vertex presentation, the girdle of contact of the head (that part of the circumference of the headwhich first comes in contact with the pelvic brim) being spherical, may well fit with the wall of the lower uterine segment. Thus, the amniotic cavity is divided into two compartments. The part above the girdle of contact contains the fetus with bulk of the liquor called hindwaters and the one below it containing small amount of liquor called forewaters. With the onset of labor, the membranes attached to the lower uterine segment are detached and with the rise of intrauterine pressure during contractions there is herniation of the membranes through the cervical canal. There is ball-valve like action by the well flexed head. Uterine contractions generate hydrostatic pressure in the forewaters that in turn dilate the cervical canal like a wedge. When the bag of forewater is absent (PROM) the pressure of the presenting part pushes the cervix centrifugally.

PARTURITIONPARTURITION is defined as the process of bringing forth of young which comprises of

multiple transformations in both uterine and cervical functionsThere are four phases :◦Quiescence ◦ Activation phase◦ Stimulation phase◦ Involution phase.

QUIESCENCE

ACTIVATION STIMULATION

INVOLUTION

FROM CONCEPTION TO INITIATION OF PARTURITION

BEGINNING OF PARTURITION TO ONSET OF LABOUR

UPTO DELIVERY OF CONCEPTUS

TILL THE TIME FERTILITY IS RESTORED

PREDOMINANTLY INFLUENCING FACTOR

INHIBITORS:PROGESTERONE,PROSTACYCLIN,NITROUS OXIDE,RELAXIN

UTEROTROPIC:ESTROGEN,OXYTOCIN,PROSTAGLANDINS

UTEROTONICS:OXYTOCIN, PROSTAGLANDINS

OXYTOCIN THROMBINS

UTERINE ACTIVITY CONTRACTILE UNRESPONSIVENESS

PREPARATION FOR LABOUR

CONTRACTIONS ALONG WITH FETAL & PLACENTAL EXPLUSION

INVOLUTION

CERVIX SOFTENING RIPENING DILATATION & EFFACEMENT

REPAIR

MYOMETRIAL ACTION◦Myometrial contraction is controlled by transcription of key genes, which produce

proteins that repress or enhance cellular contractility. These proteins function to: ◦ (1) enhance the interactions between the actin and myosin proteins that cause muscle

contraction, ◦ (2) increase excitability of individual myometrial cells, and ◦ (3) promote intracellular cross talk that allows development of synchronous contractions.

Actin-Myosin Interactions◦ The interaction of myosin and actin is essential to muscle contraction.◦ This interaction requires that actin be converted from a globular to a filamentous form. ◦ Actin must partner with myosin, which is composed of multiple light and heavy chains. ◦ The interaction of myosin and actin activates adenosine triphosphatase (ATPase),

hydrolyzes adenosine triphosphate, and generates force. ◦ This interaction is brought about by enzymatic phosphorylation of the 20-kDa light chain

of myosin. ◦ This is catalyzed by the enzyme myosin light-chain kinase, which is activated by calcium.◦ Calcium binds to calmodulin, a calcium-binding regulatory protein, which in turn binds to

and activates myosin light-chain kinase.

Uterine myocyte relaxation and contraction. A. Uterine relaxation is maintained by factors that increase myocyte cyclic adenosine monophosphate (cAMP). This activates protein kinase A (PKA) to promote phosphodiesterase activity with dephosphorylation of myosin light-chain kinase (MLCK). There are also processes that serve to maintain actin in a globular form, and thus to preventfibril formation necessary for contractions. B. Uterine contractions result from reversal of these sequences. Actin now assumes a fibrillar form, and calcium enters the cell to combine with calmodulin to form complexes. These complexes activate MLCK to bring about phosphorylation ofthe myosin light chains. This generates ATPase activity to cause sliding of myosin over the actin fibrils, which is a uterine contractor.

INTRACELLULAR CALCIUM◦ Agents that promote contraction act on myometrial cells to increase intracellular

cytosolic calcium concentration—[Ca2+]. Or, they allow an influx of extracellular calcium through ligand- or voltage-regulated calcium channels.

◦ Prostaglandin F2α and oxytocin bind their respective receptors during labor to open ligand-activated calcium channels.

◦ Activation of these receptors also releases calcium from the sarcoplasmic reticulum to cause decreased electronegativity within the cell. Voltage-gated ion channels open, additional calcium ions move into the cell, and cellular depolarization follows.

◦ Conditions that decrease [Ca2+]i and increase intracellular concentrations of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) promote uterine relaxation.

◦Myometrial Gap Junctions. Cellular signals that control myometrial contraction and relaxation can be effectively transferred between cells through intercellular junctional channels.

◦ Communication is established between myocytes by gap junctions, which aid the passage of electrical or ionic coupling currents as well as metabolite coupling.

◦ The transmembrane channels that make up the gap junctions consist of two protein “hemi-channels”. These connexons are each composed of six connexin subunit proteins. These pairs of connexons establish a conduit between coupled cells for the exchange of small molecules that can be nutrients, waste, metabolites, second messengers, or ions.

◦ Four described in the uterus are connexins 26, 40, 43, and 45. Connexin 43 junctions are scarce in the nonpregnant uterus, and they increase in size and abundance during human parturition.

◦Cell Surface Receptors. ◦ There are various cell surface receptors that can directly regulate myocyte contractile

state.◦ Three major classes are

1. G-protein-linked, 2. ion channel-linked, and 3. enzyme-linked.

◦Most G-protein-coupled receptors are associated with adenylyl cyclase activation. Examples are the CRH-R1 and the LH receptors.

◦Other Gprotein- coupled myometrial receptors, however, are associated with G-protein-mediated activation of phospholipase C.

◦ Ligands for the G-protein-coupled receptors include numerous neuropeptides, hormones, and autacoids. Many of these are available to the myometrium during pregnancy in high concentration via endocrine or autocrine mechanisms.

Phase 1: Uterine Quiescence and Cervical Competence◦Myometrial quiescence is induced by multiple independent and cooperative

biomolecular processes — neural, endocrine, paracrine, and autocrine— are called on to implement and coordinate a state of relative uterine unresponsiveness.

◦ A complementary “fail-safe” system that protects the uterus against agents that could perturb the tranquility of phase 1 also must be in place.

◦ Phase 1 of human parturition and its quiescence are likely the result factors that include: ◦ (1)actions of estrogen and progesterone via intracellular receptors, ◦ (2)myometrial cell plasma membrane receptor-mediated increases in cAMP, ◦ (3)generation of cGMP,and ◦ (4)modification of myometrial-cell ion channels.

◦ Theoretical fail-safe system involving endocrine, paracrine, and autocrine mechanisms for the maintenance of phase 1 of parturition, uterine quiescence.

◦ CRH = corticotropinreleasing hormone; hCG = human chorionic gonadotropin; PGE2 = prostaglandin E2; PGI2 = prostaglandin I2; PGDH = 15-hydroxyprostaglandin dehydrogenase.

◦Progesterone and Estrogen Contributions◦Both estrogen and progesterone are components of a broader-based

molecular system that implements and maintains uterine quiescence.

◦The removal of progesterone, that is, progesterone withdrawal , directly precedes progression of phase 1 into phase 2 of parturition.

◦Steroid hormone regulation of myometrial cell to cell communication ; progeterone causes decreased expression of contraction associated proteins and is also known to inhibit expression of gap junctional proteins and thus increases uterine quiescence.

◦G-Protein–Coupled Receptors◦G-protein-coupled receptors associated with Gαs-mediated activation of adenylyl cyclase and increased levels of cAMP are present in myometrium. ◦With appropriate ligands they act along with sex steroid hormones as part of a fail-safe system to maintain uterine quiescence .

◦Beta-Adrenoreceptors. ◦These receptors are prototypical examples of cAMP signaling causing

myometrium relaxation. ◦Agents binding to these receptors have been used for tocolysis with

preterm labor and include ritodrine and terbutaline. ◦β-Adrenergic receptors mediate Gαs stimulated increases in adenylyl

cyclase, increased levels of cAMP, and myometrial cell relaxation.◦The rate-limiting factor is likely the number of receptors expressed and

the level of adenylyl cyclase expression.

◦ Luteinizing Hormone (LH) and Human Chorionic Gonadotropin (hCG) Receptors. ◦ These hormones share the same receptor, and this G-protein-coupled receptor

has been demonstrated in myometrial smooth muscle and blood vessels. ◦ Levels of myometrial LH, hCG receptors during pregnancy are greater before

than during labor. ◦ Chorionic gonadotropin acts to activate adenylyl cyclase by way of a plasma

membrane receptor–Gαs-linked system. This decreases contraction frequency and force and decreases the number of tissue-specific myometrial cell gap junctions.

◦ Thus, high circulating levels of hCG may be one mechanism causing uterine quiescence.

◦Relaxin. ◦ This peptide hormone consists of an A and B chain and is structurally similar to the insulin

family of proteins. ◦ Relaxin mediates lengthening of the pubic ligament, cervical softening, vaginal relaxation, and

inhibition of myometrial contractions. ◦ There are two separate human relaxin genes, designated H1 and H2. The H1 gene is primarily

expressed in the decidua, trophoblast, and prostate, whereas the H2 gene is primarily expressed in the corpus luteum.

◦ Relaxin in plasma of pregnant women is believed to originate exclusively from corpus luteum secretion. Plasma levels peak at approximately 1 ng/mL between 8 and 12 weeks’ gestation. Thereafter, they decline to lower levels that persist until term.

◦ Its plasma membrane receptor—relaxin family peptide receptor 1 (RXFP1)—mediates activation of adenylyl cyclase.

◦ It also effects cervical remodeling through cell proliferation and modulation of extracellular matrix components such as collagen and hyaluric acid.

◦Corticotropin-Releasing Hormone (CRH). ◦ This hormone is synthesized in the placenta and hypothalamus. ◦ CRH plasma levels increase dramatically during the final 6 to 8 weeks of normal

pregnancy and have been implicated in the mechanisms controlling the timing of human parturition.

◦CRH appears to promote myometrial quiescence during most of pregnancy and aids myometrial contractions with onset of parturition.

◦ These opposing actions are achieved by differential actions of CRH via its receptor CRHR1. ◦ In the term non-laboring myometrium, the interaction of CRH with its CRHR1

receptor results in activation of the Gs-adenylate cyclase-cAMP signaling pathway. This results in inhibition of inositol triphosphate (IP3) production and a stabilization of [Ca2+]i.

◦ In term laboring myometrium, [Ca2+]i is increased by CRH activation of G proteins Gq and Gi and leads to stimulation of IP3 production and increased contractility.

G-protein-coupled receptor signal transduction pathways. A. Receptors coupled toheterotrimeric guanosine-triphosphate (GTP)-binding proteins (G proteins) are integraltransmembrane proteins that transduce extracellular signals to the cell interior. G-protein-coupledreceptors exhibit a common structural motif consisting of seven membrane-spanning regions. B.Receptor occupation promotes interaction between the receptor and the G protein on the interiorsurface of the membrane. This induces an exchange of guanosine diphosphate (GDP) for GTP on theG protein α subunit and dissociation of the α subunit from the βγ heterodimer. Depending on itsisoform, the GTP-α subunit complex mediates intracellular signaling either indirectly by acting oneffector molecules such as adenylyl cyclase (AC) or phospholipase C (PLC), or directly by regulating ion channels or kinase function.

◦ Prostaglandins. ◦ Prostaglandins usually are considered as uterotonins. ◦ The major synthetic pathways involved in prostaglandin biosynthesis are shown in

Figure.◦ Prostaglandins are produced using plasma membrane-derived arachidonic acid, which

usually is released by the action of the phospholipases A2 or C. ◦ Arachidonic acid can then act as substrate for both type 1 and type 2 prostaglandin H

synthase (PGHS-1 and -2), which are also called cyclooxygenase-1 and -2 (COX-1 and -2).

◦ Both PGHS isoforms convert arachidonic acid to the unstable endo-peroxide prostaglandin G2 and then to prostaglandin H2.

◦ Another important control point for prostaglandin activity is its metabolism, which most often is through the action of 15-hydroxyprostaglandin dehydrogenase (PGDH). Expression of this enzyme can be regulated in the uterus, which is important because of its ability to rapidly inactivate prostaglandins.

◦ This family of receptors is classified according to the binding specificity of a given receptor to a particular prostaglandin.

◦ Both PGE2 and PGI2 could potentially act to maintain uterine quiescence by increasing cAMP signaling, yet PGE2 can promote uterine contractility through binding to prostaglandin E receptors 1 and 3 (EP1 and EP3).

◦ Also, PGE2, PGD2, and PGI2 have been shown to cause vascular smooth muscle relaxation and vasodilatation in many circumstances.

◦ COX-2 expression is spatially regulated in the myometrium and cervix in pregnancy and labor, with an increasing concentration gradient from the fundus to the cervix. Thus, it is entirely possible that prostanoids contribute to myometrial relaxation at one stage of pregnancy and to regional fundal myometrial contractions after parturition initiation.

◦Atrial and Brain Natriuretic Peptides and Cyclic Guanosine Monophosphate (cGMP)◦ Activation of guanylyl cyclase increases intracellular cGMP levels, which promotes smooth

muscle relaxation. Intracellular cGMP levels are increased in the pregnant myometrium and can be stimulated by atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) receptors, and nitric oxide.

◦ BNP is secreted by amnion in large amounts and ANP is expressed in placenta

◦Accelerated Uterotonin Degradation◦ In addition to pregnancy-induced compounds that promote myometrial cell refractoriness,

there are striking increases in the activity of enzymes that degrade or inactivate endogenously produced uterotonins.

◦ Some of these and their degradative enzymes include: ◦ PGDH and prostaglandins; ◦ enkephalinase and endothelins; ◦ oxytocinase and oxytocin; ◦ diamine oxidase and histamine; ◦ catechol O-methyltransferase and catecholamines; ◦ angiotensinases and angiotensin-II; and ◦ platelet-activating factor (PAF) acetylhydrolase and PAF.

◦ Activities of several of these enzymes are increased by progesterone.

Phase 2: Uterine Activation and Cervical RipeningTo prepare for labor, the myometrial tranquility of phase 1 of parturition must be suspended—so called uterine awakening or activation. This phase 2 is a progression of uterine changes during the last 6 to 8 weeks of pregnancy.

◦Myometrial Changes-- Phase 2 myometrial changes prepare it for labor contractions-- expression of key proteins that control contractility-- contraction-associated proteins (CAPs) include the oxytocin receptor, prostaglandin F receptor, and connexin 43. Together these leads to increased uterine irritability and responsiveness to uterotonins.

◦ Another critical change in phase 2 is formation of the lower uterine segment from the isthmus. With this development, the fetal head often descends to or even through the pelvic inlet—so-called lightening. The abdomen commonly undergoes a shape change, sometimes described by women as “the baby dropped.”

◦Cervical Ripening- Before contractions begin, the cervix must undergo more extensive remodeling -- the total amount and composition of proteoglycans and glycosaminoglycans within the matrix are altered.

◦ The cervix is made up of only 10 to 15 percent smooth muscle and remaining is connective tissue which includes type 1,3 and 4 collagen, glycosaminoglycans, proteoglycans and elastin.

◦ Changes in cervical connective tissue – collagen, Glycosaminoglycans, Proteoglycans

◦ Inflammatory Changes. The marked changes within the extracellular matrix during cervical ripening in phase 2 are accompanied by stromal invasion with inflammatory cells. In phase 3 or 4 of parturition, there is increased cervical expression of chemokines and collagenase/protease activity.

◦ Functional Progesterone Withdrawal in Human Parturition◦ Functional progesterone withdrawal or antagonism is possibly mediated through several

mechanisms: ◦ (1) changes in the relative expression of the nuclear progesterone-receptor isoforms, PR-A, PR-B,

and PR-C; ◦ (2) changes in the relative expression of membrane-bound progesterone receptors; ◦ (3) posttranslational modifications of the progesterone receptor; ◦ (4) alterations in PR activity through changes in the expression of coactivators or corepressors that

directly influence receptor function; ◦ (5) local inactivation of progesterone by steroid-metabolizing enzymes or synthesis of a natural

antagonist; and ◦ (6) microRNA regulation of progesterone-metabolizing enzymes and transcription factors that

modulate uterine quiescence.◦ There is evidence that progesterone-receptor activity is decreased late in gestation.

◦Oxytocin Receptors◦ There is an increase in myometrial oxytocin receptors during phase 2 of parturition. ◦ Their activation results in increased phospholipase C activity and subsequent increases in

cytosolic calcium levels and uterine contractility. ◦ Progesterone and estradiol appear to be the primary regulators of oxytocin receptor

expression.◦ These receptors also are present in human endometrium and in decidua at term and stimulate

prostaglandin production. In addition, these receptors are found in the myometrium and at lower levels in amniochorion-decidual tissues.

◦Relaxin◦ Although relaxin may contribute to uterine quiescence, it also has roles in phase 2 of

parturition.◦ These include remodeling of the extracellular matrix of the uterus, cervix, vagina,

breast, and pubic symphysis as well as promoting cell proliferation and inhibiting apoptosis.

◦ Its actions on cell proliferation and apoptosis are mediated through the G-protein-coupled receptor, RXFP1.

◦ Relaxin appears to mediate glycosaminoglycan and proteoglycan synthesis and degrade matrix macromolecules such as collagen by induction of matrix metalloproteases.

◦ Relaxin promotes growth of the cervix, vagina, and pubic symphysis and is necessary for breast remodeling for lactation.

Fetal Contributions to Initiation of Parturition◦ Although signals may arise from the fetus, the uterus and cervix likely first must be

prepared for labor before a uterotonin produced by or one whose release is stimulated by the fetus can be optimally effective.

◦ Uterine Stretch and Parturition ◦ Fetal growth is an important component in uterine activation in phase 1 of parturition. ◦ In association with fetal growth, significant increases in myometrial tensile stress and amnionic

fluid pressure follow. ◦ With uterine activation, stretch is required for induction of specific contraction-associated

proteins (CAPs). ◦ Specifically, stretch increases expression of the gap junction protein—connexin 43 and of

oxytocin receptors. ◦ Gastrin-releasing peptide, a stimulatory agonist for smooth muscle, is increased by stretch in

the myometrium.◦ Stretch plays an integrated role with fetal-maternal endocrine cascades of uterine activation. ◦ Clinical support – Cases of multifetal pregnancy , polyhydramnios.◦ Cell signaling systems used by stretch to regulate the myometrial cell. This process—

mechanotransduction—may include activation of cell-surface receptors or ion channels, transmission of signals through extracellular matrix, or release of autocrine molecules that act directly on myometrium.

FETAL ENDOCRINE CASCADEAt term the fetal adrenal glands weigh same as those in the adults and similar in

size.

The daily production of steroid by adrenal glands near term is 100 to 200mg/day higher than 30 to 40mg/day seen in adult glands at rest.

Fetal cortisol levels increase during the last weeks of gestation during the same period levels of DHEA-S also increases significantly leading to increase in maternal oestrogens particularly estriol.

◦ Fetal Endocrine Cascades Leading to Parturition◦ Activation of the human fetal hypothalamic-pituitary-

adrenal-placental axis is considered a critical component of normal parturition.

◦ Moreover, premature activation of this axis is considered to prompt many cases of preterm labor.

◦ A key component in the human may be the unique ability of the placenta to produce large amounts of CRH, as shown in Figure.

The placental–fetal adrenal endocrine cascade. In late gestation, placental corticotropin-releasing hormone (CRH) stimulates fetal adrenal production of dehydroepiandrosterone sulfate (DHEA-S) and cortisol. The latter stimulates production of placental CRH, which leads to a feed-forward cascade that enhances adrenal steroid hormone production. ACTH = adrenocorticotropic hormone.

Placental Corticotropin-Releasing Hormone Production◦A CRH hormone identical to maternal and fetal hypothalamic CRH is

synthesized by the placenta in relatively large amounts. ◦One important difference is that, unlike hypothalamic CRH,

which is under glucocorticoid negative feedback, cortisol has been shown to stimulate placental CRH production.

◦This is by activation of the transcription factor, nuclear factor kappa B (NF-κB). This ability makes it possible to create a feed-forward endocrine cascade that does not end until delivery.

◦Maternal plasma CRH levels are low in the first trimester and rise from midgestation to term. In the last 12 weeks, CRH plasma levels rise exponentially, peaking during labor and then falling precipitously after delivery.

◦Amnionic fluid CRH levels similarly increase in late gestation. ◦CRH is the only trophic hormone-releasing factor to have a specific serum

binding protein.◦During most of pregnancy, it appears that CRH-binding protein (CRH-BP)

binds most maternal circulating CRH, and this inactivates it. ◦During later pregnancy, however, CRH-BP levels in both maternal plasma

and amnionic fluid decline, leading to markedly increased levels of bioavailable CRH.

CRH & PARTURITION TIMING◦ Placental CRH may enhance fetal cortisol production to provide positive feedback so that

the placenta produces more CRH. ◦ Late in pregnancy—phase 2 or 3 of parturition—modification in the CRH receptor favors a

switch from cAMP formation to increased myometrial cell calcium levels via protein kinase C activation.

◦ Oxytocin acts to attenuate CRH-stimulated accumulation of cAMP in myometrial tissue. And, CRH augments the contraction-inducing potency of a given dose of oxytocin in human myometrial strips.

◦ CRH acts to increase myometrial contractile force in response to PGF2α.◦ CRH has been shown to stimulate fetal adrenal C19-steroid synthesis, thereby increasing

substrate for placental aromatization. Increased production of estrogens would shift the estrogen-to-progesterone ratio and promote the expression of a series of myometrial contractile proteins.

◦ Rising level of CRH at the end of gestation reflects a fetal-placental clock.

Fetal lung surfactant & Parturition◦ Surfactant protein A (SP-A) produced by the fetal lung is required for lung

maturation. ◦ Increasing SP-A concentrations in amnionic fluid activate fluid macrophages to

migrate into the myometrium and induce NF-κB .This factor activates inflammatory response genes in the myometrium, which in turn promote uterine contractility.

Fetal anomalies & delayed Parturition◦ Pregnancies with markedly diminished estrogen production may be associated with

prolonged gestation- includes fetal anencephaly with adrenal hypoplasia and those with inherited placental sulfatase deficiency.

Phase 3: Uterine Stimulation◦ This parturition phase is synonymous with uterine contractions that bring about

progressive cervical dilatation and delivery.◦Uterotonin theory of labor initiation ◦Uterotonins that are candidates for labor induction include oxytocin, prostaglandins,

serotonin, histamine, PAF, angiotensin II, and many others. All have been shown to stimulate smooth muscle contraction through G-protein coupling.

CAUSES OF ONSET OF LABOUR

Mechanical Biochemical

Uterine distension Oxytocin theory

Prostaglandins PAF

Stretch of the lower Angiotensin II Uterine segment by Histamine presenting pact Serotonin & OthersMechanical stretching of cervix (Ferguson’s Reflex) & stripping of fetal membranes

Oxytocin and Phase 3 of Parturition

◦ Late in pregnancy, during phase 2 of parturition, there is a 50-fold or more increase in the number of myometrial oxytocin receptors. This increase coincides with an increase in uterine contractile responsiveness to oxytocin.

◦Oxytocin—literally, quick birth—was the first uterotonin to be implicated in parturition initiation.

◦ This nanopeptide is synthesized in the magnocellular neurons of the supraoptic and paraventricular neurons. The prohormone is transported with its carrier protein, neurophysin, along the axons to the neural lobe of the posterior pituitary gland in membrane-bound vesicles for storage and later release.

◦ The prohormone is converted enzymatically to oxytocin during transport.

OxytocinIt was first uterotonin to be implicated in parturition initiation following observations

provide support for this theoryThe number of oxytocin receptors strikingly increases in myometrial and decidual

tissues near end of gestationOxytocin acts on decidual tissue to promote prostaglandin release.Oxytocin is synthesized directly in decidual and extraembryonic fetal tissues and in

the placenta.

ProstaglandinsEvidence supportive of this theory includes;Levels of prostaglandins or their metabolites in amniotic fluid ,maternal plasma and

maternal urine are increased during labourTreatment of pregnant women with PGs by any of several routes of administration,

causes abortion or labour at all stages of gestation.Administration of PGHS type 2 inhibitors to pregnant women will delay spontaneous

onset of labour and sometimes arrest preterm labour.

Prostaglandins and Phase 3 of Parturition

◦ Levels of prostaglandins—or their metabolites—in amnionic fluid, maternal plasma, and maternal urine are increased during labor.

◦ Uterine Events Regulating Prostaglandin Production. ◦ During labor, prostaglandin production within the myometrium

and decidua is an efficient mechanism of activating contractions. ◦ Prostaglandin synthesis is high and unchanging in the decidua

during phase 2 and 3 of parturition.◦ The receptor level for PGF2α is increased in the decidua at term,

and this increase most likely is the regulatory step in prostaglandin action in the uterus.

◦ The myometrium synthesizes PGHS-2 with labor onset ◦ The fetal membranes and placenta also produce prostaglandins. ◦ Primarily PGE2, but also PGF2α, are detected in amnionic fluid at

all gestational stages. As the fetus grows, prostaglandins levels in the amnionic fluid increase gradually. Their major increases in concentration within amnionic fluid, however, are demonstrable after labor begins. These higher levels likely result as the cervix dilates and exposes decidual tissue

◦ These increased levels in the fore-bag compared with those in the upper compartment are believed to follow an inflammatory response that signals the events leading to active labor. Together, the increases in cytokines and prostaglandins further degrade the extracellular matrix, thus weakening fetal membranes.

Platelet activating factorThe PAF receptor is a member of the G-protein- coupled receptor family of

transmembrane receptors.

Its stimulation by PAF increases myometrial cell calcium levels and promotes uterine contractions.

Levels of PAF in amnionic fluid are increased during labor. PAF treatment of myometrial tissue promotes contraction.

Endothelin-1The endothelins are a family of 21-amino acid peptides that powerfully

induce myometrial Contraction.

Endothelin-1 is produced in myometrium of term gestations and is able to induce synthesis of other contractile mediators such as prostaglandins and inflammatory mediators.

The requirement of endothelin-1 in normal parturition physiology remains to be established.

Angiotensin-IIThere are two G-protein-linked angioteneism II receptors in the uterus - AT1 and

AT2.

In non pregnant women the AT2 receptors is predominant, but the AT1 receptor is preferentially expressed in pregnant.

Angiotensin II binding to the plasma-membrane receptor evokes contraction & is another component of the uterotonin system of parturition phase 3.

Corticotropin- Releasing Hormone (CRH) Late in pregnancy – phase 2 or 3 of parturition – modification in the CRH receptor

favours a switch cAMP formation to increased myometrial cell calcium levels via protein kinase C activation.

Oxytocin acts attentuate CRH-stimulated accumulation of cAMP myometrial tissue and CRH augments the contraction-inducing potency of a given dose of oxytocin n human myometrial strips.

Finally CRH acts to increase myometrial contractile force in response to PGF2α.

Contribution of Intrauterine Tissues to Parturition◦ Amnion◦ Virtually all of the tensile strength—resistance to tearing and rupture—of the fetal membranes is

provided by the amnion. ◦ This avascular tissue is highly resistant to penetration by leukocytes, microorganisms, and

neoplastic cells. ◦ It also constitutes a selective filter to prevent fetal particulate-bound lung and skin secretions

from reaching the maternal compartment. In this manner, maternal tissues are protected from amnionic fluid constituents that could worsen decidual or myometrial function or could promote adverse events such as amnionic-fluid embolism.

◦ During pregnancy, the transport of prostaglandins from the amnion to maternal tissues is limited by expression of the inactivating enzymes, prostaglandin dehydrogenase (PGDH), in the chorion.

◦ During labor, PGDH levels decline, and amnion-derived prostaglandins can influence membrane rupture and uterine contractility.

◦Chorion Laeve◦ This tissue layer also is primarily protective and provides immunological acceptance. The chorion

laeve is also enriched with enzymes that inactivate uterotonins.◦ Enzymes include prostaglandin dehydrogenase (PGDH), oxytocinase, and enkephalinase .◦ With chorionic rupture, this barrier would be lost, and prostaglandins could readily influence adjacent

decidua and myometrium.◦Decidua

◦ A metabolic contribution of decidual activation to parturition initiation ◦ Generation of decidual uterotonins ◦ Decidua expresses steroid metabolizing enzymes such as 20α-HSD and steroid 5αR1 that may

regulate local progesterone withdrawal.◦ Decidual activation is characterized by increased proinflammatory cells and increased expression of

proinflammatory cytokines, prostaglandins, and uterotonins such as oxytocin receptors and connexin 43.

◦ Cytokines produced in the decidua can either increase uterotonin production—principally prostaglandins. Or they can act directly on myometrium to cause contraction. Examples are tumor necrosis factor-α (TNF-α) and interleukins 1, 6, 8, and 12. These molecules also can act as chemokines that recruit to the myometrium neutrophils and eosinophils, which further increase contractions and labor.

Phase 3 of Parturition : LABOURThis phase is synonymous with active labour, which comprise of,• First stage: It starts from the onset of true labor pain and ends with full dilatation of the cervix. It is, in other words, the “cervical stage” of labor. Its average duration is 12 hours in primigravidae and 6 hours in multiparae.• Second stage: It starts from the full dilatation of the cervix (not from the rupture of the membranes) and ends with expulsion of the fetus from the birth canal. It has got two phases—(a) The propulsive phase – starts from full dilatation upto the descent of the presenting part to the pelvic floor. (b) The expulsive phase is distinguished by maternal bearing down efforts and ends with delivery of the baby. Its average duration is 2 hours in primigravidae and 30 minutes in multiparae.• Third stage: It begins after expulsion of the fetus and ends with expulsion of the placenta and membranes (after-births). Its average duration is about 15 minutes in both primigravidae and multiparae. The duration is, however, reduced to 5 minutes in active management.• Fourth stage: It is the stage of observation for at least 1 hour after expulsion of the after-births. During this period, general condition of the patient and the behavior of the uterus are to be carefully monitored.

Uterine distension theoryThis theory is supported by the observation that multifetal pregnancy and

pregnancies associated with polyhydramnios are at much greater risk for preterm labour than singletons.

Fergusons reflex mechanical stretching of cervix enhances uterine activity ,release of oxytocin has been suggested but not proven. manipulation of the cervix and stripping the fetal membranes is associated with

an increase in PGF2αmetabolite in blood.

exact mechanism : not clear

Biochemical and Physiological processesCurrent data favour uterotonins theory of labour initiation

Increased number of uterotonin production would follow once phase 1 is suspended and uterine phase 2 processes are implemented

THE PARTURITION CASCADE

To summarize,Causes of Onset of Labour◦ Uterine distension: Stretching effect on the myometrium by the growing fetus and liquor amnii

can explain the onset of labor at least in twins or polyhydramnios. Uterine stretch increases gap junction proteins, receptors for oxytocin and specific contraction associated proteins (CAPS).

◦ Fetoplacental contribution: Cascade of events activate fetal hypothalamic pituitary adrenal axis prior to onset of labor → increased CRH → increased release of ACTH → fetal adrenals → increased cortisol secretion → accelerated production of estrogen and prostaglandins from the placenta.

◦ Estrogen—the probable mechanisms are:◦ — Increases the release of oxytocin from maternal pituitary.◦ — Promotes the synthesis of myometrial receptors for oxytocin (by 100–200 folds), prostaglandins and

increase in gap junctions in myometrial cells.◦ — Accelerates lysosomal disintegration in the decidual and amnion cells resulting in increased

prostaglandin (PGF2α) synthesis.◦ — Stimulates the synthesis of myometrial contractile protein—actomyosin through cAMP.◦ — Increases the excitability of the myometrial cell membranes.

◦ Progesterone: Increased fetal production of dehydroepiandrosterone sulfate (DHEA-S) and cortisol inhibits the conversion of fetal pregnenolone to progesterone. Progesterone levels therefore fall before labor. It is the alteration in the estrogen: progesterone ratio rather than the fall in the absolute concentration of progesterone which is linked with prostaglandin synthesis.

◦ Prostaglandins: Prostaglandins are the important factors which initiate and maintain labor. The major sites of synthesis of prostaglandins are—amnion, chorion, decidual cells and myometrium. Synthesis is triggered by—rise in estrogen level, glucocorticoids, mechanical stretching in late pregnancy, increase in cytokines (IL–1, 6, TNF), infection, vaginal examination, separation or rupture of the membranes. Prostaglandins enhance gap junction (intermembranous gap between two cells through which stimulus flows) formation.

◦ Biochemical mechanisms involved in the synthesis of prostaglandins◦ Phospholipase A2 in the lysosomes of the fetal membranes near term → esterified arachidonic

acid → formation of free arachidonic acid → synthesis of prostaglandins through prostaglandin synthetase. Prostaglandins (E2 and F2α) diffuse in the myometrium → act directly at the sarcoplasmic reticulum → inhibit intracellular cAMP generation → increase local free calcium ions → uterine contraction. Once the arachidonic acid cascade is initiated, prostaglandins themselves will activate lysosomal enzyme systems. The prostaglandin synthesis reaches a peak during the birth of placenta probably contributing to its expulsion and to the control of postpartum hemorrhage.

Oxytocin and myometrial oxytocin receptors: (i) Large number of oxytocin receptors are present in the fundus compared to the lower segment and the

cervix.(ii) Receptor number increases during pregnancy reaching maximum during labor. (iii) Receptor sensitivity increases during labor. (iv) Oxytocin stimulate synthesis and release of PGs (E2 and F2α) from amnion and decidua. Vaginal

examination and amniotomy cause rise in maternal plasma oxytocin level (Ferguson reflex). (v) Fetal plasma oxytocin level is found increased during spontaneous labor compared to that of mother.

Its role in human labor is not yet established.Neurological factor: Although labor may start in denervated uterus, labor may also be initiated through nerve pathways. Both α and β adrenergic receptors are present in the myometrium; estrogen causing the α receptors and progesterone the β receptors to function predominantly. The contractile response is initiated through the α receptors of the postganglionic nerve fibers in and around the cervix and the lower part of the uterus. This is based on observation that onset of labor occurs following stripping or low rupture of the membranes.

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