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Causes and onset of normal labour
1. CAUSES AND ONSET OF
NORMAL LABOUR
MODERATOR – DR ROHINI RAO
PRESENTED BY – DR SWATI SUGANDHA
2. 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
3. ◦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
completed weeks of pregnancy. After birth, mother and
are in good condition”1
1World Health Organization, Maternal and Newborn Health/Safe Motherhood Unit. Care in normal birth: a practical guide.
4. NORMAL LABOR (EUTOCIA):
◦ Labor is called normal if it fulfils the following criteria.
Spontaneous onset
Spontaneous 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.
5. Onset of labour
PRELABOUR (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.
6. ONSET OF LABOUR
1. Characterized by
The show
True labour pains
Dilatation and effacement of cervix
Formation of bag of forewaters
7. 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.
8. TRUE LABOUR PAINS
CHARACTERIZED 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.
10. UTERINE CONTRACTIONS IN LABOUR
Characteristics 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.
11. ◦ 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.
12. 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
5minutes and at the height of contractions uterine wall can not be indented
by fingers.
13. 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.
14. 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.
15. 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
16. 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 )
17. 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”.
19. 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.
21. 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 decidua
lining 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 head
which 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.
23. PARTURITION
PARTURITION is defined as the process of bringing forth of young which comprises of multiple
transformations in both uterine and cervical functions
There are four phases :
◦ Quiescence
◦ Activation phase
◦ Stimulation phase
◦ Involution phase.
24. 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
UNRESPONSIVENES
PREPARATION FOR
LABOUR
CONTRACTIONS
ALONG WITH FETAL
& PLACENTAL
EXPLUSION
INVOLUTION
CERVIX SOFTENING RIPENING DILATATION &
EFFACEMENT
REPAIR
25. 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.
26. 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.
27. 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 prevent
fibril 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 of
the myosin light chains. This
generates ATPase activity to
cause sliding of myosin over the
actin fibrils, which is a uterine
contractor.
28. 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.
29. ◦ 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
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.
30. ◦ 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
endocrine or autocrine mechanisms.
31. 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.
32. ◦ 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.
33. ◦ 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
and is also known to inhibit expression of gap junctional proteins and thus
increases uterine quiescence.
34. ◦ G-Protein–Coupled Receptors
◦ G-protein-coupled receptors associated with Gαs-mediated
of adenylyl cyclase and increased levels of cAMP are present in
myometrium.
◦ With appropriate ligands they act along with sex steroid hormones
part of a fail-safe system to maintain uterine quiescence .
35. ◦ Beta-Adrenoreceptors.
◦ These receptors are prototypical examples of cAMP signaling causing
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.
36. ◦ 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
the number of tissue-specific myometrial cell gap junctions.
◦ Thus, high circulating levels of hCG may be one mechanism causing uterine quiescence.
37. ◦ Relaxin.
◦ This peptide hormone consists of an A and B chain and is structurally similar to the insulin family of
◦ 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
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.
38. ◦ 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
Gi and leads to stimulation of IP3 production and increased contractility.
39. G-protein-coupled receptor signal transduction pathways. A. Receptors coupled to
heterotrimeric guanosine-triphosphate (GTP)-binding proteins (G proteins) are integral
transmembrane proteins that transduce extracellular signals to the cell interior. G-protein-coupled
receptors 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 interior
surface of the membrane. This induces an exchange of guanosine diphosphate (GDP) for GTP on the
G protein α subunit and dissociation of the α subunit from the βγ heterodimer. Depending on its
isoform, the GTP-α subunit complex mediates intracellular signaling either indirectly by acting on
effector molecules such as adenylyl cyclase (AC) or phospholipase C (PLC), or directly by regulating ion channels or
kinase function.
40. ◦ 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 -
◦ 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
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
labor, with an increasing concentration gradient from the fundus to the cervix. Thus, it
entirely possible that prostanoids contribute to myometrial relaxation at one stage of
pregnancy and to regional fundal myometrial contractions after parturition initiation.
41. ◦ 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
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
42. ◦ 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.
43. Phase 2: Uterine Activation and Cervical
Ripening
To 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.
44. ◦ 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
inlet—so-called lightening. The abdomen commonly undergoes a shape change,
described by women as “the baby dropped.”
45. ◦ 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
4 of parturition, there is increased cervical expression of chemokines and
activity.
47. ◦ Functional Progesterone Withdrawal in Human Parturition
◦ Functional progesterone withdrawal or antagonism is possibly mediated through several
◦ (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;
◦ (6) microRNA regulation of progesterone-metabolizing enzymes and transcription factors that modulate
quiescence.
◦ There is evidence that progesterone-receptor activity is decreased late in gestation.
48. ◦ 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
production. In addition, these receptors are found in the myometrium and at lower levels in
decidual tissues.
49. ◦ 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
symphysis as well as promoting cell proliferation and inhibiting apoptosis.
◦ Its actions on cell proliferation and apoptosis are mediated through the G-protein-coupled
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.
50. 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.
51. ◦ 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.
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.
52. FETAL ENDOCRINE CASCADE
At 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.
53. ◦ Fetal Endocrine Cascades Leading to Parturition
◦ Activation of the human fetal hypothalamic-pituitary-
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.
54. 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.
55. ◦ 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.
56. 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.
57. 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.
58. 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.
59. 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 & Others
Mechanical stretching of cervix
(Ferguson’s Reflex) & stripping
of fetal membranes
60. 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.
61. Oxytocin
It was first uterotonin to be implicated in parturition initiation following observations provide
support for this theory
The number of oxytocin receptors strikingly increases in myometrial and decidual tissues near
end of gestation
Oxytocin acts on decidual tissue to promote prostaglandin release.
Oxytocin is synthesized directly in decidual and extraembryonic fetal tissues and in the placenta.
62. Prostaglandins
Evidence supportive of this theory includes;
Levels of prostaglandins or their metabolites in amniotic fluid ,maternal plasma and maternal
urine are increased during labour
Treatment 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.
63. Prostaglandins and Phase 3 of Parturition
◦ Levels of prostaglandins—or their metabolites—in amnionic fluid, maternal plasma, and
maternal urine are increased during labor.
64. ◦ Uterine Events Regulating Prostaglandin Production.
◦ During labor, prostaglandin production within the myometrium and
is an efficient mechanism of activating contractions.
◦ Prostaglandin synthesis is high and unchanging in the decidua during
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
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
membranes.
65. Platelet activating factor
The 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.
66. Endothelin-1
The 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.
67. Angiotensin-II
There 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.
68. 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.
69. 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.
70. ◦ Chorion Laeve
◦ This tissue layer also is primarily protective and provides immunological acceptance. The chorion laeve is
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
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.
they can act directly on myometrium to cause contraction. Examples are tumor necrosis factor-α (TNF-α)
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.
71. Phase 3 of Parturition : LABOUR
This 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.
72. Uterine distension theory
This theory is supported by the observation that multifetal pregnancy and pregnancies
associated with polyhydramnios are at much greater risk for preterm labour than singletons.
73. 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
74. Biochemical and Physiological processes
Current 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
76. 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.
77. ◦ 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
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
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
placenta probably contributing to its expulsion and to the control of postpartum hemorrhage.
78. 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
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
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
progesterone the β receptors to function predominantly. The contractile response is initiated through the α
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.
Because of its longstanding application for labor induction, it seemed logical that oxytocin must play a central role in spontaneous human labor. But this venerable hormone may have only a minor supporting role. Currently, it still is controversial whether oxytocin plays a role in the early phases of uterine activation or whether its sole function is in the expulsive phase of labor.
Clinical support for a role of stretch comes from the observation that multifetal pregnancies are at a much greater risk for preterm labor than singletons. And preterm labor is also significantly more common in pregnancies complicated by hydramnios.
In pregnancies in which the fetus can be considered to be “stressed” from various complications, concentrations of CRH in fetal plasma, amnionic fluid, and maternal plasma are increased compared with those seen in normal gestation. The placenta is likely the source for this increased CRH concentration.