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9/14/2017 Physiology of parturition - UpToDate
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Physiology of parturition
Author: Errol R Norwitz, MD, PhD, MBA
Section Editor: Charles J Lockwood, MD, MHCM
Deputy Editor: Vanessa A Barss, MD, FACOG
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2017. | This topic last updated: May 02, 2017.
INTRODUCTION — Labor is a physiological event involving a sequential, integrated set of changes within the
myometrium, decidua, and uterine cervix that occur gradually over a period of days to weeks. Biochemical
connective tissue changes in the uterine cervix appear to precede uterine contractions and cervical dilation, and
all of these events usually occur before rupture of the fetal membranes.
Labor is a clinical diagnosis, which includes (i) the presence of regular phasic uterine contractions increasing in
frequency and intensity, and (ii) progressive cervical effacement and dilatation. A show (bloody discharge) may or
may not be present. Cervical dilatation in the absence of uterine contractions is seen most commonly in the
second trimester and is suggestive of cervical insufficiency (see "Cervical insufficiency"). Similarly, the presence
of uterine contractions in the absence of cervical change does not meet criteria for the diagnosis of labor. Such
contractions are often attributed to "false labor" or uterine irritability. The myometrial contractility pattern changes
in labor from "contractures" (longlasting, low frequency activity) to "contractions" (high intensity, high frequency
activity) [1].
Labor and delivery are not passive processes by which uterine contractions push a rigid object through a fixed
aperture. The ability of the fetus to successfully negotiate the pelvis during labor and delivery depends upon a
complex interaction of three variables: power (uterine contractions), passenger (fetus), and passage (both bony
pelvis and pelvic soft tissues). Although conventional wisdom dictates that powerful contractions are more likely
to be associated with a successful outcome, there are no data to support this conclusion. Furthermore,
precipitous labor probably results from low resistance of the pelvic soft tissues (the cervix in the first stage of
labor and the muscles of the pelvic floor in the second stage) rather than from high myometrial activity [2].
LABOR AT TERM — The mean duration of human singleton pregnancy is 280 days (40 weeks) from the first day
of the last menstrual period. A term pregnancy is defined as the period from 259 to 293 days after the first day of
the last menstrual period (370/7ths to 416/7ths weeks).
Term labor may be regarded physiologically as a release from the inhibitory effects of pregnancy on the
myometrium, rather than as an active process mediated by uterine stimulants. As an example, strips of
myometrium obtained from a quiescent uterus at term and placed in an isotonic water bath will contract
vigorously and spontaneously without added stimuli [3,4]. Nevertheless, both inhibitory and stimulatory
mechanisms likely play a role in uterine activity.
PHYSIOLOGICAL PHASES OF MYOMETRIAL ACTIVITY — The regulation of uterine activity during pregnancy
can be divided into four distinct physiologic phases [5,6]:
Phase 0: inhibitors active — Throughout most of pregnancy the uterus is maintained in a state of functional
quiescence through the action of various putative inhibitors including, but not limited to:
● Progesterone
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● Prostacyclin (prostaglandin I2)
● Relaxin
● Parathyroid hormonerelated peptide
● Nitric oxide
● Calcitonin generelated peptide
● Adrenomedullin
● Vasoactive intestinal peptide.
Phase 1: myometrial activation — As term approaches, the uterus becomes activated in response to
uterotropins, such as estrogen. This phase is characterized by increased expression of a series of contraction
associated proteins (CAPs) (including myometrial receptors for prostaglandins and oxytocin), activation of
specific ion channels, and an increase in connexin43 (a key component of gap junctions). An increase in gap
junction formation between adjacent myometrial cells leads to electrical synchrony within the myometrium and
allows for effective coordination of contractions.
Phase 2: stimulatory phase — Following activation, the "primed" uterus can be stimulated to contract by the
action of uterotonic agonists, such as the stimulatory prostaglandins E2 and F2 alpha and oxytocin.
Phase 3: involution — Involution of the uterus after delivery occurs during phase 3 and is mediated primarily by
oxytocin.
Parturition cascade — It is likely that a "parturition cascade" exists at term which removes the mechanisms
maintaining uterine quiescence and recruits factors promoting uterine activity [2,7,8]. Given its teleological
importance, such a cascade would likely have multiple redundant loops to ensure a failsafe system of securing
pregnancy success (and thus preserving the species). In such a model, each element is connected to the next in
a sequential fashion, and many of the elements demonstrate positive feedforward characteristics typical of a
cascade mechanism.
The sequential recruitment of signals that serve to augment the labor process suggest that it may not be possible
to single out any one signaling mechanism as being responsible for the initiation of labor. Therefore, it is prudent
to describe such mechanisms as being responsible for "promoting," rather than "initiating," the process of labor
[9].
THE ROLE OF THE FETUS — Considerable evidence suggests that, in most viviparous animals, the fetus
controls the timing of onset of labor [1012]. During the Hippocratic period, the fetus was thought to be positioned
head down at term so it could kick its legs up against the fundus of the uterus, thereby propelling itself through
the birth canal. While we have moved away from this simple and mechanical view of labor, the factors
responsible for the initiation and maintenance of labor at term are not well defined. Initial investigations focused
on endocrine events, such as changes in the profile of circulating hormone levels in the maternal and fetal
circulations. Subsequent studies have concentrated on the dynamic biochemical dialogue between the fetus and
mother (paracrine/autocrine events) in an attempt to understand the molecular mechanisms that regulate such
interactions. The genetic regulation of the molecular events that occur during parturition are also being
investigated [13].
The hypothesis that the fetus is in control of the timing of labor was elegantly demonstrated in domestic
ruminants [1418]. As an example, parturition in sheep is initiated by a sharp rise in fetal adrenal cortisol
secretion related to increased fetal concentrations of and responsiveness to corticotropin [16]. Cortisol acts on
placental enzymes active in the biosynthesis of estrogens from progesterone to augment secretion of estrogen
and decrease progesterone production. The resulting increase in the ratio of estrogen to progesterone stimulates
placental release of prostaglandin F2 alpha, which enhances the myometrial response to oxytocin and stimulates
contractions.
However, the human placenta lacks the glucocorticoidinducible 17alphahydroxylase/17,20lyase enzyme that is
essential to this process [12,19,20]. Therefore, activation of the hypothalamicpituitaryadrenal axis in humans
likely results in a different mechanism for initiation of labor (see 'Estrogen' below).
A role for the fetal genotype in the initiation of labor was suggested by horsedonkey crossbreeding experiments
that resulted in a gestational length intermediate between that of horses (340 days) and that of donkeys (365
days) [12,19]. This concept holds true whether pregnancy is maintained by the fetoplacental unit (as in the sheep
and human) or by extrauterine tissues (as in the mouse and goat) [15].
The slow progress in our understanding of the biochemical mechanisms involved in the process of labor in
humans reflects, in large part, the difficulty in extrapolating from the endocrinecontrol mechanisms in various
animals to the paracrine/autocrine mechanisms of human parturition, processes that preclude direct investigation.
MYOMETRIAL ACTIVATION — Regardless of whether the trigger originates within or outside the fetus, the final
common pathway for labor ends in the maternal tissues of the uterus and is characterized by the development of
regular phasic uterine contractions. As in other smooth muscles, myometrial contractions are mediated through
ATPdependent binding of myosin to actin. This interaction is dependent upon the phosphorylation of myosin light
chain by a calcium/calmodulindependent enzyme, myosin light chain kinase. The availability of free intracellular
calcium is thus a key modulator of myometrial contractility.
GTPbinding proteins (Gproteins) play a pivotal role in myometrial contractility by coupling cell membrane
receptors to effector enzymes and ion channels. As an example, activation of betaadrenergic and/or PGE2
receptors promote myometrial relaxation via the Gas/adenyl cyclase/cAMP signal transduction pathway [3,21].
Oxytocin receptors, on the other hand, couple to Gaq/Gai/phospholipase C pathways leading to an increase in
inositol1,4,5trisphosphate (which releases calcium from the sarcoplasmic reticulum) and 1,2diacylglycerol
(which activates protein kinase C) [22]. The end result is an increase in intracellular calcium and myometrial
contractions [22,23].
Pregnancy affects not only cell surface receptor concentrations, but also the concentrations and coupling of the
various Gproteins. Gaq and Gai are expressed at similar levels in nonpregnant and pregnant myometrium, both
before and after the onset of labor. By comparison, Gas levels are higher in pregnant as compared with
nonpregnant myometrium [24], and levels have been shown to decrease before labor, both at term and preterm
[25]. It has been suggested, therefore, that labor results from a downregulation of pathways that favor uterine
quiescence leading to a relative dominance of stimulatory pathways that increase intracellular calcium
bioavailability and promote myometrial contractility [3].
Other myometrial factors (eg, mechanotransduction via stretching or shortening) which could affect initiation,
frequency, or strength of contractions are under investigation [26,27].
In contrast to vascular smooth muscle, myometrial cells have sparse innervation, which is further reduced during
pregnancy [28]. The regulation of the contractile mechanism of the uterus is therefore largely humoral and/or
dependent upon intrinsic factors within myometrial cells. A number of hormones have been implicated in this
regard. Some of these are discussed below.
HORMONES INVOLVED IN THE PARTURITIONAL CASCADE — Comprehensive analyses of each of the
individual paracrine/autocrine pathways involved in the process of labor have been reviewed in detailed
elsewhere [2,59,15,19]. A few of the hormones implicated in this process are discussed below.
Prostaglandins — Prostaglandins are predominantly paracrine/autocrine hormones (ie, they act locally at their
site of production on contiguous cells). An increase in uterine prostaglandin biosynthesis is a consistent element
in the transition into labor [29], and is probably common to all viviparous species [30]. It seems likely that
hormonal factors controlling the final pathway for the onset of labor in women, both at term and preterm, is an
increased synthesis of prostaglandins of the E and F series within the uterine compartment, predominantly from
the decidua and fetal membranes. The evidence can be summarized as follows:
● Human uterine tissues are selectively enriched with arachidonic acid, the obligate precursor of prostaglandin
biosynthesis.
● Concentrations of prostaglandins in amniotic fluid and in maternal plasma and urine are increased during
parturition [29,31,32]. Moreover, prostaglandin levels appear to rise prior to the onset of myometrial
concentrations suggesting that they are a cause, rather than a consequence, of labor [33].
● The intraamniotic, intravenous, or vaginal administration of exogenous prostaglandins can initiate labor at
any stage of gestation and in all species [34].
● Prostaglandins have been implicated in the three events most temporally related to the onset of labor [4,35]:
the onset of synchronous uterine contractions, cervical ripening, and the increase in myometrial sensitivity to
oxytocin due to an increase in myometrial gap junction formation and/or oxytocin receptor concentrations.
● Inhibitors of prostaglandin synthesis (including cyclooxygenase inhibitors such as indomethacin) are capable
of suppressing myometrial contractility both in vitro and in vivo, and of prolonging the length of gestation
[4,36,37].
Taken together, these data affirm the critical role of prostaglandins in the process of labor. It appears that
withdrawal of fetalparacrine support of the quiescent uterus leads to decidual activation, followed by PGF2 alpha
release and subsequent spontaneous labor [32]. PGE2 appears to play a more important role in cervical ripening
(a remodeling process in which collagen is degraded leading to softening of the cervix) and rupture of the fetal
membranes than in uterine contractility [29].
Progesterone — Administration of a progesterone receptor antagonist [38,39] or removal of the corpus luteum
[40] readily induces abortion in early pregnancy (before seven weeks of gestation), suggesting that progesterone
is necessary for early pregnancy maintenance. Administration of exogenous progesterone after early lutectomy
prevents abortion, further supporting the hypothesis that ovarian progesterone production is essential in
maintenance of early pregnancy. Placental progesterone production increases between five and seven weeks,
and the placenta is the dominant source of progesterone thereafter.
However, the role of progesterone in late pregnancy is not as well defined [41]. Progesterone withdrawal does
not occur in all women before labor, and mean circulating progesterone levels during labor are similar to those
measured one week prior [42]. Moreover, the administration of progesterone late in pregnancy does not delay the
onset of labor in primates [43], and progesterone receptor antagonists are not an effective way of inducing labor
at term (although they may promote cervical ripening) [44,45]. Finally, pregnancies complicated by maternal
hypobetalipoproteinemia (LDL deficiency with very low levels of progesterone) culminate in spontaneous labor at
term without incident [46].
These data suggest that systemic progesterone withdrawal is not a prerequisite for labor in humans. This is in
contrast to most mammalian species in which systemic progesterone withdrawal is an essential component of
parturition [47]. However, circulating hormone concentrations do not necessarily reflect activity at the tissue level.
The onset of labor in women does appear to be preceded by a physiologic withdrawal of progesterone activity
("functional progesterone withdrawal") at the level of the uterus [47].
On the other hand, there is increasing evidence that supplemental progesterone administration reduces the rate
of preterm birth in highrisk women. Further investigation is needed to confirm the effectiveness of progesterone
supplementation and to understand its mechanism of action. (See "Progesterone supplementation to reduce the
risk of spontaneous preterm birth".)
Estrogen — The placenta is the primary source of estrogen biosynthesis during pregnancy. Estrogens do not
themselves cause myometrial contractions, and maternal administration of estradiol to rhesus macaques from
130 days of gestation has no effect on length of pregnancy [48]. Instead, estrogens act by upregulating
myometrial gap junctions [49] and uterotonic receptors (including Ltype calcium channels and oxytocin
receptors) [50], thereby enhancing the capacity of the myometrium to generate contractions.
Longitudinal measurements of circulating estrogen concentrations prior to the onset of labor show an increase in
all primate species [51]. Because the primate placenta is an incomplete steroidogenic organ, placental estrogen
synthesis has an obligate need for C19 steroid precursors (it cannot synthesize estrogen from progesterone)
[2,7]. The fetal adrenal provides an abundant C19 estrogen precursor (dehydroepiandrostenedione) directly from
its intermediate (fetal) zone. In the rhesus monkey, continuous infusion of C19 precursor (androstenedione) leads
to preterm delivery [5254]. This effect is blocked by concurrent infusion of an aromatase inhibitor [54],
demonstrating that localized conversion of progesterone to estrogen is important in promoting contractions in this
species. A similar effect has been shown using a continuous intraamniotic infusion of estrogen [48]. However,
systemic infusion of estrogen failed to induce delivery [48], suggesting that the action of estrogen is likely
paracrine/autocrine.
Oxytocin — Oxytocin is a peptide hormone synthesized in the hypothalamus and released from the posterior
pituitary in a pulsatile fashion. It is also produced by the placenta. Its biologic halflife in the maternal circulation is
approximately three to four minutes, but appears to be shorter when higher doses are infused. Oxytocin is
inactivated in the liver and kidney, although during pregnancy it is primarily degraded by placental oxytocinase.
The evidence in support of a role for oxytocin in parturition can be summarized briefly as follows:
● Oxytocin is the most potent endogenous uterotonic agent, and is capable of stimulating uterine contractions
at intravenous infusion rates of 1 to 2 mU/min at term [55,56].
● The frequency and amplitude of oxytocininduced uterine contractions are identical to those occurring during
spontaneous labor.
● More than 100 mU/min oxytocin is needed to elicit uterine contractions in nonpregnant women, while 16 mU/
min is sufficient to elicit contractions at 20 weeks of gestation, 2 to 3 mU/min at 32 weeks, and 1 mU/min at
term [55].
● Uterine contractions can be induced by electrical stimulation of the posterior pituitary gland or by nipple
stimulation, presumably by increasing oxytocin concentrations in the blood.
● Oxytocin analogues that act as competitive antagonists of endogenous oxytocin are capable of inhibiting
uterine contractions [57].
Circulating levels of oxytocin do not change significantly during pregnancy or prior to the onset of labor [55,56].
However, myometrial oxytocin receptor concentrations increase approximately 100 to 200fold during pregnancy,
reaching a maximum during early labor [55,56,58,59]. This rise in receptor concentration accounts for the
increased sensitivity of the myometrium to circulating levels of oxytocin during the second half of pregnancy.
Specific highaffinity oxytocin receptors have also been isolated apart from the myometrium in the human amnion
and decidua parietalis, but not decidua vera [50,55]. Neither amnion nor decidual cells are contractile, and the
action of oxytocin on these tissues is uncertain. Oxytocin may play a dual role in the mechanism of parturition
[55,58]: It acts directly through oxytocin receptormediated and nonreceptor, voltagemediated calcium channels
to affect intracellular biochemical pathways and promote uterine contractions and it acts indirectly through
stimulation of amniotic and decidual prostaglandin production. Indeed, induction of labor at term is successful
only when the oxytocin infusion is associated with an increase in PGF2 alpha production, in spite of apparently
adequate uterine contractions [50].
Studies examining fetal pituitary oxytocin production, the umbilical arteriovenous difference in plasma oxytocin
concentration, amniotic fluid oxytocin levels, and fetal urinary oxytocin output demonstrate conclusively that the
fetus secretes oxytocin into the maternal circulation [55,60]. Furthermore, the calculated oxytocin secretion rates
from the fetus suggest an increase from a baseline of 1 mU/min prior to labor to approximately 3 mU/min after
spontaneous labor [60]. The latter is similar to the dose of oxytocin normally administered to women to induce
labor at term (2 to 8 mU/min). Although maternal serum oxytocin levels are not increased prior to the onset of
labor or during the first stage of labor, oxytocin derived from the fetus and possibly from local decidual and other
uterine sources could act on myometrial oxytocin receptors in a paracrine/autocrine fashion to initiate and
maintain effective uterine contractions. (See "Induction of labor with oxytocin".)
It is unlikely that oxytocin provides the trigger for the initiation of labor, but the release of oxytocin during labor
results in more forceful uterine contractions and undoubtedly facilitates delivery of the fetus and placenta. The
existence of the socalled Ferguson reflex (release of maternal oxytocin from the posterior pituitary in response to
distention of the cervix and/or vagina) remains controversial. Originally described in feline species, it almost
certainly does not exist in humans [61].
Hypothalamicpituitaryadrenal factors — The final common pathway for initiation of labor appears to be
activation of the fetal hypothalamicpituitaryadrenal axis, which is probably a common pathway for all species.
Corticotropin releasing hormone — Activation of the fetal hypothalamicpituitaryadrenal axis during the
latter part of pregnancy results in release of large amounts of fetal cortisol [62,63]. Glucocorticoids (including
cortisol) are potent stimulants of placental corticotropin releasing hormone (CRH) production, in contrast to their
negative effect on hypothalamic CRH production [64]. Inflammatory cytokines, catecholamines, acetylcholine,
and oxytocin also increase placental CRH secretion [6], while progesterone and nitric oxide (NO) decrease
placental CRH release. Circulating maternal plasma CRH levels increase progressively throughout the latter half
of pregnancy, with a dramatic increase in the final six to eight weeks before delivery [62,63].
During pregnancy, CRH bioactivity (as measured by its ability to promote ACTH release from the pituitary and to
stimulate decidual PGE2 production) is decreased due to an increase in highaffinity CRHbinding protein (CRH
BP). However, in the last three to five weeks of gestation, CRHBP concentrations fall, resulting in a rapid rise in
circulating free CRH [65,66].
Women with an early rapid rise in plasma CRH tend to deliver earlier and those with a slow rise tend to deliver
later, suggesting that production of CRH is an important factor in the timing of delivery. This hypothesis has been
termed the "placental clock" [67].
CRH has no direct inotropic action on human myometrium, but the increase in placental CRH at term is thought
to have multiple actions on the uterus [68]:
● It is secreted back into the fetal compartment where it can act to drive pituitary ACTH release, thereby
providing a positive feedforward loop for labor
● It may act locally within the placenta to promote fetoplacental vasodilatation [69]
● It can directly and preferentially stimulate DHEAS secretion in fetal adrenal cortical cells via a protein kinase
system [70,71]
● It exerts effects on the uterus and cervix by upregulation of the nitric oxide pathway and by augmenting
estrogen effects on these tissues [72]
● It enhances prostaglandin production in the amnion, chorion, and decidua
● It primes the myometrium and potentiates the effects of oxytocin [73]
Glucocorticoids — These hormones have several actions that can also help prepare the uterus for labor.
● Glucocorticoids act directly to upregulate prostaglandin production in fetal membranes at term [6,74].
● Cortisol appears to stimulate expression of placental (but not hypothalamic) CRH in vitro [64]. Studies
demonstrating an increase in circulating CRH concentrations (as well as a decrease in ACTH and cortisol
levels) in women receiving antepartum glucocorticoids to promote fetal lung maturation suggest that this
mechanism may also be operative in vivo [75,76]. In addition, measurement of elevated maternal plasma
CRH levels between 28 and 30 weeks of gestation may predict women at increased risk of preterm delivery
[77].
● In addition, cortisol enhances amnionic cyclooxygenase to enhance prostaglandin synthesis and inhibits
chorionic prostaglandin dehydrogenase activity, thereby preventing prostaglandin metabolism [6,68].
Taken together, these data suggest the gradual increase in fetal pituitaryadrenal activity over the last few weeks
of gestation may have a role in the initiation of labor at term. (See "Pathogenesis of spontaneous preterm birth".)
Other — Various neuropeptides and hormones can affect myometrial contractility. The concentration of some of
these agents changes in maternal serum during pregnancy suggesting that they might act in an endocrine
fashion, while others are produced locally within myometrial smooth muscle cells and act in an
autocrine/paracrine manner. However, their role in the initiation and maintenance of labor at term remains
controversial. Some of these factors are illustrated below:
Parathyroid hormonerelated peptide — Parathyroid hormonerelated peptide is a potent smooth muscle
relaxant capable of inhibiting oxytocininduced contractions in baboons [78]. It is unclear whether it has a
physiologically important role in maintaining uterine quiescence prior to the onset of labor.
Luteinizing hormone/human chorionic gonadotropin — Luteinizing hormone/human chorionic
gonadotropin may be important for maintaining uterine quiescence, especially in the first half of pregnancy.
Human chorionic gonadotropin decreases gap junction formation in strips of myometrium in vitro, leading to a
decrease in contraction frequency and intensity [79]. This effect is likely mediated through the adenyl cyclase
signal transduction system resulting in an increase in intracellular cAMP, which favors uterine relaxation.
Relaxin — Relaxin is a member of the insulinlike growth factor family of proteins. Plasma levels are highest
at 8 to 12 weeks of gestation and thereafter decline to low levels, which persist until term [80]. The primary
source of relaxin is thought to be the corpus luteum.
Relaxin appears to act indirectly to promote myometrial relaxation by stimulating myometrial prostacyclin
production. This effect can be negated by inhibitors of prostaglandin synthesis. Relaxin also has been implicated
in cervical ripening and/or rupture of the fetal membranes, but this remains controversial [81].
Cytokines — Cytokines have long been implicated in the pathophysiology of preterm labor associated with
intraamniotic infection [82]. These agents may also be a component of the process of normal term labor [8386].
Proinflammatory mediator levels (IL1, IL6, TNFalpha) appear to increase in the maternal peripheral circulation
before the onset of spontaneous term labor [87]. The developing fetus may produce physical and hormonal
signals that stimulate macrophage migration to the uterus, with release of cytokines and activation of
inflammatory transcription factors.
Concentrations of interleukin (IL) 8 (but not IL2 or tumor necrosis factor alpha) in human myometrium, decidua,
and fetal membranes are increased during labor [83]. IL8 is a potent chemotactic cytokine acting primarily on
neutrophils. It may cause an increase in collagenase enzyme activity leading to cervical ripening and/or
spontaneous rupture of membranes. Moreover, cytokines and eicosanoids appear to interact and to accelerate
each other's production in a cascadelike fashion, resulting in further increases in prostaglandin production [88]. It
has also been proposed that the increased inflammatory response promotes uterine contractility via direct
activation of contractile genes (eg, COX2, oxytocin receptor, connexin) and/or impairment of the capacity of
progesterone to mediate uterine quiescence [89].
MEMBRANE RUPTURE — The strength and integrity of fetal membranes derive from extracellular membrane
proteins including collagens, fibronectin, and laminins. Matrix metalloproteases (MMPs) are a family of enzymes
with varied substrate specificities that decrease membrane strength by increasing collagen degradation [90].
Tissue inhibitors of MMPs (TIMPs) bind to MMPs and shut down proteolysis, thereby helping to maintain
membrane integrity [90,91]. The fetal membranes normally remain intact until term due to low MMP activity and
high levels of TIMPs [9195]. Periparturitional activation of MMPs at term may trigger a cascade of events that
reduce fetal membrane integrity and promote rupture of membrane [96]. Stretch and shear forces from uterine
contractions during labor probably contribute to membrane rupture, as well.
Although the precise etiology of periparturitional MMP activation is not known, several factors may play a role in
this process:
● Compounds such as tumor necrosis factoralpha, interleukin1, prostaglandins E2 and F2 alpha appear to
increase collagenase activity and activate inflammatory pathways in fetal membranes at parturition [97100].
(See "Pathogenesis of spontaneous preterm birth".)
● Relaxin, a hormone similar to insulin, may induce MMP9 and MMP3 activity in fetal membranes by
antagonizing the suppressive actions of progesterone and estradiol [101].
● Distension of the fetal membranes may initiate cellular events leading to periparturitional destabilization.
Mechanical stretching of fetal membranes activates MMP1 and MMP3 and induces interleukin8
expression in amnion and chorion cells [102,103].
● The neuro and placental peptides corticotropin releasing hormone (CRH) and urocortin (a member of the
CRH family of peptides) may induce local MMP9 activity in fetal membranes [104].
Genetic or epigenetic factors that predispose women to membrane rupture and preterm delivery may be
superimposed on these biochemical pathways.
SUMMARY AND RECOMMENDATIONS
● Human labor at term is a multifactorial physiological event involving an integrated set of changes within the
maternal tissues of the uterus (myometrium, decidua, and uterine cervix) which occur gradually over a period
of days to weeks.
● Such changes include, but are not limited to, an increase in prostaglandin synthesis and release within the
uterus, an increase in myometrial gap junction formation, and upregulation of myometrial oxytocin receptors
(uterine activation).
● Once the myometrium and cervix are prepared, endocrine and/or paracrine/autocrine factors from the
fetoplacental unit bring about a switch in the pattern of myometrial activity from irregular contractures to
regular contractions (uterine stimulation).
● The fetus appears to control the initiation of labor by coordinating the switch in myometrial activity via
placental steroid hormone production, mechanical distension of the uterus, and by secretion of
neurohypophyseal hormones and other stimulators of prostaglandin synthesis.
● Labor is a clinical diagnosis based upon regular phasic uterine contractions increasing in intensity and
frequency, and progressive cervical effacement and dilatation.
● The ability of the fetus to successfully negotiate the pelvis during labor and delivery is dependent on the
complex interaction of three variables: the powers, the passenger, and the passage.
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Topic 6758 Version 10.0
Contributor Disclosures
Errol R Norwitz, MD, PhD, MBA Grant/Research/Clinical Trial Support: Illumina [Preeclampsia (primary
investigator on a prospective cohort study to collect samples from patients with preeclampsia to facilitate
development of a biomarker test to predict/diagnose this disorder)]. Consultant/Advisory Boards: Hologic
[Preterm birth (Fetal fibronectin test to predict preterm birth)]; Natera [Fetal aneuploidy testing (NIPT as a
screening test for fetal aneuploidy)]; Seracare [Fetal aneuploidy testing (Developing controls for NIPT screening
test for fetal aneuploidy)]. Bayer [Prediction test for preeclampsia (Use of urinary angiogenic factors to predict
preeclampsia)]. Charles J Lockwood, MD, MHCM Consultant/Advisory Boards: Celula [Aneuploidy screening
(No current products or drugs in the US)]. Vanessa A Barss, MD, FACOG Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
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