Presented by Taufiq RN

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 characterized by an increase in myometrial activity or, more precisely, a change in the myometrial contractility pattern from "contractures" (long-lasting, low frequency activity) to "contractions" (high intensity, high frequency activity), resulting in effacement and dilatation of the uterine cervix It is a clinical diagnosis, classically defined by the triad of regular painful uterine contractions, progressive cervical effacement and dilatation, and show (bloody discharge).

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). precipitous labor likely 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

1. Head Floating (Before engagement) 2. Engagement 3. Descent (Internal rotation) 4. Beginning extension 5. Complete extension 6. External rotation 7. Delivery of anterior shoulder 8. Delivery of posterior shoulder

The regulation of uterine activity during pregnancy can be divided into four distinct physiologic phases Phase 0: (inhibitors active) Phase 1: myometrial activation Phase 2: stimulatory phase Phase 3: involution

During pregnancy the uterus is maintained in a state of functional quiescence through the action of various putative inhibitors including, but not limited to:

Progesterone Prostacyclin (prostaglandin I-2) Relaxin Parathyroid hormone-related peptide Nitric oxide Calcitonin gene-related peptide Adrenomedullin Vasoactive intestinal peptide.

As term approaches the uterus becomes activated in response to uterotopins, 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 connexin-43 (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.

Extended

Band I

Band H Band A Z line

2300 nm Band I Band H Band A Z line

Contracted

1500 nm

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.

Corticotropin Increasing cortisol elevate progesterone converted to estrogen estrogen increse and progesterone decrease or ratio progesterone-estrogen decreasing placental prostaglandin elevate myometrium more responsive to oxytocin

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, and is probably common to all species

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. 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 The intraamniotic, intravenous, or vaginal administration of exogenous prostaglandins can initiate labor at any stage of gestation and in all species

Prostaglandins have been implicated in the three events most temporally related to the onset of labor: 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

Membrane phospholipid
Phospholipase A2

Prostanoids PGD2 PGE2 PGF2 PGI2 TXA2

Inisiator of labor

Diet COOH

Lipoxin LXA4 LXB4 LXC4 LXD4 LXE4 Leukotriens LTA4 LTB4 LTC4 LTD4 LTE4

Arachidonate

Maternal and Fetal Endocrine Systems Involved in Increased Placental Production of CRH

Administration of a progesterone receptor antagonist or removal of the corpus luteum readily induce abortion in early pregnancy (less than 49 days amenorrhea), suggesting that progesterone is necessary for early pregnancy maintenance. However, the role of progesterone in late pregnancy is not as well defined. 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.

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. Instead, estrogens act by upregulating myometrial gap junctions [51] and uterotonic receptors (including L-type calcium channels and oxytocin receptors), thereby enhancing the capacity of the myometrium to generate contractions.

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 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

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 effectively inhibit labor

Circulating levels of oxytocin do not change significantly during pregnancy or prior to the onset of labor [57,58]. However, myometrial oxytocin receptor concentrations increase approximately 100 to 200-fold during pregnancy, reaching a maximum during early labor

The final common pathway for initiation of labor appears to be activation of the fetal hypothalamic-pituitary-adrenal axis, which is probably a common pathway for all species.

Activation of the fetal hypothalamicpituitary-adrenal axis during the latter part of pregnancy results in release of large amounts of fetal cortisol. Glucocorticoids (including cortisol) are potent stimulants of placental corticotropin releasing hormone (CRH) production, in contrast to their negative effect on hypothalamic CRH production

Inflammatory cytokines, catecholamines, acetylcholine, and oxytocin also increase placental CRH secretion, 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

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 high-affinity CRHbinding protein (CRH-BP). However, in the last three to five weeks of gestation, CRH-BP concentrations fall, resulting in a rapid rise in circulating free CRH 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"

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 Cortisol appears to stimulate expression of placental (but not hypothalamic) CRH in vitro Measurement of elevated maternal plasma CRH levels between 28 and 30 weeks of gestation may predict women at increased risk of preterm delivery Cortisol enhances amnionic cyclooxygenase to enhance prostaglandin synthesis and inhibits chorionic prostaglandin dehydrogenase activity, thereby preventing prostaglandin metabolism

Parathyroid hormone-related peptide Parathyroid hormone-related peptide is a potent smooth muscle relaxant capable of inhibiting oxytocin-induced contractions in baboons 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. This effect is likely mediated through the adenyl cyclase signal transduction system resulting in an increase in intracellular cAMP, which favors uterine relaxation.

Relaxin is a member of the insulin-like 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. 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. Effect of relaxin can be negated by inhibitors of prostaglandin synthesis.

Concentrations of interleukin (IL) -8 (but not IL-2 or tumor necrosis factor alpha) in human myometrium, decidua, and fetal membranes are increased during labor IL-8 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 cascade-like fashion, resulting in further increases in prostaglandin production

Involution of the uterus after delivery occurs during phase 3 and is mediated primarily by oxytocin.

It is likely that a "parturition cascade" exists at term which removes the mechanisms maintaining uterine quiescence and recruits factors promoting uterine activity

Considerable evidence suggests that in most viviparous animals the fetus controls the timing of onset of labor. 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. 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.