Timely onset of labor and delivery has an important role in pregnancy outcome. Both preterm and postterm births are at higher risk for poor outcomes than pregnancies delivered at term.
Preterm labor
Preterm labor is the onset of labor before 37 weeks’ gestation. It is the final common pathway for a number of conditions that induce uterine contractions at a time when the uterus is normally quiescent.
Preterm labor complicates 7–10% of all pregnancies and is a very large contributor to perinatal morbidity and mortality. Although over half the cases of preterm labor occur without warning, some factors do carry an identifiable risk: multiple gestation, uterine anomalies, third trimester bleeding, intrauterine infection, excessive amniotic fluid volume, maternal smoking and a history of prior preterm delivery. There have been many unsuccessful attempts to use risk scoring, close clinical observation and home uterine contraction monitoring to predict women at high risk for preterm labor. Several biochemical markers suggest increased risk of preterm labor: raised salivary estriol, which reflects activation of the fetal hypothalamic–pituitary–adrenal axis, and cortisol-releasing hormone, which is synthesized by the placenta (Chapters 19 and 22). Fetal fibronectin is normally restricted to the fetal compartment but will appear in vaginal secretions of women who are at risk for preterm delivery. Therefore the absence of fetal fibronectin in maternal vaginal secretions is highly predictive of women who will not experience preterm labor.
Potential mechanisms for preterm labor
The normal mechanisms involved in labor (Chapter 22) predict the pathways for stimuli that start labor prematurely. For instance, intrauterine infection is associated with an elevation in the amniotic fluid levels of the cytokines interleukin-1β, interleukin-6 and tumor necrosis factor α (TNF-α). Products of the cyclo-oxygenase and prostaglandin pathways are also elevated in patients with intrauterine infections. Cytokines and prostaglandins act synergistically to stimulate the myometrium. Their premature elevation with intrauterine infection could activate the uterus prematurely. Recently, thrombin has been shown to be an extremely potent uterotonic agent. The increase in thrombin production that accompanies bleeding in pregnancy may cause preterm labor. Multiple gestations and excessive amniotic fluid excessively stretch the myometrial syncytium. While this may stimulate muscle activity, it is unclear how fiber stretching produces the regular, coordinated contractions of labor.
Pharmacologic interventions
In some cases of preterm labor, contractions represent an attempt by the uterus to expel the fetus from a hostile intrauterine environment. This may be the goal when premature labor accompanies intrauterine infection. It is usually not prudent to intervene by attempting to stop labor in these clinical situations. When the cause of preterm labor does not independently place the fetus in danger, pharmacologic attempts to stop the premature contractions may be used (Fig. 37.1). Several agents, called tocolytics, are available to inhibit premature uterine contractions. Tocolytics work by interrupting one of four processes: (i) intracellular Ca2+ homeostasis; (ii) myosin phosphorylation; (iii) prostaglandin synthesis; and (iv) oxytocin binding to its receptors (Fig. 37.1). Calcium ions are required for normal myometrial contractions. Magnesium sulfate (MgSO4) acts as a competitive antagonist for Ca2+ and is a commonly used tocolytic. High extracellular magnesium concentrations inhibit Ca2+ entry into myometrial cells via voltage-operated channels. In addition, intracellular magnesium competes with Ca2+ for binding sites on calmodulin. Decreased calcium–calmodulin binding decreases the activity of myosin light chain kinase and muscle contraction. Nifedipine and nitrendipine are type II (dihydropyridine) calcium channel blockers. They prevent Ca2+ influx through the cell membrane into the myometrial cells via the voltage-operated Ca2+ channels. Beta-adrenergic agonists, such as ritodrine, salbutamol, isoxsuprine and terbutaline, bind to β2-adrenergic receptors on the myometrial cell membrane, activate G proteins and increase intracellular cAMP levels. An increase in cAMP levels activates protein kinase A. Activated protein kinase A inhibits myosin light chain phosphorylation. Prostaglandins E and F2α stimulate uterine contractions. The tocolytic, indomethacin, reduces prostaglandin production. It competitively inhibits cyclo-oxygenases that are necessary for conversion of arachidonic acid to prostaglandins. Oxytocin antagonists bind to the oxytocin receptor but do not activate it. Antagonist-binding blocks activation by the agonist oxytocin. Progesterone prophylaxis has been shown to reduce the rate of preterm birth among women with a history of spontaneous preterm delivery. The mechanism of action of the supplemental progesterone is not known.
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