Uterine contraction agents, tocolytics, vaginal therapeutics and local contraceptives

Pharmacology and toxicology

Prostaglandins (PG) have a large number of biologic and reproductive functions. Of practical significance during pregnancy are the prostaglandins designated as PGE ₂ , PGF _2α and PGI ₂ ( prostacyclin ).

Prostaglandins are synthesized from arachidonic acid by the enzyme phospholipase A ₂ . The half-life of naturally occurring prostaglandins, such as those produced in the uterus is only a few minutes. The kidneys, liver, intestinal tract, and lungs contain enzymes that quickly destroy prostaglandins and limit their activity. The synthesis of prostaglandins in the genital tract is influenced by the hormones estradiol, progesterone and by catecholamines.

PGE ₂ causes so-called ripening of the cervix, characterized by connective tissue changes that facilitate softening, effacement, and dilatation of the cervix during uterine contractions. PGF _2α promotes contractions. PGI ₂ is an arteriolar dilator. Deficiency of prostacyclin is associated with hypertensive disorders of pregnancy.

In practice, the following uses of prostaglandins can be distinguished:

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  Preparation for labor induction by ripening the cervix with dineprostone , a PGE ₂ analog, applied in the form of intravaginal suppositories or as a gel intracervically, or with misoprostol (a PGE ₂ analog) applied.

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  Induction intravaginally of labor or enhancement of contractions with dinoprostone, applied as intravaginal suppositories, as vaginal inserts, or as a gel intracervically or extra-amniotically.

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  Treatment of post-partum uterine atony with dinoprostol or sulprostone application intravenously or into the myometrium, or transcervically into the uterus, or misoprostol rectally or orally.

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  Induction of abortion with dinoprostone (PGE ₂ ) as an intracervical gel, with sulprostone cervically or in the myometrium, with dinoprostone extra-amniotically, and with gemeprost , intravaginally or misoprostol intravaginally or orally.

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  Sub-involution of the uterus after birth can be treated with oxytocin or ergotamine derivatives like methylergometrine.

With all contraction stimulants, overstimulation of the myometrium can occur. Because myometrial contractions are associated with a decrease in perfusion of the uterine vessels, a potential adverse effect of these agents is embryonic or fetal hypoxia. A disruption type malformation due to reduced perfusion and, in extreme cases, fetal death might be the consequences ( ). Misoprostol is a complementary drug for medical termination of pregnancy up to 63 days of gestation; where this is permitted under national law and where culturally acceptable, and for induction of labor ( ). Failed abortion attempts with misoprostol have been associated with the occurrence of Moebius sequence (cranial nerve defects and limb defects) in the offspring. Other malformations, such as cranial bone defects, omphalocele, and gastroschisis, have also been observed. In these abortion attempts, misoprostol was used orally, often combined with vaginal administration as well. The most common total dose was 800 μg, with a range from 200 to 16,000 μg (four tablets daily for 20 days). All cases were exposed in the first trimester, most commonly in the second month ( ). In a retrospective Brazilian case-control study it was found that nearly half of the 94 women with a child with Moebius sequence had used misoprostol orally or vaginally ( ).

A 200 μg dose of misoprostol has been associated with increased uterine artery resistance indices by Doppler ultrasound, suggesting that perfusion reduction could underlie the disruption-type malformations ( ).

In a relatively small prospective controlled study in 86 women, on the contrary, no adverse effects on pregnancy or neonates were observed ( ). The same held for a French collaborative study of 125 pregnancies exposed to misoprostol ( ).

However, a systematic review and meta-analysis, including 4,899 cases of congenital anomalies and 5,742 controls, concluded that misoprostol is associated with an increased risk of Moebius sequence (OR = 25; 95% CI 11–58), and terminal transverse limb defects (OR = 12; 95% CI 5–29) ( ). In a subsequent study of 118 pregnancies, these authors found a doubling of the incidence of congenital malformations as compared to non-exposed infants not exposed to misoprostol at early gestation ( ).

In summary, an increased teratogenic risk after (accidental) exposure to misoprostol may exist. Amongst women with an offspring with Moebius syndrome, the likelihood of exposure to misoprostol in the first trimester is high; however, the absolute risk is probably low following misoprostol exposure in the first trimester of pregnancy ( ).

Misoprostol given either orally or rectally in a dose of up to 800 μg is increasingly used in low-income settings to prevent post-partum hemorrhage. It is cheap, stable and can be easily distributed at community level. However, current evidence has not shown a reduction in maternal mortality, with maternal pyrexia as a side-effect ( ). Oxytocin infusion as a first-line therapy has been shown to be more effective in preventing post-partum hemorrhage ( ). Off-label use of misoprostol for this indication may be the first choice in a low resource setting, but there remains a need for large randomized trials to further elucidate the relative effectiveness and risks of various dosages ( ).

Misoprostol is also increasingly used for the induction of an abortion or labor, and in the post-partum period, due to its simple oral administration and favorable costs. Titrating the misoprostol dose on the basis of the frequency and intensity of uterine contractions is frequently applied, particularly in developing countries. For labor induction after rupture of the membranes, it is the most effective drug that can be applied without an increased risk for infection. Overstimulation and pathologic fetal heart rate patterns in individual cases, however, are a reason to warn against indiscriminate use of misoprostol ( ). Misoprostol should not be used in term pregnancies with a uterine scar from a previous caesarean section or from major uterine surgery ( ).

Misoprostol is not approved for any indication in pregnancy, and administration of misoprostol for cervical ripening and/or labor induction currently is considered off-label ( ).

Pharmacology and toxicology

Oxytocin is an octapeptide produced in the hypothalamus, stored in the posterior pituitary, and from there released into the blood. Inactivation occurs via a specific oxytocinase in the liver, spleen, and ovaries. During pregnancy, oxytocin is inactivated by another enzyme produced by the placenta, a cystinaminopeptidase. Oxytocin has a plasma half-life of about 10 minutes.

The sites of oxytocin action are the uterine muscle and the myoepithelial cells surrounding the milk-producing units of the breast. The conditions for the action of oxytocin on a pregnant uterus are complex and controlled by several factors. Among these factors are decreases in estrogen and progesterone concentrations in the blood, with a reduction in the α- and β-adrenergic activity in the uterine muscles. During pregnancy the concentration of oxytocin in the blood is slightly elevated, but towards the end of pregnancy both the concentration and the number of oxytocin receptors in the myometrium increase significantly. During the course of labor, a three- to four-fold increase in the plasma concentration of oxytocin is observed.

Because of its structural similarity to vasopressin, oxytocin has antidiuretic hormone activity, promoting the reabsorption of salt-free fluid in the distal renal tubules. High doses of oxytocin (>40 mU/min) given with electrolyte-free solutions can lead to water intoxication, with cramps, coma and, rarely, death. Reduction of fluid intake and monitoring of electrolytes can eliminate the risk of water intoxication.

The oxytocin analog pitocin is used in low doses intravenously as a standard treatment for the induction or augmentation of labor. As with all contraction stimulants, overstimulation of the myometrium can occur. In that case, oxytocin increases the basal tone in the uterus, leading to a decrease in uteroplacental perfusion, with the possibility of fetal hypoxia and even fetal death occurring.

A second risk from overstimulation is uterine rupture, particularly in the presence of a scarred uterus; this may lead to fetal death and substantial maternal blood loss, shock, loss of the uterus, and even maternal death. Uterine rupture, except when an emergency caesarean delivery can be performed, will inevitably lead to the death of the child. Oxytocin should be applied with extreme caution for induction or augmentation of labor, and only in combination with careful monitoring of maternal uterine contractions and the fetal heart rate (i.e. electronic fetal heart rate monitoring, cardiotocography).

Oxytocin, either given intravenously or intramuscularly is the agent of first choice for routine primary prevention of post-partum hemorrhage. The long acting oxytocin derivate carbetocin has been developed to reduce post-partum hemorrhage following a caesarean delivery. A recent Cochrane review has indicated that this agent significantly reduced the need for therapeutic uterotonics as compared to oxytocin (RR 0.62. 95% CI 0.44–0.88), without reducing the overall incidence of post-partum hemorrhage. It is also associated with less blood loss, as compared to syntometrine in the prevention of post-partum hemorrhage in women having a vaginal delivery ( ).

Pharmacology and toxicology

Ergot alkaloids (ergotamine derivatives; see also Chapter 2.1.7 ) are used to increase the strength of uterine contraction to limit post-partum bleeding and promote post-partum involution. Because ergot-associated contractions are tonic rather than rhythmic, these agents cannot be used during labor. Tonic contraction of the uterus during labor could result in fetal hypoxia and even death. The use of these agents is associated with a slight risk of acute coronary syndrome or myocardial infarction, especially in hypertensive women, but the combined risk is relatively low (<1 per 10,000) ( ). It is also associated with an increased risk for manual removal of a retained placenta. For primary prevention of post-partum hemorrhage, oxytocin is generally considered an agent of first choice.

Pharmacologic agents in this group include ergometrine and methylergometrine (methylergonovine).