TY - JOUR
AU1 - Briggs, Gerald, G.
AU2 - Wan, Stephanie, R.
AB - Abstract Purpose. The drug therapy of common conditions and complications during labor and delivery and the fetal and neonatal effects of this therapy are examined. Summary. The pharmacologic therapy of common conditions that occur in labor and delivery primarily involves oxytocin and prostaglandins for cervical ripening and labor induction and systemic and regional narcotic analgesics for pain. Because most medications used in women during labor and delivery do not have Food and Drug Administration-approved labeling, pharmacists should understand the benefits and limitations of medications used in the mother. Although induction and augmentation of labor and the control of pain often require drug therapy, other, less frequent, complications may occur in labor. Drug therapies for these complications include anti-infective agents to treat maternal infection and prevent neonatal diseases; antiretrovirals to reduce perinatal HIV-1 transmission from the mother to the fetus; corticosteroids to prevent fetal lung immaturity; antihypertensives to treat preeclampsia; anticonvulsants to treat eclampsia; antibiotics to prolong pregnancy and improve neonatal outcomes after premature rupture of the membranes; tocolytics for premature labor; and oxytocin, ergot alkaloids, and prostaglandin analogues for postpartum hemorrhage. The fetal and neonatal effects of therapy for the conditions that occur during labor and delivery are usually benign, but significant morbidity and mortality involving the mother, the fetus, and the newborn are ever-present risks. Conclusion. Awareness of the conditions and complications requiring drug therapy during labor and delivery will allow hospital pharmacists to make knowledgeable decisions about the rapid accessibility of critical medications in the labor and delivery unit. Anticonvulsants, Antiinfective agents, Antiretroviral agents, Eclampsia, Ergot alkaloids, HIV infections, Hypotensive agents, Infections, Labor, Opiates, Oxytocics, Oxytocin, Pediatrics, Placental transfer, Postpartum hemorrhage, Preeclampsia, Pregnancy, Prostaglandins, Steroids, cortico-, Tocolytics, Toxicity Preeclampsia and eclampsia Gestational hypertension, previously known as pregnancy-induced hypertension, is defined as a systolic blood pressure of >140 mm Hg or a diastolic pressure of >90 mm Hg occurring after 20 weeks’ gestation. Preeclampsia is gestational hypertension and proteinuria (urinary excretion of ≥0.3 g protein in a 24-hour urine specimen), and eclampsia is new-onset grand mal seizures in a woman with preeclampsia.72 These pathological conditions affect a number of maternal systems, including vascular (hemoconcentration), hematologic (thrombocytopenia and hemolysis), hepatic (increases in alanine aminotransferase and aspartate aminotransferase, hyperbilirubinemia, hepatic hematoma, and rupture), neurologic (blurred vision, headaches, scotomata, hyperreflexia, transient blindness, seizures, and intracranial hemorrhage), and renal (oliguria, acute tubular necrosis, and acute renal failure).72 The major goals of therapy are the control of hypertension and the prevention of maternal seizures.71 Treatment of hypertension is generally recommended for diastolic blood pressures of ≥105 mm Hg and systolic blood pressures of ≥160 mm Hg.72 Treatment of hypertension near or at term is a careful balance between reducing the potential for maternal complications and the prevention of direct or indirect fetal toxicity. In women with long-standing essential hypertension, placental perfusion may be compromised by even mild decreases in maternal blood pressure. In 2000, a meta-analysis revealed that a statistically significant decrease of approximately 5 mm Hg in the mean arterial pressure (MAP) adversely affected fetal growth.73 Moreover, some antihypertensives, such as the angiotensin-converting-enzyme inhibitors and angiotensin II-receptor antagonists, may cause fetal renal toxicity.74,–76 Atenolol and other β-blockers, especially those without intrinsic sympathomimetic activity, are generally avoided because of the risks of reducing placental perfusion secondary to vasoconstriction and increased vascular resistance and β-blockade in the newborn.77,78 During labor and delivery, the most commonly used antihypertensive agents are i.v. hydralazine hydrochloride (5–10 mg every 15–20 minutes until desired response) and i.v. labetalol hydrochloride (20 mg, then 40 mg if not effective within 10 minutes, then 80 mg every 10 minutes to a maximum total dose of 220 mg).72 These agents safely decrease maternal blood pressure without fetal compromise. Prevention of maternal seizures (i.e., eclampsia) is the second major goal of therapy; i.v. magnesium sulfate is the treatment of choice.72 A number of randomized, controlled studies, retrospective studies, and observational studies found that magnesium sulfate was superior to phenytoin and diazepam in the prevention of eclampsia.79,–82 Typical protocols for i.v. magnesium sulfate involve a 4–6-g loading dose in 100 mL of fluid administered over 15–20 minutes, followed by 2 g/hr as a continuous i.v. infusion.81 Therapeutic serum magnesium concentrations are thought to range from 4.8 to 8.4 mg/dL (2.0 to 3.5 mmol/L), but they are not known with exact certainty as they have been empirically determined by levels preventing eclamptic seizures.81 Higher serum concentrations may produce loss of tendon (patella) reflexes (>12 mg/dL), respiratory depression (>14 mg/dL), muscular paralysis and respiratory arrest (15–17 mg/dL), and cardiac arrest (30–35 mg/dL) in the mother.83 Cervical ripening and labor induction Labor is defined as an increase in myometrial activity, with uterine contractions and the effacement and dilation of the cervix, resulting in the delivery of the fetus from the uterus.84 Induction of labor involves artificial stimulation of the uterus, leading to regular or rhythmic contractions, before the spontaneous onset of labor. The goal of labor induction is a vaginal delivery. Induction is indicated when the continuation of pregnancy clearly endangers the well-being of the mother or fetus.85 Conditions that necessitate labor induction include preeclampsia or eclampsia, fetal death or nonreassuring status, placental abruption (separation of the placenta from the uterine wall), chorioamnionitis, and a pregnancy that has exceeded 42 weeks of duration.85 Contraindications to labor induction are similar to those for spontaneous labor and vaginal delivery in general: mothers with absolute cephalopelvic disproportion, active genital herpes infection, previous high-vertical hysterotomy or cesarean section with a classic incision, uteroplacental complications such as complete placenta previa (i.e., the placenta covering the cervix) or umbilical cord prolapse, and fetal malpresentation.85 Induction of labor occurs in two phases: cervical ripening and induction of contractions. The status of the cervix plays an important role in the success or failure of labor induction. The Bishop scoring system is a tool used to evaluate the clinical cervical state and assigns points for dilation, effacement (thinning), station (degree of engagement of the fetal head in the maternal pelvis), consistency (firm to soft), and position (posterior to anterior) (Table 11).85,86 Studies have demonstrated that if the total Bishop score is greater than 8, the rate of vaginal delivery after induction is similar to that of spontaneous labor.85 Low Bishop scores are associated with high rates of failed induction, leading to increased maternal–fetal morbidity and mortality and increased rates of cesarean section. ACOG recommends that the Bishop score be 6 or greater before proceeding with labor induction.85 A favorable cervical status, and the labor induction that follows, may be achieved by pharmacologic and non-pharmacologic techniques. Non-pharmacologic methods for cervical ripening and induction of contractions include membrane stripping and amniotomy, placement of an intracervical balloon catheter, and insertion of hygroscopic or osmotic dilators. Mechanical dilators, such as laminaria, may cause discomfort to the patient and may increase infection. While they are equally as effective as pharmacologic agents, they may be indicated in patients for whom pharmacologic agents are contraindicated or unavailable due to supply or cost.84,85 Table 1. Bishop Scoring System85,86 Score Parameter 0 1 2 3 aNot applicable. Dilation (cm) Closed 1–2 3–4 ≥5 Effacement (%) 0–30 40–50 60–70 ≥80 Station −3 −2 −1 or 0 1 or 2 Consistency Firm Medium Soft . . .a Cervical position Posterior Midposition Anterior . . . Score Parameter 0 1 2 3 aNot applicable. Dilation (cm) Closed 1–2 3–4 ≥5 Effacement (%) 0–30 40–50 60–70 ≥80 Station −3 −2 −1 or 0 1 or 2 Consistency Firm Medium Soft . . .a Cervical position Posterior Midposition Anterior . . . Open in new tab Table 1. Bishop Scoring System85,86 Score Parameter 0 1 2 3 aNot applicable. Dilation (cm) Closed 1–2 3–4 ≥5 Effacement (%) 0–30 40–50 60–70 ≥80 Station −3 −2 −1 or 0 1 or 2 Consistency Firm Medium Soft . . .a Cervical position Posterior Midposition Anterior . . . Score Parameter 0 1 2 3 aNot applicable. Dilation (cm) Closed 1–2 3–4 ≥5 Effacement (%) 0–30 40–50 60–70 ≥80 Station −3 −2 −1 or 0 1 or 2 Consistency Firm Medium Soft . . .a Cervical position Posterior Midposition Anterior . . . Open in new tab Oxytocin and prostaglandins (i.e., misoprostol and dinoprostone) are used for labor induction. The dosages, routes of administration, and cost of these agents are summarized in Tables 22 and 3 3. Maternal vital signs, fetal heart rate, and uterine activity should be continuously monitored. Knowledge of the drugs’ half-lives and duration of action is important in anticipating both their effectiveness and potential adverse effects.87 Table 3. Oxytocin Dosing: Examples of Low-Dose and High-Dose Regimens85,87 Starting Dosage (milliunits/min) Incremental Increase (milliunits/min) Interval between Increases (min) Maximum Dose (milliunits/min) aReduce incremental rate increase to 3 milliunits/min for uterine hyperstimulation; reduce to 1 milliunit/min for recurrent hyperstimulation. Low dose     0.5–1 1 30–40 20     1–2 2 15 20 High dose     6 6a 20–40 40 until adequate contractility reached     4 4 15 Starting Dosage (milliunits/min) Incremental Increase (milliunits/min) Interval between Increases (min) Maximum Dose (milliunits/min) aReduce incremental rate increase to 3 milliunits/min for uterine hyperstimulation; reduce to 1 milliunit/min for recurrent hyperstimulation. Low dose     0.5–1 1 30–40 20     1–2 2 15 20 High dose     6 6a 20–40 40 until adequate contractility reached     4 4 15 Open in new tab Table 3. Oxytocin Dosing: Examples of Low-Dose and High-Dose Regimens85,87 Starting Dosage (milliunits/min) Incremental Increase (milliunits/min) Interval between Increases (min) Maximum Dose (milliunits/min) aReduce incremental rate increase to 3 milliunits/min for uterine hyperstimulation; reduce to 1 milliunit/min for recurrent hyperstimulation. Low dose     0.5–1 1 30–40 20     1–2 2 15 20 High dose     6 6a 20–40 40 until adequate contractility reached     4 4 15 Starting Dosage (milliunits/min) Incremental Increase (milliunits/min) Interval between Increases (min) Maximum Dose (milliunits/min) aReduce incremental rate increase to 3 milliunits/min for uterine hyperstimulation; reduce to 1 milliunit/min for recurrent hyperstimulation. Low dose     0.5–1 1 30–40 20     1–2 2 15 20 High dose     6 6a 20–40 40 until adequate contractility reached     4 4 15 Open in new tab Table 2. Prostaglandins Used in Cervical Ripening85,87 Agent Dosage Route t½(min) Duration of Action Cost Comments Misoprostol tablets 25 μg every 4 hr or 25–50 μg every 3–6 hr Intravaginal 20–40 1.5–3 hr $0.36–$1.20/100-μg tablet Supplied as 100-μg oral tablets; continuous fetal heart rate and uterine monitoring required throughout administration Dinoprostone cervical gel 0.5 mg (in 2.5 mL syringe) Endocervical 2.5–5 May repeat dose in 6 hr $65–$75/dose Patient to remain recumbent for 30 min to prevent leakage; may initiate oxytocin ≥6 hr after cervical placement; fetal heart rate and uterine monitoring required before and for at least 2 hr after administration Dinoprostone vaginal insert 10 mg (released slowly at 0.3 mg/hr) Intravaginal 2.5–5 Slowly over 12 hr $165/dose May initiate oxytocin ≥30 min after removal of insert; fetal heart rate and uterine monitoring required after placement and for at least 15 min after removal Agent Dosage Route t½(min) Duration of Action Cost Comments Misoprostol tablets 25 μg every 4 hr or 25–50 μg every 3–6 hr Intravaginal 20–40 1.5–3 hr $0.36–$1.20/100-μg tablet Supplied as 100-μg oral tablets; continuous fetal heart rate and uterine monitoring required throughout administration Dinoprostone cervical gel 0.5 mg (in 2.5 mL syringe) Endocervical 2.5–5 May repeat dose in 6 hr $65–$75/dose Patient to remain recumbent for 30 min to prevent leakage; may initiate oxytocin ≥6 hr after cervical placement; fetal heart rate and uterine monitoring required before and for at least 2 hr after administration Dinoprostone vaginal insert 10 mg (released slowly at 0.3 mg/hr) Intravaginal 2.5–5 Slowly over 12 hr $165/dose May initiate oxytocin ≥30 min after removal of insert; fetal heart rate and uterine monitoring required after placement and for at least 15 min after removal Open in new tab Table 2. Prostaglandins Used in Cervical Ripening85,87 Agent Dosage Route t½(min) Duration of Action Cost Comments Misoprostol tablets 25 μg every 4 hr or 25–50 μg every 3–6 hr Intravaginal 20–40 1.5–3 hr $0.36–$1.20/100-μg tablet Supplied as 100-μg oral tablets; continuous fetal heart rate and uterine monitoring required throughout administration Dinoprostone cervical gel 0.5 mg (in 2.5 mL syringe) Endocervical 2.5–5 May repeat dose in 6 hr $65–$75/dose Patient to remain recumbent for 30 min to prevent leakage; may initiate oxytocin ≥6 hr after cervical placement; fetal heart rate and uterine monitoring required before and for at least 2 hr after administration Dinoprostone vaginal insert 10 mg (released slowly at 0.3 mg/hr) Intravaginal 2.5–5 Slowly over 12 hr $165/dose May initiate oxytocin ≥30 min after removal of insert; fetal heart rate and uterine monitoring required after placement and for at least 15 min after removal Agent Dosage Route t½(min) Duration of Action Cost Comments Misoprostol tablets 25 μg every 4 hr or 25–50 μg every 3–6 hr Intravaginal 20–40 1.5–3 hr $0.36–$1.20/100-μg tablet Supplied as 100-μg oral tablets; continuous fetal heart rate and uterine monitoring required throughout administration Dinoprostone cervical gel 0.5 mg (in 2.5 mL syringe) Endocervical 2.5–5 May repeat dose in 6 hr $65–$75/dose Patient to remain recumbent for 30 min to prevent leakage; may initiate oxytocin ≥6 hr after cervical placement; fetal heart rate and uterine monitoring required before and for at least 2 hr after administration Dinoprostone vaginal insert 10 mg (released slowly at 0.3 mg/hr) Intravaginal 2.5–5 Slowly over 12 hr $165/dose May initiate oxytocin ≥30 min after removal of insert; fetal heart rate and uterine monitoring required after placement and for at least 15 min after removal Open in new tab Misoprostol Misoprostol, a prostaglandin E1 analogue, is used both for cervical ripening and induction. Its only FDA-approved indication is for the prevention of gastric ulcers induced by nonsteroidal antiinflammatory drugs (NSAIDs); however, it is widely used in obstetrics for preinduction cervical ripening, stimulation of uterine contractions, treatment of postpartum hemorrhage in the presence of uterine atony, and as an adjunct to mifepristone in medical abortion.88 When used for cervical ripening and labor induction, the 100-μg tablet is broken in halves and in quarters to achieve the 50- and 25-μg doses, respectively. Intravaginal misoprostol has been reported to be either superior or comparable to dinoprostone gel, and the benefits of misoprostol over dinoprostone include ease of administration, stability, storage (misoprostol may be stored at room temperature; dinoprostone requires sterile handling and refrigeration), and cost.85 A general complication associated with prostaglandins is uterine hyperstimulation. This is defined as either a series of single contractions lasting 2 minutes or more or a contraction frequency of five or more in 10 minutes.85 Fetal heart rate abnormalities may also occur. Higher rates of hyperstimulation have been reported with intravaginal dinoprostone inserts when compared with the intracervical gel; removing the vaginal insert typically reverses the effect. Higher doses (e.g., ≥50 μg) and shorter administration intervals (e.g., every three hours) of misoprostol are also associated with greater rates of hyperstimulation compared with lower doses (e.g., 25 μg) and longer administration intervals (e.g., every six hours). Administration of a β-sympathomimetic agent (e.g., terbutaline sulfate 0.125–0.25 mg subcutaneously or i.m.) usually resolves hyperstimulation by decreasing the frequency of uterine contractions. Unresolved hyperstimulation may result in uterine rupture or placental abruption. In patients with prior cesarean section, misoprostol should be avoided due to the increased risk for incisional uterine rupture. Other adverse effects and general precautions with prostaglandin use include gastrointestinal effects and relative precautions when used in patients with glaucoma or pulmonary disease.85,87,88 Oxytocin Oxytocin is a potent endogenous uterotonic agent.87 Given exogenously, it is used for both artificial induction and augmentation of labor. Oxytocin increases the frequency, force, and duration of uterine contractions. Its uterine effects increase throughout pregnancy, starting at 20 weeks and leveling out at 34 weeks until term, when uterine sensitivity to oxytocin increases dramatically due to increases in the number of oxytocin receptors at term and during labor. Maternal parity, stage of cervical advancement, and gestational age are important predictors in individual oxytocin dose response. Both low- and high-dosage oxytocin regimens administered by continuous infusion are used; balancing oxytocin dosage selection and frequency of incremental rate increase requires special attention to the potential for uterine hyperstimulation or fetal distress, while still effectively promoting strong uterine contractions to shorten labor, decrease cesarean deliveries, and reduce perinatal morbidity.85 One protocol recommended by ACOG initiates oxytocin at 0.5–2 milliunits/min, increasing by 1–2 milliunits/min every 30–60 minutes and using a cervical dilation rate of 1 cm/hr to gauge adequate progression of active labor.85 The maximum doses of oxytocin range from approximately 20 milliunits/min for augmentation of delivery to 40 milliunits/min for induction of labor.85,87 Oxytocin is generally prepared as 10 units diluted in 1000 mL of isotonic (electrolyte containing) solution of 10 milliunits/mL. Adverse effects of oxytocin include water intoxication (a rare effect secondary to its antidiuretic effect at large dosages), cardiovascular effects (premature ventricular contractions, hypotension, and mild and transient hypertension), and uterine hypertonicity.87 Premature labor Labor occurring before 37 weeks of gestation (as determined from the first day of the last menstrual period or by ultrasound estimation of fetal age) is called premature labor. Regular uterine contractions and changes in the cervix are required for the diagnosis. Agents that have been used as tocolytics (drugs that inhibit myometrial contractions) include ethanol (no longer used), β-sympathomimetics, magnesium sulfate, calcium channel blockers, NSAIDs, and nitroglycerin. However, none of these agents are very effective, and none can be called a first-line agent.89 Terbutaline Since ritodrine was withdrawn from the market, terbutaline is the only β-sympathomimetic used as a tocolytic in the United States. The typical dosage is 0.25 mg subcutaneously every 20 minutes to three hours. The drug is discontinued if the maternal heart rate exceeds 120 beats/min. Terbutaline is contraindicated if the mother has cardiac arrhythmia. The principal maternal adverse effects are hyperglycemia, cardiac arrhythmias, myocardial ischemia, pulmonary edema, hypotension, and tachycardia. The infrequent fetal and newborn adverse effects are fetal tachycardia, hyperinsulinemia, hyperglycemia, myocardial and septal hypertrophy, and myocardial ischemia.89 Because of the risk of hyperinsulinemia, newborns may develop hypoglycemia. Magnesium sulfate The tocolytic dose of i.v. magnesium sulfate is the same as that used to prevent eclamptic seizures: 4–6 g i.v. over 20 minutes followed by 2–3 g/hr as a continuous infusion. Myasthenia gravis and renal failure are contraindications to the use of magnesium sulfate. Early signs and symptoms of maternal toxicity include flushing, feelings of warmth, muscle weakness, headache, somnolence, double vision, dry mouth, and slurred speech.83,89 Fetal and neonatal effects include lethargy, hypotonia, and respiratory depression.89 Fetal bone demineralization, potentially resulting in congenital rickets, may occur with prolonged use (e.g., one week or longer).89,90 Calcium channel blockers The primary calcium channel blocker used as a tocolytic is nifedipine, but nicardipine has also been used. The usual dosage of nifedipine, 10–20 mg p.o. every four to six hours, may cause flushing, headache, dizziness, and nausea. In normotensive women, transient hypotension is rare. No adverse effects have been observed in newborns. The only maternal contraindications to the tocolytic use of nifedipine are cardiac disease and hypotension.89 Clinically significant drug interactions have been reported between i.v. magnesium sulfate and oral nifedipine.91 Hypotension occurred in two women, resulting in the death of one newborn. In a third case, a woman developed pronounced muscle weakness, jerky movements of the extremities, difficulty in swallowing, paradoxical respirations, and an inability to lift her head.92 The fourth case involved a newborn, exposed in utero to magnesium sulfate (24 g over 32 hours), who was treated with i.m. gentamicin every 12 hours starting 12 hours after birth.93 Respiratory arrest occurred after the second dose. The interaction was confirmed in experimental animals. NSAIDs Three NSAIDs have been used as tocolytics: indomethacin, ketorolac, and sulindac.89 However, the manufacturer of ketorolac states that the drug’s use in labor and delivery is contraindicated.94 Limiting the use of any NSAID to 48 hours will usually eliminate the potential for fetal toxicity. NSAIDs should not be used in women with significant renal or hepatic disease, active peptic ulcer disease, coagulation disorders, thrombocytopenia, NSAID-sensitive asthma, or other sensitivity to NSAIDs.89 The recommended tocolytic dosages (all limited to a 48-hour duration) are indomethacin (50 mg rectally [prepared extemporaneously] or 50–100 mg p.o., then 25–50 mg p.o. every 6 hours), ketorolac tromethamine (60 mg i.m., then 30 mg i.m. every 6 hours), and sulindac (200 mg p.o. every 12 hours). The maternal adverse effects, primarily gastrointestinal upset (nausea, heartburn), are mild in comparison to the potential for fetal or neonatal harm. Fetal toxicity includes constriction of the ductus arteriosus and reversible renal impairment that may result in oligohydramnios, whereas neonatal toxicity includes pulmonary hypertension, intraventricular hemorrhage, hyperbilirubinemia, and necrotizing enterocolitis. Restricting the duration of therapy to 48 hours will limit the potential for fetal and neonatal toxicity.89 The sensitivity of the ductus arteriosus to NSAID-induced premature closure is related to gestational age. Transient constriction of the ductus by indomethacin has been documented to occur as early as 26–27 weeks’ gestation.95,–97 At this gestational age, about 5–10% of fetuses were affected, but the greatest rate of premature closure (about 50%) was found at 32 weeks’ gestation.97 No correlation between ductus constriction and indomethacin serum levels has been found.95 Thus, restricting the use of NSAIDs to gestational ages of <32 weeks should significantly reduce this complication. Nitroglycerin A number of reports have described the use of nitroglycerin for both emergency and routine tocolysis. I.V. nitroglycerin has been used to relax a hypertonic uterus during delivery, thereby allowing safe delivery of the fetus.98,99 Both doses used, 0.1 and 1 mg, have been associated with maternal hypotension (systolic and diastolic in one patient, systolic only in another patient) that required ephedrine to reverse. Reports also have described the use of nitroglycerin as a tocolytic to allow turning of the fetus into a headfirst position (i.e., version) for delivery.98,–107 The doses used were 0.05–0.2 mg i.v.,100,–102 0.4–0.8 mg sublingual by aerosol,103,–106 and 1–1.5 mg i.v.107 Significant decreases in maternal blood pressure were observed in the women receiving ≥0.1 mg of i.v. nitroglycerin. Sublingual nitroglycerin was associated with headache.106 Compared with β-sympathomimetics (i.v. ritodrine or subcutaneous terbutaline), the use of nitroglycerin resulted in fewer successful versions.102,105 Transdermal108,–110 and sublingual111 nitroglycerin have also been used in an attempt to prolong pregnancy but appear to be less effective than β-sympathomimetics.110,111 Pain control The pain of childbirth has been characterized as the most severe type of pain a woman will experience in her lifetime.112 This pain comprises visceral pain from uterine contractions and cervical dilation (involves thoracic and lumbar vertebrae T-10 through L-1) and, as labor progresses, somatic pain transmitted by the pudendal nerve (involves sacral vertebrae S2–4).113 Somatic pain is caused by pressure from the descent of the fetal head on the pelvic floor, vagina, and perineum.113 Systemic analgesics Narcotic agonists or agonist–antagonists have been frequently used to control the pain of childbirth. However, when given by intermittent injection or patient-controlled analgesia, these agents are relatively ineffective.113 NSAIDs, by any route, are contraindicated for this use because of their toxicity profile. Narcotic agonists used most frequently are meperidine, fentanyl, and morphine. For meperidine hydrochloride, the typical dosage is 25–50 mg i.v. every 1–2 hours (onset, 5 minutes) or 50–100 mg i.m. every 2–4 hours (onset, 30–45 minutes). Fentanyl 50–100 μg (as the citrate salt) i.v. is given every hour (onset, 1 minute), whereas morphine sulfate is given as 2–5 mg i.m. (onset, 5 minutes) or 10 mg i.m. (onset, 30–40 minutes), both every 4 hours.113 The elimination half-lives in the newborn are important, since all narcotics cross the placenta to the fetus and can produce dosage-related neonatal respiratory and neurobehavioral depression. Half-lives for each agent are as follows: meperidine, 13–22.4 hours; meperidine metabolite normeperidine, 63 hours; fentanyl, 5.3 hours; and morphine, 7.1 hours.113 Dose-related neonatal respiratory depression secondary to the use of narcotic analgesics immediately before delivery is well-known.113 In contrast to other agents, the rate of meperidine-induced toxicity is also time dependent, increasing markedly if delivery occurs 60 minutes or longer after i.m. or i.v. injection.114 Neonatal neurobehavior depression lasting for several days has been associated with meperidine. This toxicity is probably a result of accumulation of the parent compound and its active metabolite, normeperidine, in the fetus. In general, parenteral analgesics are associated with an increased risk of newborn depression, as evidenced by low Apgar scores (twofold to threefold increased risk of a score of <7 at five minutes) and an increased use of naloxone (fourfold increase).113 The Apgar score is an evaluation of the newborn infant’s physical status based on a 10-point scale; scores of 8–10 indicate the best possible condition, and scores of <7 are considered abnormal.115 Two parenteral narcotic agonist–antagonist analgesics that have been used for labor pain are butorphanol tartrate (1–2 mg i.v. or i.m. every four hours) (analgesia onset, 1–2 minutes after i.v. dose or 10–30 minutes after i.m. dose) and nalbuphine hydrochloride (10 mg i.v. or i.m. every three hours) (analgesia onset, 2–3 minutes after i.v. dose or 15 minutes after i.m. dose).113 Although they do not provide better analgesia than do narcotic agonists, their use may be associated with less nausea and vomiting and a lower rate of newborn respiratory depression. Butorphanol should be avoided if there is hypertension or preeclampsia, because it can increase blood pressure.113 A sinusoidal fetal heart pattern, with or without evidence of fetal heart rate decelerations (a sign of fetal hypoxia), has been observed with these agents. In one study of 51 women who received butorphanol (1 mg i.v.), 75% of the fetuses developed a sinusoidal pattern.116 No adverse effects from the abnormal heart rate pattern were observed in the neonates. Regional analgesia Because of ineffective analgesia and the potential for neonatal toxicity, the majority of women in labor are now treated with regional analgesia, of which there are three types: epidural, spinal, and combined spinal–epidural.113 Drugs include local anesthetics (e.g., bupivacaine, levobupivacaine, ropivacaine) with or without a narcotic agonist (e.g., morphine, fentanyl). Several adverse effects are associated with regional anesthesia: hypotension (incidence up to 31% with epidural, up to 67% with spinal), fever (≥100.4 °F [≥38.0 °C], up to 24% with epidural), postdural puncture headache (up to 3% with epidural or spinal), transient painful sensations in the buttocks or lower extremities (spinal, up to 7%), transient fetal heart rate decrease (8%), pruritus (epidural, up to 26%; spinal, up to 85%), and inadequate pain relief (epidural, up to 15%).113 The prevalence of hypotension can be decreased, but not completely prevented, by i.v. prehydration with 500–1000 mL of non-glucose-containing isotonic crystalloid fluid. I.V. ephedrine may be required to prevent decreased uterine perfusion if hypotension occurs. Absolute contraindications to regional anesthesia are “refractory maternal hypotension, maternal coagulopathy, administration of once-daily doses of low-molecular-weight heparin (LMWH) within 12 hours, untreated maternal bacteremia, skin infection over site of needle placement, and increased intracranial pressure caused by a mass lesion.”113 Delaying regional anesthesia for 24 hours after the last dose of twice-daily LMWH has been advocated, but it is not known if this is adequate.117,118 Obtaining an anti-factor Xa level before placement of an epidural catheter is not recommended because a normal value may not adequately predict the risk of bleeding.117 ACOG recommends switching patients to unfractionated heparin as they approach term.118 At our institution, patients are switched to unfractionated heparin at 36 weeks’ gestation, earlier if preterm delivery is threatened. This allows for quick normalization of the activated partial thromboplastin time (aPTT) before placement of anesthesia or cesarean delivery. Protamine may be administered to reverse the aPTT if necessary. Local anesthesia Anesthetic agents, such as lidocaine hydrochloride (1–2%) and chloroprocaine hydrochloride (1–3%), are sometimes used for local infiltration of the perineum and vagina before episiotomy and repair of lacerations.113 The duration of action of these agents is approximately 20–40 minutes. These agents are also used for pudendal block, which provides temporary pain relief for operative vaginal deliveries. Adverse effects, such as seizures, hypotension, and cardiac arrhythmias, are rare complications that occur primarily with inadvertent intravascular injection. Hematoma and infection are additional complications of pudendal block. Fetal bradycardia is strongly associated with paracervical blocks.113 General anesthesia General anesthesia is administered if regional anesthesia is not an option.113 Nitrous oxide, combined with oxygen, is typically used and may be supplemented with halogenated hydrocarbons at low concentrations (e.g., desflurane, enflurane, isoflurane, sevoflurane). Sodium pentothal i.v. is also used. All of these agents rapidly cross the placenta to the fetus and can cause neonatal depression. Reducing the induction-to-delivery time (e.g., less than eight minutes) may reduce the frequency of this complication.113 The inhaled halogenated agents cause dose-related uterine relaxation.113 This can be beneficial when uterine relaxation is desired but can also increase the risk of blood loss. However, the low concentrations typically administered do not usually have a detrimental effect on maternal blood loss.113 Postpartum hemorrhage Postpartum hemorrhage (PPH) accounts for significant maternal mortality, with 28% of maternal deaths in developing countries caused by excessive blood loss after parturition.119 The frequency of PPH in vaginal delivery and cesarean delivery is 3.9% and 6.4%, respectively.120,121 PPH is defined as either a 10% change in hematocrit values between admission and the postpartum period or a need for erythrocyte transfusion.120 The most common causes of PPH are uterine atony and vaginal or cervical lacerations from obstetric trauma.122 Retained placental tissue after delivery and hemorrhage from placenta accreta (placenta attached directly to the uterine wall muscle), placenta increta (placenta extends into the muscle), or placenta percreta (placenta extends through the entire uterine wall) are other causes of PPH.122 Several risk factors for PPH have been identified: episiotomies, maternal obesity, uterine overdistention (e.g., from macrosomia, multifetal gestation, or polyhydramnios), infections (chorioamnionitis), preeclampsia, oxytocin use, rapid or prolonged labor, and use of uterine-relaxing medications.119 The management of PPH involves prevention, early recognition by the physician or nurse, and expeditious treatment. The urgency of this life-threatening condition is underscored by excessive postpartum blood loss, in some cases as much as 600 mL/min.123 After PPH is identified, fundal massage and compression, use of blood products, surgical intervention, and pharmacologic treatment are warranted. Because treatment failure may be secondary to delay in administration of pharmacologic agents,124 easy accessibility (i.e., in the labor and delivery unit, operating rooms, and recovery rooms) of the medications used to treat PPH is vital and mandatory. Prevention of PPH involves the routine administration of oxytocin immediately following delivery of the placenta to promote uterine contraction and vasoconstriction (thus preventing the uterus from becoming atonic). Oxytocin 10–20 units i.m. or diluted in 500–1000 mL of parenteral fluid containing electrolytes and given as an i.v. infusion of 20 milliunits/min until the uterus is firmly contracted reduces the risk for PPH caused by uterine atony.125 Misoprostol 400–600 μg may also be administered orally or rectally to prevent PPH. Because misoprostol is a prostaglandin E1 analogue, it helps to prevent PPH by increasing uterine tone.125 The treatment of PPH due to uterine atony involves agents that increase uterine contractions and vasoconstriction (Table 44). In addition to bimanual fundal massage and compression and routine administration of oxytocin, other treatment options include the use of ergot alkaloids (e.g., methylergonovine) and the prostaglandin analogues (i.e., carboprost tromethamine and misoprostol).123 Table 4. Pharmacologic Agents Used in Early Postpartum Hemorrhage125 Medication Dose Route of Administration Frequency of Dose Oxytocin 10–40 units in 500–1000 mL parenteral fluids, given at ~200 milliunits/min I.V. Continuous infusion Methylergonovine 0.2 mg I.M. or intramyometrial Every 2–4 hr Carboprost tromethamine 0.25 mg I.M. or intramyometrial Every 15–90 min (not to exceed 8 doses) Misoprostol 1000 μg Rectal, vaginal, or buccal Single dose Medication Dose Route of Administration Frequency of Dose Oxytocin 10–40 units in 500–1000 mL parenteral fluids, given at ~200 milliunits/min I.V. Continuous infusion Methylergonovine 0.2 mg I.M. or intramyometrial Every 2–4 hr Carboprost tromethamine 0.25 mg I.M. or intramyometrial Every 15–90 min (not to exceed 8 doses) Misoprostol 1000 μg Rectal, vaginal, or buccal Single dose Open in new tab Table 4. Pharmacologic Agents Used in Early Postpartum Hemorrhage125 Medication Dose Route of Administration Frequency of Dose Oxytocin 10–40 units in 500–1000 mL parenteral fluids, given at ~200 milliunits/min I.V. Continuous infusion Methylergonovine 0.2 mg I.M. or intramyometrial Every 2–4 hr Carboprost tromethamine 0.25 mg I.M. or intramyometrial Every 15–90 min (not to exceed 8 doses) Misoprostol 1000 μg Rectal, vaginal, or buccal Single dose Medication Dose Route of Administration Frequency of Dose Oxytocin 10–40 units in 500–1000 mL parenteral fluids, given at ~200 milliunits/min I.V. Continuous infusion Methylergonovine 0.2 mg I.M. or intramyometrial Every 2–4 hr Carboprost tromethamine 0.25 mg I.M. or intramyometrial Every 15–90 min (not to exceed 8 doses) Misoprostol 1000 μg Rectal, vaginal, or buccal Single dose Open in new tab Methylergonovine is a potent uterotonic that may be administered i.m. or by intramyometrial injection. It is the first-line agent used to treat PPH after oxytocin and uterine massage because of its intense vasoconstrictive effects.125 It is contraindicated in patients with hypertensive disease because of its potential to produce arrhythmias, seizures, and cerebrovascular accidents. Additional adverse effects include nausea and vomiting.122,125 Prostaglandin analogues have a high success rate when used alone or in combination with other uterotonic agents, reported as high as 88–95%.126 Adverse effects associated with prostaglandins include gastrointestinal distress (nausea, vomiting, diarrhea), hypertension and hypotension, chills or shivering, fever, and headache.125 Summary This review briefly covers the pharmacologic therapy of common conditions that occur in labor and delivery: antiinfective therapy (therapeutic and prophylactic), fetal lung immaturity, preeclampsia and eclampsia, cervical ripening and labor induction, premature labor, pain control, and PPH. This review has also examined the fetal and neonatal effects of these therapies. Treatment of these conditions is usually evidence based and involves relatively few pharmacologic agents. Nevertheless, significant morbidity and mortality involving the mother, fetus, and newborn are ever-present risks. The use of drugs in any patient is always a careful balance between obtaining a desired therapeutic effect and the prevention of toxicity. What makes prescribing drugs during childbirth so different is that there are always at least two patients involved: the mother and the fetus. Moreover, the recipients differ markedly in ways other than age and body size, such as how their systems handle drugs (e.g., immature brain, hepatic, and renal functions in the fetus and newborn) and the toxicities that the drugs might cause. For example, therapy immediately before delivery is a risk for two types of developmental toxicity (functional or behavioral deficits and death) in the fetus and newborn. 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TI - Drug therapy during labor and delivery, part 2
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp050265.p2
DA - 2006-06-15
UR - https://www.deepdyve.com/lp/oxford-university-press/drug-therapy-during-labor-and-delivery-part-2-MoS5w7mNnn
SP - 1131
VL - 63
IS - 12
DP - DeepDyve
ER -